Prostate cancer has many tricks that most men don’t know about, and this one is a doozy. It doesn’t just stop responding to drugs. Sometimes it learns to use the drugs as a catalyst for growth.

There is a well-documented molecular mechanism in which specific mutations in the prostate cancer cell cause a drug designed to block cancer growth to start fueling it instead. This ability to flip the drug from an antagonist (blocker) to an agonist (activator) is called the antagonist-to-agonist switch.

When the drug flips from blocker to activator, the cancer keeps growing, the PSA keeps rising, and neither the patient nor the doctor necessarily understands why. That’s because the mutation driving this flip is usually undetected unless the doctor is savvy enough to know it probably occurred or to test for it.

The androgen receptor is the lock that controls everything

At its foundation, prostate cancer is driven by hormones. Most of these cancer cells contain a protein called the androgen receptor (AR).

Think of the AR as a gate that swings open when testosterone or another androgen fits into the receptor. Once in the cell, these androgens act as fuel, stimulating the cancer to grow, divide, and spread.

Most drugs used to treat prostate cancer attempt to keep that gate shut or reduce the flow of fuel through it. Androgen deprivation therapy drugs like Lupron starve the system by reducing testosterone in the blood.

A newer, more powerful class called androgen receptor pathway inhibitors (ARPIs) addresses the problem from multiple angles. Some block the receptor directly so testosterone can’t bind to it, while others cut off the tumor’s ability to manufacture its own androgens.

ARPIs include:

• enzalutamide (Xtandi)

• apalutamide (Erleada)

• darolutamide (Nubeqa)

• abiraterone acetate (Zytiga, Yonsa)

Older first-generation drugs called antiandrogens, such as bicalutamide, work similarly to ARPIs but with less potency and more vulnerability to resistance.

These drugs work at first, but the pressures they exert at the molecular level cause these very smart cancer cells to figure out how to survive.

How the drug becomes the enemy’s recruit

Over time, under the constant pressure of the drug, the cancer mutates. It causes mutations in the androgen receptor’s ligand-binding domain, the region where drugs and hormones bind. This specific type of mutation creates an error in the genetic code and is called a point mutation in which one amino acid in the receptor is swapped for a different one.

This amino acid swap reshapes the docking site just enough to flip the drug’s entire function, creating this antagonist-to-agonist switch.

Think of the drug as a security guard you hired to stand at the front gate to keep intruders out. The mutation is like the cancer brainwashing that guard. He still stands at the gate, but instead of blocking the intruders, he opens the door and waves them in.

The specific drugs and what happens to them

Not every drug triggers the same mutation, and not every mutation affects every drug the same way. Here is what the research shows:

Bicalutamide and the W742 mutations

Bicalutamide is an older first-generation antiandrogen used for decades. Mutations at position 742 of the receptor, specifically W742C and W742L, cause bicalutamide to activate the receptor rather than block it.

In patients who develop these mutations, bicalutamide is literally feeding the cancer, causing the PSA to rise. If the clinician knows the potential for this to occur and stops the drug, one might see a significant PSA drop. This phenomenon is called the bicalutamide withdrawal response.¹

Bicalutamide monotherapy is rarely used in the United States today, where it is more commonly added to ADT as combination therapy or used in other specific clinical contexts. This withdrawal response is more common in countries where clinicians use it as monotherapy.

Enzalutamide and F877L

Enzalutamide is a far more potent second-generation drug, designed to overcome some of the resistance mechanisms that defeated older drugs like bicalutamide. But the cancer can still find a way to overcome it.

The F877L mutation, involving an amino acid substitution at position 877, reshapes the receptor’s docking site so that enzalutamide now acts as a partial agonist rather than a blocker.² The same mutation has been documented with apalutamide (Erleada), where F877L similarly converts the drug from a blocker into an activator, detected in approximately 3.7% of patients who progressed on apalutamide in a prospective trial.¹⁶

The agonist activity of F877L alone is weak to moderate. When F877L occurs alongside a second mutation called T878A, the agonist activity becomes substantially stronger — an effect that has been studied specifically with enzalutamide.² Whether the same compounding effect applies equally to apalutamide is not yet known.

Abiraterone’s two unique traps

Abiraterone works differently from the antiandrogens above. Rather than blocking the androgen receptor directly, it blocks an enzyme called CYP17A1 that the body uses to produce testosterone and other androgens.

Abiraterone is effective enough to extend survival significantly in men with metastatic castration-resistant prostate cancer, but it has two separate trap doors built into the way it works.

The first is the prednisone trap.

When abiraterone blocks CYP17A1, cortisol production falls. The body responds by releasing a surge of ACTH, a hormone that signals the adrenal glands to produce more steroids. That surge drives overproduction of the compounds deoxycorticosterone and corticosterone, which accumulate upstream of the CYP17A1 block.

These compounds act like mineralocorticoids, promoting sodium absorption and fluid retention, which raises blood pressure and lowers potassium.⁴ Prednisone or prednisolone is given alongside abiraterone specifically to suppress that ACTH surge and blunt this chain reaction.

The problem arises when the L702H mutation develops, involving an amino acid substitution at position 702 that alters the receptor’s binding pocket and makes it sensitive to glucocorticoids, including prednisone and the body’s own cortisol.

In men with the L702H mutation, the prednisone that must accompany abiraterone directly activates the androgen receptor and drives cancer growth. The drug given to manage abiraterone’s side effects becomes the cancer’s new fuel source.

L702H has been detected in approximately 10% to 15% of patients after abiraterone treatment, though rates vary by detection method and patient population.³

The second trap involves progesterone.

When abiraterone blocks CYP17A1, hormone precursors such as progesterone, which would normally be converted to androgens, start to back up, causing progesterone levels to rise dramatically, up to 50-fold above normal.⁴

Normally, that wouldn’t matter much because a healthy androgen receptor isn’t sensitive to progesterone. But the T878A mutation changes that, making the receptor responsive to progesterone and other steroid hormones it would normally ignore, such as estradiol.

The T878A mutation, which substitutes an amino acid at position 878, creates a promiscuous receptor that is now activated by a much wider range of hormones, including progesterone. This mutation occurs in approximately 21% of patients after abiraterone treatment.⁴

There is also a third, less discussed mechanism. The body metabolizes abiraterone to 5α-abiraterone, which can act as a direct androgen receptor agonist independent of any mutations.⁵

A rant from me

On a side note, these occurrences with abiraterone are on my list of several reasons why I don’t like this drug. It is a dirty drug, meaning it has a slew of serious side effects and mutation potentials, and requires that you take a corticosteroid, which has its own list of serious side effects.

For example, the LATITUDE clinical trial showed that 37% of men with mCSPC taking abiraterone developed hypertension, with 20% being severe (Grade 3).¹⁷ Even when researchers attempt to reduce the cost burden to patients by showing efficacy with a lower 250 mg dose taken with a low-fat meal, hypertension as a side effect was prevalent.

A case series from the University of Washington and Fred Hutchinson Cancer Center, though only a small case series and not validated in prospective studies, found that 76.9% of patients receiving this low-dose regimen developed high blood pressure during treatment.¹⁸ While these cases were manageable with additional medication, that incidence rate illustrates the high cardiovascular burden abiraterone carries compared to ARPIs like darolutamide.

The table below summarizes each mutation, the drug responsible, what it does, and how rarely it appears before treatment begins.

Why these mutations happen

These mutations are rarely found before treatment but frequently emerge as a response to the pressure of therapy. In treatment-naive patients, meaning those who have not yet received hormonal therapy, AR ligand-binding domain mutations are essentially undetectable in tumor tissue and circulating tumor DNA.¹⁴

The mutations described in this article are, in the overwhelming majority of cases, a direct consequence of treatment itself. The drugs create the very mutations that defeat them.

There is one narrow exception worth knowing. The T878A mutation, which emerges primarily under abiraterone treatment, has been detected in approximately 3% of men who had already received prior hormonal therapy before starting their first ARPI.¹⁵ But this still occurs in men exposed to hormonal therapy, whether it is ADT or abiraterone.

For all practical purposes, these mutations are created by the drugs used to treat this disease, which is precisely what makes them so clinically important to detect.

The data make this pattern visible. As men progress through more lines of therapy, the prevalence of these mutations climbs — and as that prevalence climbs, survival shortens.

When the clinical picture becomes a maze

These mutations don’t announce themselves. Without specific molecular testing, neither you nor your doctor can see them. What you can see is a rising PSA in the presence of an agonist-producing mutation, which can lead to a series of clinical decisions that make things worse rather than better.

Scenario 1 - The ARPI switch that backfires

A man is on enzalutamide, and his PSA starts rising. His doctor interprets this, reasonably, as the drug failing and considers switching to abiraterone, the other major ARPI available.

This is where knowing the mutation status becomes critical, because the outcome of that switch depends entirely on what is driving the rise in PSA.

If the reason enzalutamide stopped working is the F877L mutation, switching to abiraterone works through a different mechanism and isn’t directly affected by that mutation, so there may be a chance of a response.

But if the reason enzalutamide stopped working is L702H, switching to abiraterone introduces mandatory prednisone administration to a patient whose cancer is already primed to feed on glucocorticoids.

The doctor made a standard clinical consideration and inadvertently created conditions that allowed an accelerant to be poured on the fire.

Even when none of the agonist-switch mutations described in this article are present, switching one ARPI to another often fails for a separate reason entirely. Examples of ARPI switching classically involve switching a man failing enzalutamide to abiraterone acetate, or vice versa.

Prostate cancer can develop variants of the androgen receptor (AR) called AR splice variants that lack the docking site where all ARPIs bind. The most common of these variants is AR-V7.

A receptor lacking a docking site cannot be blocked or activated by any drug in this class, making it invisible to all ARPIs, regardless of which ARPI the doctor tries next.

This is one of the primary reasons the major oncology guidelines have become increasingly cautious about ARPI switching as a strategy. I have previously written about this issue as a design flaw in clinical trials that allow ARPI switching in control arms.

Given the generally low efficacy of an ARP switch, its use in clinical trials in a control arm is a disservice to men in the control arms and may make the study drug appear better than it is. Men in control arms of prostate cancer trials should be receiving the best of care options, which is not what they get with an ARPI switch.

The NCCN guidelines list switching from one ARPI to another as an option only for select patients who are not candidates for other recommended therapies, and it is conspicuously absent from the preferred and other recommended options in their post-ARPI treatment algorithm.⁶

The preferred recommendation after ARPI progression is docetaxel chemotherapy.⁶ The 2025 ASCO guideline on metastatic CRPC similarly does not recommend ARPI switching as a standard approach and instead directs clinicians toward docetaxel for patients who have received prior ARPI.⁷

The PLATO trial examining ARPI sequencing found that switching from abiraterone to enzalutamide yielded only a 27% PSA response rate and a median PSA progression-free survival of 5.7 months. Switching from enzalutamide to abiraterone was even worse, producing a 4% PSA response rate and just 1.7 months to PSA progression.⁸

The trial authors concluded that other available therapies, including taxane chemotherapy, should be strongly considered for patients who progress after first-line ARPI.⁸

Scenario 2 - The contaminated signal

A man on bicalutamide with a W742 mutation experiences PSA progression. His doctor stops bicalutamide and immediately starts the next drug. The PSA subsequently drops.

Two things are now happening simultaneously. Removing bicalutamide triggers a withdrawal response, where the W742-driven agonist activity disappears, and the PSA falls on its own. The new drug may or may not be contributing to that drop. With both changes happening at once, it becomes impossible to tell what’s actually causing the PSA to fall.

A brief drug holiday before starting the next therapy would have separated these two effects and given a much cleaner picture of what the cancer is actually responding to.

Scenario 3 - The L702H trap

The L7202H mutation is the most extensively documented in the peer-reviewed literature, and the one most likely to trap a patient in a cycle of ineffective sequential therapy.

L702H emerges primarily during abiraterone treatment because prednisone, which must be co-administered, activates the mutated receptor directly. But L702H does not disappear when a patient switches from abiraterone to enzalutamide.

A large real-world study detected L702H in 18% of patients treated with abiraterone alone, in 32% of patients treated with enzalutamide alone, and in 25% of patients treated with both drugs.⁹

The problem is that in real-world clinical practice, many patients continue glucocorticoids after switching from abiraterone to enzalutamide, for pain management, fatigue, or because clinicians are wary about abrupt steroid withdrawal after prolonged abiraterone use.

As long as glucocorticoids are circulating, L702H-positive clones remain activated. The cancer continues to grow, the PSA continues to rise, and the new drug gets blamed when the actual culprit is the steroid that nobody stopped.

Pearl: If glucocorticoids genuinely need to continue during enzalutamide therapy for legitimate symptom management, some clinicians prefer switching from prednisone to dexamethasone. Based on evidence that dexamethasone has a lower affinity for the L702H-mutated receptor than prednisone does.¹⁰

Scenario 4 - The prednisone trap compounded

A man on abiraterone develops L702H. His prednisone is now activating his cancer, his PSA is rising steadily, and it looks clinically like he is failing abiraterone. His doctor stops both abiraterone and prednisone and starts a new drug.

The PSA drops. But the drop may not indicate that the new drug is working. It may simply be that removing prednisone cuts off the fuel supply to the L702H clone. The new treatment gets credit it may not deserve, and weeks or months later, the PSA climbs again. At no point did anyone test for L702H.

A structurally different approach

Darolutamide (Nubeqa) is the newest ARPI drug, and its chemical structure gives it an advantage over its predecessors. While enzalutamide and apalutamide lose their blocking activity against the F877L mutation and in fact become activators, darolutamide retains its antagonist activity against F877L and T878A due to structural differences in how it binds to the receptor’s docking site.¹²

In patients who have already progressed on other drugs and carry these mutations, darolutamide has shown activity even after the older drugs have undergone an antagonist-agonist switch.

That said, darolutamide is not immune to all resistance mechanisms. The broader problem of cross-resistance among all ARPI agents, mediated in part by AR splice variants such as AR-V7 that bypass the ligand-binding domain entirely, also applies to darolutamide.¹³

Darolutamide is a better-trained guard, but the cancer keeps finding new ways to recruit.

What this means for you

Only 15% of patients with metastatic castration-resistant prostate cancer receive baseline circulating tumor DNA (ctDNA) testing, and only 15% receive more than one test during their course of treatment.¹¹ That means the vast majority of men going through exactly the scenarios described above are doing so without the molecular information that might change the decisions doctors are making on their behalf.

The most concrete action you can take is to ask about circulating tumor DNA (ctDNA) testing, also called a liquid biopsy, at every point of progression.

As a tumor grows, it sheds tiny fragments of its DNA into the bloodstream. Think of them as puzzle pieces of the tumor’s genetic code floating in your blood.

A simple blood draw collects those fragments and reads them, identifying the specific mutations your tumor is carrying right now, without any needle going into bone or the prostate.

The mutation profile can change as the cancer evolves, which is why a single test early in your disease history is not sufficient. You need to know what mutations are present at the moment decisions are being made about your next treatment.

The second action is to understand what the guidelines actually say about switching from one ARPI to another. Both the NCCN and ASCO guidelines are explicit: ARPI switching is not a preferred strategy for patients who progress on ARPIs.⁶˒⁷

After ARPI progression, docetaxel chemotherapy carries a Category 1 (highest level) NCCN recommendation, meaning it is supported by high-quality evidence and uniform expert consensus.⁶

If your doctor is considering moving you from one ARPI to another without molecular testing, that is a conversation worth having.

The PLATO trial data make clear that the benefit of sequential ARPI therapy is modest at best and essentially absent in the reverse direction, and the mutation scenarios described in this article explain why.⁸ Non-AR-directed options include taxane chemotherapy, PARP inhibitors if homologous recombination repair mutations are present, and lutetium-177 PSMA therapy if PSMA expression is retained.⁶˒⁷

The third action is to consider a second opinion at a prostate cancer center of excellence if your PSA is rising through multiple lines of therapy and your doctor hasn’t performed comprehensive molecular testing.

Places like MD Anderson Cancer Center, Memorial Sloan Kettering, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, and Mayo Clinic have molecular tumor boards that meet specifically to work through cases in which standard sequencing logic no longer makes sense.

These cases are complex enough that specialized infrastructure and experience make a real difference. The NCCN acknowledges that “although the optimal sequence of therapies remains undefined, some data are emerging that can help with treatment selection in some cases." ⁶ A prostate center of excellence is where that emerging data is most likely to be applied to your specific situation.

Conclusion

The field of prostate cancer oncology is moving toward strategic, repeated molecular profiling, especially at key inflection points where results could change management. The tests are there, and the science backs them.

What lags behind is consistent clinical application. Until that changes, the burden falls on informed patients to ask the right questions. I hope I’ve provided you enough information to ask some of those questions.

Until the next one, I wish you good health and much love,

Keith

References

1. Hara T, Miyazaki J, Araki H, et al. Novel mutations of androgen receptor: possible mechanism of bicalutamide withdrawal syndrome. Cancer Res. 2003;63(1):149–153.

2. Prekovic S, van Royen ME, Voet AR, et al. The effect of F877L and T878A mutations on androgen receptor response to enzalutamide. Mol Cancer Ther. 2016;15(7):1702–1712.

3. Antonarakis ES, Zhang N, Saha J, et al. Real-world assessment of AR-LBD mutations in metastatic castration-resistant prostate cancer. J Clin Oncol. 2023.

4. Attard G, Reid AH, Auchus RJ, et al. Clinical and biochemical consequences of CYP17A1 inhibition with abiraterone given with and without exogenous glucocorticoids in castrate men with advanced prostate cancer. J Clin Endocrinol Metab. 2012;97(2):507–516.

5. Li Z, Alyamani M, Li J, et al. Redirecting abiraterone metabolism to fine-tune prostate cancer anti-androgen therapy. Nature. 2016;533(7604):547–551.

6. National Comprehensive Cancer Network. Prostate Cancer. NCCN Clinical Practice Guidelines in Oncology. Version 1.2026. Updated January 23, 2026.

7. Garje R, Riaz IB, Naqvi SAA, et al. Systemic therapy in patients with metastatic castration-resistant prostate cancer: ASCO guideline update. J Clin Oncol. 2025.

8. Khalaf DJ, Annala M, Taavitsainen S, et al. Optimal sequencing of enzalutamide and abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label, phase 2, crossover trial. Lancet Oncol. 2019;20(12):1730–1739.

9. Stewart T, Chandiwana D, Doyle A, et al. Real-world outcomes of patients with metastatic castration-resistant prostate cancer and tumors harboring androgen receptor ligand-binding domain mutations. J Clin Oncol. 2024.

10. Wyatt AW, Azad AA, Volik SV, et al. Genomic alterations in cell-free DNA and enzalutamide resistance in castration-resistant prostate cancer. JAMA Oncol. 2016;2(12):1598–1606.

11. Stewart T, Chandiwana D, Doyle A, et al. Real-world outcomes of patients with metastatic castration-resistant prostate cancer and tumors harboring androgen receptor ligand-binding domain mutations. J Clin Oncol. 2024.

12. Moilanen AM, Riikonen R, Oksala R, et al. Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies. Sci Rep. 2015;5:12007.

13. Bernstad Salas A, Hofman MS, et al. Cross-resistance among next-generation anti-androgen drugs through the AKR1C3/AR-V7 axis in advanced prostate cancer. Front Oncol. 2021.

14. Miyazaki J, Nishiyama T, et al. Androgen receptor mutations for precision medicine in prostate cancer. Endocr Relat Cancer. 2022;29(10):R133–R152.

15. Rathkopf DE, Morris MJ, Fox JJ, et al. Androgen receptor mutations in patients with castration-resistant prostate cancer treated with apalutamide. Ann Oncol. 2017;28(9):2264–2271.

16. Rathkopf DE, Morris MJ, Fox JJ, et al. Androgen receptor mutations in patients with castration-resistant prostate cancer treated with apalutamide. Ann Oncol. 2017;28(9):2264–2271.

17. Fizazi K, Tran N, Fein L, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017;377(4):352–360.

18. Abiraterone-associated mineralocorticoid excess: a case report. Cureus. 2024. PMC10843236.

19. Yasunaga T, Ruplin A, Fritzsche D, Cheng H. Low-dose abiraterone with a low-fat diet in metastatic prostate cancer. National Community Oncology Dispensing Association (NCODA). Available at: https://www.ncoda.org/news/low-dose-abiraterone-with-a-low-fat-diet-in-metastatic-prostate-cancer/

Disclaimer: The content in this article is for informational and educational purposes only. It does not represent medical advice. Always discuss treatment decisions with your own healthcare provider.

TL;DR: PSA doubling time is very important for biochemical recurrence after surgery or radiation and in nonmetastatic castration-resistant prostate cancer, but only if calculated correctly with 3+ tests over 3+ months. Fast doubling (<3 months) = 27× higher death risk. Always verify that your doctor used a validated calculator.

Changes in prostate-specific antigen (PSA) help doctors track prostate cancer. This post reviews how PSA levels change across disease stages and what these changes may indicate.

We examine PSA doubling time (PSADT), which estimates how long it takes for PSA to double and is usually, but not always, a reflection of how rapidly the cancer is growing.

We also cover common PSA changes, such as the temporary PSA bounce that occurs in some men after radiation and the rise that occurs when starting certain therapies.

I also explain how PSA behaves after stopping hormone therapy and why some aggressive prostate cancers grow without making any PSA at all.

Common abbreviations

• PSA (Prostate-Specific Antigen): A protein made by cells in the prostate gland.

• PSADT (Prostate-specific doubling time): The amount of time it takes for a PSA level to double.

• AUA (American Urological Association): A leading medical organization that establishes standards for urologic healthcare.

• NCCN (National Comprehensive Cancer Network): A non-profit alliance of cancer centers that develops guidelines for treatment.

• MRI (Magnetic Resonance Imaging): A scan using magnets and radio waves to create detailed images of organs like the prostate.

• ADT (Androgen Deprivation therapy): Treatment that suppresses male hormones to slow the growth of prostate cancer.

Important points for PSADT

Prognostic Tool: PSA doubling time (PSADT) is one of the most reliable methods for estimating risk when PSA begins to rise again. It’s especially useful in two situations where imaging still looks normal:

• Biochemical recurrence after surgery or radiation, when the cancer has not spread and is still hormone-sensitive, and

• Nonmetastatic castration-resistant prostate cancer (nmCRPC), when the PSA is rising despite hormone therapy, but scans remain negative.

In both situations, a fast PSADT is a standard reason to intensify treatment, because it identifies men most likely to develop visible metastases sooner.

• Predicting Future Risks: After surgery or radiation therapy, a confirmed PSA rise without evidence of cancer on imaging is termed biochemical recurrence (BCR).

In BCR, PSA doubling time is one of the strongest predictors of whether the cancer will spread and become life-threatening.

A landmark study looked at men with BCR after radical prostatectomy. It found that compared with men whose PSADT was 15 months or longer, men with a PSADT under 3 months had about a 27-times higher risk of dying from prostate cancer.

Standards for measuring PSA changes

PSA doubling time is the number of months it takes for the PSA level to double. This tool assumes that the cancer grows at a steady rate over time. To get an accurate number, you must have at least three PSA results over at least three months. These tests should be at least four weeks apart to avoid being fooled by random fluctuations.

If you use only two results or examine a very short time interval, the final number will be unstable and will not reflect how rapidly the cancer is moving.

Several factors can make these numbers inaccurate. Testosterone levels should be stable because they directly affect PSA production. Medications such as 5-alpha reductase inhibitors (finasteride and dutasteride) or herbs (saw palmetto) must remain at the same dose throughout the measurement period.

Pearl: If you have been on a 5-alpha reductase inhibitor for at least six months, multiply the PSA by 2 to get the correct PSA level.

Patients should also use the same laboratory for all PSA tests to avoid errors arising from different testing methods.

When PSA does not show the whole picture

PSA is a very helpful tool, but it does not always show when the cancer is growing. In certain conditions, the cancer can spread even if the PSA remains low or does not change.

Some men have a very aggressive type of cancer from the onset that never makes much PSA. These tumors lack the features that allow regular prostate cells to produce PSA.

Some studies show that up to 15% of men with a PSA < 4.0 ng/mL actually have cancer when they get a biopsy. Relying only on PSA changes in these men can lead to a dangerous delay in finding the disease.

Pearl: The key is that PSA doesn’t work in isolation. A ‘normal’ PSA of 3.0 ng/mL means something very different for a 45-year-old man with a suspicious lump on exam than for a 75-year-old with a smooth prostate and stable PSA for 10 years. These factors are why doctors use risk calculators that combine multiple factors before recommending a biopsy.

In metastatic castrate-resistant prostate cancer (mCRPC) after years on hormone therapy, treatments can sometimes cause the cancer to change into a different type of cell called treatment-emergent neuroendocrine prostate cancer (t-NEPC). These prostate cancer cells usually do not produce PSA.

Signs of this change include new pain or new growth on imaging, while the PSA remains unchanged. Doctors must watch for these patterns in late-stage disease to avoid missing this type of cancer.

Red flags for t-NEPC include rising LDH with stable PSA and elevated chromogranin A or synaptophysin levels on biopsy samples.

Active surveillance

Men with low-risk cancer often choose to monitor the disease instead of having immediate treatment. In the past, a rapid doubling time was a common reason to stop active surveillance (AS) and start treatment.

However, studies show that PSA changes do not always correlate with microscopic findings. Many men have PSA changes because of an enlarged prostate or inflammation.

Modern guidelines now favor the use of MRIs and genetic tests to help decide if a cancer is high-risk and needs treatment or not. A rapid doubling time is now used as a prompt to get a new scan or biopsy, but not a stand-alone reason to initiate treatment.

NCCN recommends asking about family history and considering germline testing for hereditary mutations, such as BRCA, for specific patients at the time of initial diagnosis. In addition, tumor-based genetic tests, such as Oncotype DX Genomic Prostate Score, Prolaris, or Decipher, may help determine whether AS is appropriate for select patients.

Biochemical recurrence after definitive treatment

The definition of when cancer recurs after surgery varies among medical groups. The AUA defines biochemical recurrence as a PSA rise to ≥0.2 ng/mL with a confirmatory value >0.2 ng/mL.

The NCCN guidelines call it PSA Recurrence and define it as an undetectable PSA after surgery, followed by a detectable PSA that increases on two or more determinations or reaches a PSA > 0.1 ng/mL.

Both the AUA and NCCN agree that the optimal time to initiate radiation for biochemical recurrence is when the PSA is between 0.1 and 0.2 ng/mL. And that the most crucial deadline for initiating radiation for biochemical recurrence after surgery is before the PSA moves above 0.5 ng/mL.

Delaying treatment until PSA > 0.5 ng/mL is associated with poorer outcomes; however, the NCCN notes that patients with very slow PSA doubling times (> 24 months) may consider delaying treatment.

Biochemical failure, signalling the recurrence of cancer after radiation therapy, is defined by the Phoenix criteria: a PSA increase of 2 ng/mL or more above the nadir (the lowest PSA level achieved).

PSADT as a gatekeeper

Before 2018, men with high-risk (PSADT of 3 months or less) nonmetastatic castration-resistant prostate cancer had no therapy proven in phase 3 trials to delay metastasis or extend survival. Standard care was continued androgen deprivation therapy with observation, and older add-on approaches showed at best modest activity without a clear survival benefit.

Then three landmark trials arrived in rapid succession, and all three used a PSADT of 10 months or less as the entry requirement. This cutoff wasn’t arbitrary. Shorter doubling times are strongly associated with increased risk of metastasis and death, and the median baseline PSADT across all three trials was under 5 months.

Across all three studies, the primary question was whether intensifying androgen receptor blockade could delay the transition from invisible to radiographically visible disease.

The answer was yes. SPARTAN (apalutamide), PROSPER (enzalutamide), and ARAMIS (darolutamide) each demonstrated substantial reductions in metastasis and death, extending metastasis-free survival by approximately 2 years compared with ADT alone, and all three ultimately showed improvements in overall survival as well.

Pearl: If you have nmCRPC and your PSA is rising despite hormone therapy and your PSADT is 10 months or less, you are exactly the patient these trials were designed for, and three FDA-approved options now exist to discuss with your doctor.

PSA bounce

PSA changes after radiation to the prostate can be due to a phenomenon known as PSA bounce. PSA bounce is a mild, temporary rise in PSA that occurs in 30-33% of patients around 17-24 months after radiation, then drops back down without additional treatment.

Treatment and recovery transitions

The timing of tests is critical when a patient starts or stops a drug. Sometimes, starting a new treatment can temporarily increase PSA levels.

PSA changes can be hard to read when a patient stops ADT. Often, PSA levels increase as the ADT wears off and testosterone levels recover. However, testosterone production doesn’t always return to baseline, and providers should not use PSA values during this rebound period to calculate doubling time.

Taxane chemotherapy (docetaxel, cabazitaxel) and abiraterone can cause an early but temporary rise in PSA. Thus, PSA changes during initiation of these therapies can be misleading, and a PSA rise alone should not automatically trigger treatment discontinuation, provided the patient is clinically stable, feels better, and appears better on imaging.

The problem with guessing PSA doubling times

The PSA doubling time is effective only when used correctly. A study presented at a major 2025 medical meeting showed that many doctors do not use formal calculators to determine PSADT.

Researchers found that doctors had not documented doubling time in the medical record for 63% of men with high-risk nonmetastatic castrate sensitive prostate cancer and biochemical recurrence. Those who did record a number in the chart often failed to use validated digital tools for verification.

Among men whose physicians reported a doubling time in the medical record, the reported values were longer than the retrospectively calculated values in 88% of cases. This overestimation suggests that physicians may underestimate how aggressive a tumor actually is by relying on gut feeling instead of a calculator.

The doctors who guessed the PSADT instead of using a calculator thought the cancer was moving more slowly than it really was. This finding represents a serious problem that affects the speed with which patients receive life-saving care.

Men with properly calculated doubling times in their charts were three times more likely to receive appropriate treatment in a timely manner.

Pearl: Ask your doctor if they used a formal calculator to determine your PSADT.

Until the next newsletter, I wish you good health and much love.

Keith

Image made with ChatGPT

In prostate cancer, clinicians associate “Decipher” with a genomic classifier test that reports a risk score for distant metastasis over five years. They use this score to guide critical treatment decisions.

However, there is a major distinction between the test a patient receives and the platform behind it. The Decipher Prostate Genomic Classifier is the clinical product, but it is derived from the Decipher Genomic Resource Information Database (Decipher GRID).

To understand the future of prostate cancer care, we must understand the relationship between the product and the platform.

The product vs. the factory

The Decipher Prostate Genomic Classifier is a 22-gene signature test. When a patient undergoes a biopsy or surgery, clinicians send a small piece of the tumor tissue to a laboratory.

The lab measures the activity of 22 specific genes associated with aggressive cancer. The test uses a machine-learning algorithm to generate a score between 0 and 1.

The Decipher Prostate score is prognostic. It predicts the five-year probability of metastasis. A low score may allow a patient to confidently choose active surveillance, while a high score suggests the tumor is biologically aggressive and requires intensive treatment.

The Decipher GRID is the vast research engine that enabled this 22-gene test. The most significant difference between the test and the platform is the amount of data captured.

When the lab analyzes a tumor for the 22-gene test, it examines the entire transcriptome (the complete set of RNA transcripts in a cell). This process captures the activity levels of approximately 1.4 million markers per patient.

While the patient receives a report based on just 22 markers, the platform saves the other 1.4 million. This massive, deidentified dataset is the Decipher GRID.

The strategic value of the GRID platform

This platform creates a continuous feedback loop that turns every clinical test into a discovery tool.

1. A patient receives the 22-gene score for their personal care.

2. The lab simultaneously captures the 1.4 million-marker profile from that same sample and adds it to the GRID.

3. With over 200,000 patient profiles now in the database, researchers can mine this data to discover new biomarkers associated with prostate cancer.

This data bank is the fundamental value of the GRID. It allows researchers to validate new biomarkers at a speed and scale that is impossible with traditional research methods.

When scientists have a new hypothesis, they do not need to start a decade-long study from scratch. They can query the 200,000 profiles already stored in the GRID and cross-reference them with real-world outcomes.

Where the data comes from

To build a database this powerful, the GRID draws from three main sources:

1. The GRID Registry: The backbone of the platform is a formal, prospective observational study titled “Prospective Expression Analysis Using The Decipher Genomics Resource for Intelligent Discovery (GRID)”. When patients receive the standard Decipher test, they may choose to share their deidentified data with this study. The goal is to reach one million patients, which provides the statistical power to understand even the rarest types of prostate cancer.

2. Academic Partnerships: Veracyte, the owner of Decipher GRID, works with top academic researchers. These scientists use the GRID to answer their own research questions, thereby adding new findings and greater value to the database.

3. Clinical Trial Integration: The GRID includes data from over 90 clinical trials, including Phase 3 trials such as STAMPEDE, CHAARTED, and TITAN. By revisiting old clinical trials and applying genomic signatures from the GRID, researchers can determine why a drug helped some men but failed others. This kind of analysis could rescue a treatment that had been previously written off as a failure by showing which patient subset benefits from the drug.

Linking genes to real-world outcomes

Genomic data becomes meaningful when it is tied to a clinical context. The true power of the GRID lies in its role as an observational registry that links genomic data to three key areas:

1. Standard information, such as PSA levels and Gleason scores

2. What actually happened to the patient? Did they have surgery, radiation, or hormone therapy?

3. Years later, did the cancer spread, or did the patient survive?

Decipher GRID merges deep genomics with long-term clinical follow-up. These mergers allow a researcher to ask a specific question, such as which genes are active in patients who had surgery but still saw their cancer return. This process can now take days instead of years.

The GRID as a biomarker factory

The original 22-gene Decipher test was just the first product off the assembly line. The platform is now producing a new generation of “predictive” biomarkers. While a prognostic test tells you the risk of what might happen, a predictive test tells you which specific therapy will actually work.

Here are the three most significant examples of this evolution:

1. Molecular subtyping - the Prostate Subtyping Classifier (PSC)

Researchers used the GRID’s computational power to analyze the whole transcriptomes of 32,000 prostate cancer profiles. From this, they developed a novel “Prostate Subtyping Classifier” (PSC). They then validated this PSC model on an additional 68,547 profiles.

This PSC model successfully classifies prostate tumors into four distinct molecular subtypes with unique biological and clinical features:

• Luminal Differentiated: Respond well to antiandrogen therapy and are associated with less aggressive tumors and the longest time to metastasis after surgery.

• Luminal Proliferating: Has higher expression of cell proliferation genes and was shown in a phase 3 trial to derive survival benefit from docetaxel chemotherapy.

• Basal Immune: Possesses significant immune infiltration and was the only subtype in one cohort that derived benefit from radiation therapy after surgery.

• Basal Neuroendocrine-like: Characterized by lower androgen receptor activity.

2. Predicting hormone therapy response - the PAM50 signature

Antiandrogen therapy is a cornerstone of prostate cancer treatment, but comes with significant side effects, such as bone loss, hot flashes, and fatigue. Can we identify who will actually benefit from it and who can be spared the toxicity?

The PAM50 molecular signature, derived from breast cancer research, is a biomarker available on the GRID platform for research. The GRID report classifies tumors into one of three subtypes:

1. Luminal A

2. Luminal B

3. Basal

PAM50 was tested in the prospective, randomized phase 2 BALANCE trial. This trial enrolled men with recurrent prostate cancer after surgery. They were randomly assigned to receive either salvage radiation therapy plus a placebo or salvage radiation therapy plus apalutamide, an androgen receptor inhibitor.

All patients were stratified at the start of the trial by PAM50 subtype, determined using the Decipher platform.

The results showed that the benefit of adding apalutamide was entirely confined to a single genomic subtype:

• In men with Luminal B tumors, adding apalutamide was highly effective: 72% remained free of biochemical failure, compared with only 54% in the placebo group.

• In men with Non-Luminal B tumors, apalutamide provided no benefit: 70% were free of biochemical failure, compared with 71% in the placebo group.

According to Daniel Spratt, M.D.

“Our findings mark the first time, to my knowledge, that a predictive biomarker has been validated in a prospective, biomarker-driven, randomized trial in non-metastatic prostate cancer. Thus, this is an unprecedented advancement for patients who can be more precisely selected to receive hormone therapy or forego the treatment and the potential side effects.”

For a patient with a Non-Luminal B tumor, this test could save them from months or years of unnecessary and toxic treatment.

3. Guiding radiation therapy dose: - the PORTOS signature

For patients who need radiation therapy after surgery, what is the correct dose? A higher dose might be more effective at killing the cancer, but it also increases the risk of side effects and toxicity. A lower dose is safer, but may be less effective.

Researchers again turned to the GRID database to find a genomic signature that could predict response to radiation. They developed the Post-Operative Radiation Therapy Outcomes Score (PORTOS), a gene-expression signature intended to predict benefit from radiation dose escalation after prostatectomy.

The PORTOS signature was validated by analyzing data from two independent Phase 3 randomized trials: SAKK 09/10 and NRG/RTOG 01-26. These trials had already compared dose-escalated radiation to conventional-dose radiation.

The GRID-derived PORTOS signature successfully predicted which patients would benefit from the higher dose. Patients with higher PORTOS scores had a significantly better response to dose-escalated radiation, whereas those with lower scores did not.

A radiation oncologist could use this signature to personalize the intensity of a patient’s radiation plan, escalating the dose only for those patients whose tumor biology suggests it will provide a significant benefit, while potentially sparing all other patients the unnecessary toxicity.

The future - a prostate cancer genomic dashboard

The ultimate vision for the Decipher GRID, with proper validation and regulatory approval, is to move beyond a single risk score. The goal is to use one tissue sample to generate a comprehensive “Prostate Cancer Genomic Dashboard.”

In the near future, when a patient’s tumor is analyzed, the physician could receive a unified report that answers all the critical questions at once:

• What is the risk of metastasis? (22-gene Classifier)

• What is the tumor’s biological subtype? (PSC)

• Will this patient benefit from hormone therapy? (PAM50)

• Will this patient benefit from more intense radiation? (PORTOS)

• Which chemotherapy is most likely to work? (PSC)

As the platform continues to grow, it is becoming a robust research foundation for more personalized care. By matching a patient’s specific biology to a massive library of real-world outcomes, the GRID provides a roadmap for discovering treatments tailored to the individual.

Even though these new markers still need to undergo formal clinical trials and obtain regulatory approval, they offer a glimpse of the future.

Your doctor can request your Decipher GRID report

If you have had a Decipher Prostate genomic classifier test, your doctor can request your Decipher GRID report at no additional charge to you or your insurance company. Since the Decipher GRID report is for “Research Use Only,” your doctor may be hesitant to use the report to guide your treatment decisions.

I have examined a friend’s GRID report and was impressed with the additional information it provides. Even though it is not supposed to be used to guide prostate cancer management, I believe the most savvy patients and clinicians would find the reports useful. 😉

Until the next newsletter, stay healthy.

Much love,

Keith

We talk about:

• My journey with prostate cancer and how I approach it from an integrative medicine perspective.

• How I view myself as a single-subject scientific study, or an “N of 1.” Because of my background in both allopathic and functional medicine, this experimentation, in combination with my oncology team, possesses a unique scientific rigor.

• The driving force behind my daily actions is an unwavering goal: a complete cure, not just long-term control.

• My intensive self-care regimen.

• How my open-minded approach to medicine was shaped by my childhood and my parents' comfortable embrace of both traditional and alternative therapies.

• How a health challenge, prior to developing prostate cancer, played a role in my real-life training in integrative medicine.

• Why a central tenet of my practice philosophy is the inseparable connection between the mind, body, and soul.

• The science behind mind-body medicine and how meditation damps down inflammation in the body.

• The link between chronic stress and the onset of illness is a recurring theme.

• How a sustained stress response compromises the immune system and how chronic stress can influence gene expression.

• Practical guidance for navigating a chronic illness diagnosis.

• Among many other topics.

• I hope you enjoy it,

Much love,

Keith

Get more from Keith R. Holden, M.D. in the Substack app

Available for iOS and Android

Get the app

You can join us in the Substack app on Monday, November 24, at:

https://open.substack.com/live-stream/81453

Much love,

Keith

A short PSADT is a grim predictor, strongly associated with metastasis and mortality.

Over the past ten months, my PSADT has slowed to 55 months. That’s 4.6 years!

From Memorial Sloan Kettering’s PSA Doubling Time Calculator

This drastic slowdown began after I started a personal experiment with repurposed drugs.

Prostate-specific antigen (PSA) doubling time (PSADT) is the time it takes for the PSA level to double, reflecting the rate of prostate cancer growth.

A shorter PSADT after definitive therapy, like prostatectomy and radiation, is associated with a higher risk of prostate cancer metastasis and death.

Disclaimer

This post is not medical advice.

There are no clinical trials that have proven Ivermectin, Fenbendazole, or Mebendazole are clinically effective for treating cancer.

However, there are some preclinical data from animal studies and cell experiments that suggest these drugs may have anticancer properties.

My report is purely anecdotal and not a clinical research account.

However, anecdotal case reports are published in peer-reviewed journals because they can document novel treatment approaches and new insights that may one day inspire a clinical trial.

Why I’m rehashing how I got here

To help you understand why the 55-month number is so remarkable, I need to provide a summary of what has happened over the past eight years.

I’m also doing this because I don’t expect new subscribers to go back and read all sixty-eight posts I’ve previously written.

A high-risk tumor profile

In November 2017, after many months of prostatitis symptoms and a PSA soaring to 47 ng/mL, a 60-core biopsy revealed aggressive Gleason 4+3=7 cancer in nearly every sample.

In April 2018, I underwent a robotic radical prostatectomy. I hoped we had caught it in time, but the pathology report delivered a harsh truth.

The cancer was staged pT3b N1. It had broken through the prostate capsule, involved 70% of the gland, invaded both seminal vesicles, and spread to two of nine lymph nodes. The surgical margins were positive for tumor cells.

To make matters worse, the pathology report showed a “tertiary pattern 5,” which is a sign of aggressive disease. This finding indicates that a Gleason pattern 5 was present but accounted for less than 5% of the tumor volume.

My post-surgical PSA didn’t drop to undetectable. It only fell to 4.8 ng/mL.

Genetic testing confirmed the grim outlook:

• DECIPHER Test: 0.81 (High-Risk)

• Foundation One genomic test: Loss of a key tumor suppressor gene - PTEN - associated with aggressive progression

Intolerance of androgen deprivation therapy

I began androgen deprivation therapy (ADT) in June 2018 with Trelstar. The side effects were immediate and unbearable. Severe hot flashes, drenching night sweats, and profound sleep deprivation led to a deep depression.

I was barely functioning, and I felt like giving up. I made the hard decision to stop ADT after only two injections.

Radiation therapy

In the fall of 2018, I underwent intensity-modulated radiation therapy (IMRT) to the prostate bed and pelvic lymph nodes. However, we were shooting in the dark because a PET scan showed no detectable cancer despite an elevated PSA.

My radiation oncologist felt it was best to radiate where the cancer most likely was.

For a time, it worked. My PSA dropped to 0.9 ng/mL by January 2019.

However, it then steadily began to rise.

My PSA continues to rise

The initial rise in PSA was pretty rapid:

May 2019: 1.72 ng/mL

June 2019: 2.4 ng/mL

July 2019: 3.0 ng/mL

In late 2019, a PSMA PET scan at UCLA showed no visible disease. But my PSA kept rising:

March 2020: 7.3 ng/mL

September 2020: 9.9 ng/mL

April 2021: 20.5 ng/mL

I had an Axumin scan in April 2021, which reported evidence of malignancy in the prostate bed, later determined to be a false positive finding.

I underwent another PSMA PET scan at UCLA. This time, it lit up as small spots in several lymph nodes in the para-aortic chain and pelvis.

My PSA continued climbing:

November 2021: 33.3 ng/mL

March 2022: 41.1 ng/mL

August 2022: 57.7 ng/mL

October 2022: 54.7 ng/mL

December 2022: 57.64 ng/mL

Another PSMA PET in December 2022 confirmed small tumors in six para-aortic lymph nodes and one near the left common iliac node.

Another round of radiation

I underwent proton therapy in January 2023, painting the para-aortic lymphatic chains and “boosting” radiation to the seven small tumors.

Three normal PET scans

Then something remarkable happened. I had three PSMA PET scans in a row, which showed no evidence of cancer despite a rising PSA.

Pivotal decision

In February 2025, my PSA continued to rise to 369.14 ng/mL, and I was forced to make a pivotal decision.

I was now two years out from my last treatment, fighting a cancer that was biochemically raging but invisible to our best scans. I felt I had to do something, but I was not going back on ADT.

On February 13, 2025, I took a different path. I began an experimental protocol of repurposed drugs and supplements:

• Ivermectin 34 mg daily

• Fenbendazole 500 mg twice daily

• Curcumin 3.5 grams daily

• Methylene Blue 13 mg twice daily

My PSA takes a dramatic drop

By the end of April 2025, for the first time in years, my PSA dropped 53 points to 316.33 ng/mL.

I increased the Ivermectin to 136 mg daily, keeping the other agents the same. However, by July, the PSA had risen 45 points to 361.69 ng/mL.

Experimenting with repurposed drugs

That’s when I switched the Fenbendazole, a veterinary drug, to Mebendazole 100 mg twice daily and began experimenting with pulse dosing Ivermectin every three days at a very high dose.

After a while, and to no surprise, I developed signs and symptoms of Ivermectin toxicity, and had to back off the dose. I also stopped the Methylene Blue, but I’ll save those details for another Substack post.

I’m not reporting my current pulse dose of Ivermectin as I don’t want others following my footsteps and taking risks without strict medical supervision.

Back pain

In September, I developed unrelenting back pain. My radiation oncologist ordered an MRI scan of the thoracic spine. There will undoubtedly be metastases on this scan.

Nope! It showed no metastases, just multilevel small disc herniations.

After almost eight years of living with advanced prostate cancer, which typically metastasizes to the bone, I have no evidence of any bone lesions despite a high PSA.

That is a miracle!

It seems the repurposed drugs may be working

My latest PSA level, as of October 28, 2025, is 395.90 ng/mL. This time, it rose only 34 points over three months, despite a rise in my testosterone level from 608 to 773 ng/dL.

A rise in testosterone should, in theory, fuel prostate cancer. Instead, my PSADT has stretched from 9 months to 55 months.

There is a pattern here in my numbers since starting these repurposed drugs. A pattern that even the most average physician could see.

It is tough to explain away these findings as chance, especially with the most recent testosterone rise of over 100 points.

The experiment of one

Nearly eight years since my diagnosis and intolerant of the mainstay therapy for prostate cancer—androgen deprivation—I’m still here. Not only am I still here, I’m thriving.

What I write here is not medical advice. It’s my story of walking a tightrope between science, faith, and personal experimentation.

When I started this Substack four years ago, I had no intention of taking experimental repurposed drugs, much less writing about that experience. Yet, this is the path that has opened for me.

My story doesn’t promise easy answers. But it does offer information that one day, I hope, may inspire a clinical trial for men with advanced prostate cancer.

I am not the grim prediction written in a medical textbook.

I am a human being with a name, a heart, a purpose, and a profound will to live.

Most importantly, I’m holding on to and acting on hope.

Conclusion

My radiation oncologist is very intrigued by what is happening. I know I chose the right doctor because he isn’t discouraging or shaming me. He’s curious and supportive.

That’s because he knows who I am - an intelligent physician who does his research and understands the calculated risks I’m taking.

I hope your doctor knows who you are, too.

Since I remain asymptomatic and my other labs are stable, we’re continuing this path and will recheck everything in three to four months.

Until the next newsletter, I wish you good health and much love.

Keith

A Necessary Note: This Substack is intended solely for informational purposes. This information is not medical advice or a recommendation for any specific treatment. I do not endorse or advise the use of any drug discussed here, including those I may personally choose to take. Always make medical decisions in consultation with a qualified healthcare professional.

In this post, I'll walk you through the report section by section to help you understand what it all means.

The test report for the Decipher Prostate Biopsy provides a three-tiered Decipher genomic score reflecting the tumor’s biological risk for distant metastases.

Decipher has been evaluated in multiple clinical trials, including those assessing outcomes during active surveillance and outcomes after definitive treatment.

The accuracy of Decipher has been confirmed through a large amount of high-quality research:

• It has been evaluated in over 25 prospective randomized clinical trials.

• More than 90 peer-reviewed scientific studies support it.

• The research on this test is based on data from over 200,000 patients.

Decipher Prostate Biopsy is for men with localized prostate cancer, whose cancer has not spread outside the prostate. Tissue from a prostate biopsy is submitted for testing to measure the activity level of 22 RNA genes to determine the tumor’s aggressiveness and potential for metastases.

It can help men and their doctors decide if active surveillance is appropriate or if they should undergo active treatment.

This post focuses on understanding the Decipher Prostate Biopsy test report.

Decipher Prostate Biopsy test report

The test report includes the patient's National Comprehensive Cancer Network (NCCN) Risk Category, based on their clinical stage, PSA, and Gleason score; however, it doesn't factor these into the Decipher score.

The NCCN risk category groups patients into statistical risk categories based on clinical and pathological features, including:

• Clinical stage

• Grade Group

• PSA level

• Number of positive cores

• Percent of cancer in any core

• Number of cores with Grade Group 4 or higher.

However, the NCCN risk category does not accurately reflect the tumor’s unique underlying biology.

That’s where Decipher comes in, providing additional information that helps refine and personalize risk assessment within each man’s NCCN risk category (group).

Decipher genomic score and interpretation section

The middle of page 1 of the Decipher Prostate Biopsy test report includes the Decipher genomic score and its interpretation.

The Decipher score risk bar, located on the left, displays the patient’s Decipher score. Although there are three risk groups in the score, the score is continuous. Thus, a score at the higher end of the “High Risk” group reflects a higher risk for metastases than a score at the lower end of the “High Risk” group.

The Decipher risk score reflects the patient’s risk for developing distant metastases.

The interpretation section discusses how the patient’s Decipher risk score and NCCN risk category intersect to form a combined risk assessment.

This combined risk assessment is based on matching the individual’s Decipher score and NCCN risk category with thousands of other men who have the same score and risk category from Phase III clinical trials using the Decipher genomic classifier test. Each clinical trial is cited in the discussion and referenced on page 3 of the report.

The Decipher score value lies in its ability to better stratify risk for metastases within a given NCCN category.

• Example: Consider two men who underwent a prostate biopsy and were both classified as "Favorable Intermediate-Risk" by NCCN guidelines.

  • Man A has a low Decipher score of 0.30.

    • His genomic risk of metastasis is significantly lower than that of the average man in his NCCN category.

    • This provides strong evidence to support choosing active surveillance, a path he might have been hesitant to take based on the "intermediate-risk" label.

  • Man B has a high Decipher score of 0.85.

    • His score indicates a tumor biology that is significantly more aggressive than his NCCN risk category suggests.

    • The report will show that his risk of metastasis is much higher than that of his NCCN peers and strongly argues against active surveillance, shifting the focus from active surveillance to definitive treatment.

Risk estimates section

The bottom of page 1 of the report is a section titled “Risk Estimates For This Patient With Standard Therapy For Their Clinical Risk Group.”

This section evaluates risk estimates for patients compared to men within clinical trials with the same Decipher risk score and with the same NCCN risk group who have received definitive treatment, either prostatectomy or radiation therapy to the prostate.

These outcomes include:

• 5- and 10-year risk of metastasis

• 15-year risk of death from prostate cancer despite undergoing either treatment

• Chance of finding adverse pathology (e.g., finding more aggressive cancer than expected after surgery)

  For patients with NCCN low-risk and favorable intermediate-risk prostate cancer, this section displays the chance of finding adverse pathology if they were to undergo a prostatectomy.

This adverse pathology may include the following findings at prostatectomy:

• Grade Group 3 (Gleason 4 + 3 = 7) or higher

• Stage pT3b (invasion of seminal vesicles) or higher, including lymph node involvement.

Risk graphic and interpretation section

Page 2 of the Decipher Prostate Biopsy Genomic Classifier patient report contains a risk graphic.

This risk graphic demonstrates the patient’s 10-year risk of metastases compared to other men in clinical trials with a similar NCCN risk category and Decipher score.

The graphic also illustrates the frequency of each Decipher risk score (Low, Intermediate, and High) within that group of similar patients. This example shows that 52% of men in that group had a Decipher Low risk score, 22% had a Decipher Intermediate risk score, and 26% had a Decipher High risk score.

The interpretation section displays the patient’s Decipher score percentile ranking in comparison to similar patients in clinical trials. This indicates where your risk falls within that group, helping you understand if your risk is higher, lower, or average compared to others like you.

Findings from clinical studies section

The "Findings From Clinical Studies Relevant To This Patient" section on page 2 provides more detailed information and evidence from Decipher’s database of clinical trials.

It discusses how similar patients have responded to various treatments or what their long-term outcomes have been. This section, based on clinical trials, helps you and your doctor understand potential treatment options by showing scientific observations for patients with the same NCCN risk category and Decipher score.

Page 3 of the Decipher Prostate Biopsy test report

Page 3 of the Decipher Prostate Biopsy patient report includes:

• A “Test Description” section.

• How the biopsy specimen was prepared for testing.

• A description of the Decipher testing technology.

• How the risk estimates shown on page 1 were calculated.

• The intended use of the test.

• Confidence intervals (a range of values that likely contain the true value) of risk estimates shown on page 1.

• A reference section of clinical trials from the Decipher database that are cited in this report.

To see a sample report and a video that walks you through it, go to

https://decipherbio.com/decipher-prostate/physicians/biopsy-test-report/

Guideline recommendations

Even though the Decipher Prostate genomic classifier is a suite of three tests, I’ve only detailed the test report for Decipher Prostate Biopsy. That’s because these test reports can be somewhat challenging to understand and should be reviewed with a clinician who is familiar with them.

The guidelines published by the NCCN and the American Urological Association (AUA) concerning active surveillance AS for prostate cancer advise against the routine use of the Decipher test.

The guidelines support its selective use in specific scenarios where the results are likely to alter or influence clinical decision-making.

Decipher is most relevant for refining risk stratification in "gray zone" areas, particularly among men considering AS for low- or favorable intermediate-risk disease. Examples include:

• Men with high-volume Grade Group 1 (Gleason 3 + 3 = 6) low-risk disease

• Men with Grade Group 1 disease who have an abnormal digital rectal exam (DRE) or high PSA density

• Men with low-volume Grade Group 2 (favorable intermediate-risk) disease

In summary, both major guidelines support the use of the Decipher test as a tool to improve prognostic accuracy selectively in men with low- or favorable intermediate-risk prostate cancer who are candidates for active surveillance.

The test may help clinicians and patients make a more informed decision about whether surveillance is safe or if treatment is warranted.

Questions for your doctor:

• What does my Decipher score and NCCN risk category mean?

• How does my 10-year metastasis risk estimate compare to men like me in the same NCCN risk category?

• Are my clinical features - PSA density, % cores, Grade Group, and MRI PI-RADS score - consistent with the findings from the Decipher test?

• Do MRI results ever overrule a Decipher score?

• How does my Decipher score impact our plan of care?

Conclusion

Ultimately, understanding your Decipher test report is a crucial step in taking control of your health journey and partnering with your doctor to choose the path that is truly right for you.

The Decipher Prostate Biopsy test is a well-validated genomic test that helps improve risk stratification of prostate cancer.

Experts in the clinical management of prostate cancer wish for more prospective studies evaluating Decipher’s long-term impact on patient outcomes, such as quality of life, need for treatment, and overall survival.

As these types of trials show success in these areas, the clinical validation of Decipher will only increase and contribute to a personalized and hopefully more accurate approach to the care of men with prostate cancer.

Genomic scores help identify risk, but they don’t replace the clinical judgment of a qualified clinician, MRI results, or patient preferences.

In the next newsletter, I’ll discuss Decipher GRID, which I believe has immense potential, when properly validated, to elevate prostate cancer management to the next level of personalized care.

Until then, I wish you good health and much love.

Keith

For decades, the conversation between clinicians and patients has centered on numbers such as PSA levels and Gleason scores. While these factors are essential, they can raise more questions than they answer.

Navigating the sheer number of options, from active surveillance to definitive treatment, can be extremely confusing and very anxiety-provoking.

Uncertainty arises from a significant limitation in the traditional approach. Luckily, modern research shows that a deeper layer of information has always existed, hidden within the tumor itself.

A test called a Decipher Genomic Classifier is shedding light on the heterogeneity of prostate cancer, offering a clearer picture by analyzing the unique biology of an individual's cancer.

This post summarizes seven essential facts about how this technology is changing the conversation between doctors and patients, empowering them to make more informed decisions based not only on statistics, but also on biology.

1. PSA and Gleason scores are only half the story

What makes prostate cancer so incredibly difficult to manage is its unpredictability, or what scientists call "heterogeneity." Not all prostate cancers behave the same way due to the vast amount of diversity that exists between tumors.

For years, doctors have relied on clinical and pathological features, such as your prostate-specific antigen (PSA), Gleason score, and the number of positive biopsy cores, to predict how aggressive a cancer might be. But these tools have a blind spot that is the source of so much patient anxiety.

Dr. Pooya Banapour, a urologic oncologist, uses a powerful analogy: there are "two sides to every story." The clinical and pathological features are on one side. Genomics, the study of the tumor's genes, is on the other side.

He explained that traditional features are "Limited in terms of capturing the whole picture of prostate cancer." This lack of the whole picture is why two men with the same PSA and Gleason score can have extremely different outcomes.

The traditional numbers alone can't always tell them apart, leaving both doctor and patient in a state of uncertainty.

2. Your Tumor Has a Unique “Biological Fingerprint”

Genomics reflects the unique biology of the tumor, also known as its molecular signature or, as Dr. Banapour calls it, its "prostate cancer fingerprint." This molecular signature is what a genomic test, such as Decipher, analyzes. It looks past the pathology and PSA level to understand how the tumor is programmed to behave at a genetic level.

The Decipher test measures the activity level of 22 RNA genes within the prostate tumor tissue. Scientists identified them by using artificial intelligence to compare the tumors of thousands of men whose cancer metastasized against those whose cancer didn't, isolating the "biological fingerprint" of aggressive disease.

The test examines what critical genes are actually turned on and turned off. These genes are involved in the very processes that drive a cancer's ability to grow and spread, including:

• Androgen signaling

• Cell cycle progression

• Immune response and modulation

• Angiogenesis

• Metabolism

• Cellular adhesion and motility

• Cell structure and organization

Decipher provides a direct look at the cancer's aggressive potential, independent of the PSA or Gleason score.

3. A single score can help refine your next step

This incredibly complex science translates these 22 gene signatures into a straightforward single, continuous score ranging from 0 to 1.0.

Based on a complex algorithm, this score determines the classification of the tumor's genomic risk as Low, Intermediate, or High, with cutoff points of 0.45 and 0.60 for the Decipher Prostate Biopsy and Decipher Prostate Radical Prostatectomy tests.

For Decipher Prostate Metastatic, the report provides a risk classification of either "Lower Risk" or "Higher Risk," with a cutoff of 0.85.

A higher score indicates a more aggressive tumor biology with a greater potential to metastasize. This one number can steer decision-making and clear away ambiguity.

For example, consider a man with NCCN low-risk disease who might be leaning toward active surveillance. If his Decipher score comes back high, it indicates that the biological activity of his tumor is not truly low-risk.

For low-risk men with a high Decipher score, NCCN recommends more intensive active surveillance (AS) given the higher likelihood of progression. For favorable intermediate-risk men, a low score can support AS, whereas a high score may favor definitive therapy.

4. Genomics helps you choose the next step

One of the biggest challenges in oncology is striking a balance between effective treatment and maintaining quality of life. Here is where Decipher can guide both the intensification of treatment for aggressive cancer and the deintensification of treatment for less aggressive cancer.

A powerful example comes from a re-analysis of the landmark NRG/RTOG 9601 clinical trial. The original trial showed that for men with a rising PSA after surgery, adding two years of hormone therapy to radiation improved survival.

Researchers tested stored prostatectomy tumor samples from the RTOG 9601 trial with the Decipher Genomic Classifier test. They checked whether the survival benefit of adding hormone therapy to salvage radiation changed across different scores.

However, when researchers applied the Decipher test to the archived tissue samples, they discovered that mainly only men with high-risk Decipher scores derived benefit from the addition of hormone therapy.

The crucial takeaway was that patients with low-risk scores derived no clinical benefit from the addition of hormone therapy. For these men, genomic testing could have spared them from life-altering treatment that wasn't helping them.

5. Three versions for three points

Decipher Genomic Classifier for prostate cancer is a suite of three distinct tests, each tailored to answer a different critical question at a key point in the cancer journey.

All three tests use the same robust 22-gene assay to interrogate the cancer. However, the final report is custom-tuned to answer the most critical question you are facing at that specific moment in your journey.

• Decipher Prostate Biopsy: Used for newly diagnosed men to answer: "Should I choose active surveillance or immediate definitive treatment, such as surgery or radiation?"

• Decipher Prostate Radical Prostatectomy: Used after prostatectomy to clarify the need for observation versus adjuvant radiation when PSA is undetectable, and when PSA is persistent or rising, to guide early salvage radiation and whether to add short-term hormone therapy.

Decipher Prostate Metastatic is for use in metastatic castration-sensitive prostate cancer (mCSPC) and provides a risk assessment designed to inform prognosis and support shared decision-making around treatment intensification. It is not yet a therapy-selection (predictive) test.

6. It's the only test of its kind in a key guideline

In the world of oncology, NCCN guidelines are highly respected. Decipher isn't just in the guidelines, but is the only test of its kind to make the cut.

It is the most scientifically validated genomic test for prostate cancer, evaluated in over 90 scientific publications and more than 25 prospective, randomized National Cancer Institute clinical trials, involving over 200,000 patients.

According to the NCCN Prostate Cancer guidelines, Version 1.2025, the Decipher 22-gene classifier is the only gene expression test included in the "Advanced Tools" table for risk stratification of localized prostate cancer.

The NCCN panel assigned it the highest Simon Level 1B evidence rating in the biopsy and post-radical prostatectomy settings.

Other tissue-based genomic tests, such as Prolaris (31-gene assay) and Oncotype DX (17-gene assay), do not meet this high threshold of Level 1 evidence.

This unique standing signifies that a consensus of leading cancer experts recognizes the test's data as robust and clinically actionable.

7. Prognostic versus predictive - what we know

The evidence from robust clinical trials shows that Decipher is a powerful prognostic tool, accurately predicting the future course and aggressiveness of the disease.

While the post-hoc analysis of NRG/RTOG 9601 suggests that it has predictive power, the question for many is whether it's a truly predictive tool, one that can predict which patients will respond to a specific therapy.

The American Urological Association (AUA) and the European Association of Urology (EAU) advise against the routine use of tissue-based genomic tests to determine therapy, pending the results of prospective trials that utilize genomic biomarkers.

Conclusion

While a prostate cancer diagnosis will always be a formidable challenge, tools like genomic classifiers are fundamentally changing how clinicians manage prostate cancer.

We are moving away from a one-size-fits-all approach based on broad statistics and toward a personalized one based on each cancer's unique biological drivers.

By providing a clearer, more individualized picture of risk, these tests empower doctors and patients to make better, more informed decisions together.

While this technology provides a much clearer picture of a cancer's individual biology, the next frontier isn't just about choosing the proper treatment, but about predicting and stopping aggressive disease before it even begins.

In the next newsletter, I'll provide a step-by-step guide to reading your Decipher Prostate Biopsy report and explain the meaning of each page.

Until then, I wish you good health.

And much love,

Keith

Your doctor just told you that you have prostate cancer. Then they tell you the best plan is to monitor it. This is the reality for thousands of men diagnosed with low-risk prostate cancer who enter what's called "active surveillance (AS)."

It’s a path supported by science.

But the emotional reality is far more complicated. Living with even low-risk cancer, while deliberately choosing not to treat it, goes against every instinct we have about fighting disease.

The psychological burden is enormous, yet most healthcare systems focus almost entirely on the medical protocols while largely ignoring the mental health challenges that come with this approach.

Men are left to navigate feelings of helplessness, anxiety about the future, and the constant weight of knowing cancer is growing inside them, however slowly.

This gap between medical best practice and psychological support creates unnecessary suffering. We can do better for men facing this difficult but increasingly common treatment path.

Why active surveillance

The goal of AS is to monitor for progression while preventing or delaying therapy with inherent side effects.

Another component of AS is curative intent. If the patient progresses and needs treatment, appropriate protocols should catch the progression early enough for treatment to result in a cure.

Real-world adherence to AS monitoring is inconsistent, primarily because repeat biopsies are hard to tolerate. Clinic culture, geography, clinician philosophy, and communication layer on top of that.

Safety of active surveillance

Multiple long-term studies show that active surveillance carries a very low risk of dying from prostate cancer. At Toronto/Sunnybrook, 15-year prostate-cancer–specific survival was ~94.3% (prostate cancer-specific mortality ~5.7%). At Johns Hopkins, among carefully selected men, the combined 15-year risk of metastasis or prostate-cancer death was ~0.1%.

These numbers show why major societies like the National Comprehensive Cancer Network (NCCN) and the American Urological Association (AUA) recommend AS as the preferred option for very-low and low-risk disease.

A quick overview of active surveillance

Who's a Good Candidate?

It is usually offered to men whose prostate cancer is low-risk and unlikely to spread quickly.

• Risk Group:

  • Very-low or low-risk prostate cancer

  • Some carefully chosen men with favorable intermediate-risk disease

• Cancer Stage: Tumor is only inside the prostate (T1c–T2a)

• Gleason Score / Grade Group:

  • Grade Group 1 (3+3=6) — most common for AS

  • Some men with Grade Group 2 (3+4=7) with a small amount of pattern 4 may also qualify

• Tumor volume: few cores, low % core involvement

• PSA Levels: Typically below 10 ng/mL

• PSA Density (PSAD): Best if below 0.15 (sometimes acceptable up to 0.20 in select men)

• Biopsy Results: Only a small amount of cancer is found in a few biopsy samples

• Genomic Testing (Tissue-Based): For some men, especially those with Grade Group 2 cancer or other borderline features, doctors may use specialized tests on the original biopsy tissue. These tests (such as Decipher, Prolaris, or Oncotype DX GPS) analyze the activity of specific genes within the cancer cells to better predict the tumor's aggressiveness. A favorable genomic score can provide greater confidence in choosing AS.

• Liquid Biomarkers (Blood or Urine Tests): Before an initial or repeat biopsy, certain blood or urine tests can help clarify the risk of having aggressive cancer. Tests like the 4Kscore Test, Prostate Health Index (PHI), or SelectMDx can augment risk stratification and may reduce unnecessary biopsies when used appropriately.

• Life Expectancy: Generally recommended for men with a life expectancy of 10 years or more.

How Active Surveillance Works

"Surveillance" means careful monitoring

• PSA Blood Test: Every 3–6 months

• Digital Rectal Exam (DRE): Once a year

• Prostate MRI:

  • Often done before or at diagnosis

  • May be repeated every 1–3 years or if PSA changes

• Biopsies:

  • Confirmatory biopsy within 1–2 years after diagnosis

  • Later biopsies every 2–5 years, or sooner if MRI/PSA suggest change

• Intervals are adjusted to risk and changes in PSA/MRI

• Rising PSA is a trigger for MRI/biopsy, not necessarily treatment

When to Switch to Treatment

Most men stay on AS for years, but treatment is recommended if the cancer shows signs of becoming more aggressive.

• Grade Progression: Biopsy shows a higher grade cancer (e.g., moving from Grade Group 1 to 2 or higher)

• Tumor Growth: More cancer found on biopsy or MRI

• PSA Changes: Rapid rise in PSA → prompts MRI or biopsy, not treatment by itself

• Personal Choice: Some men decide to switch to treatment because of anxiety or preference

The reality is that adherence rates are low

Professional organizations have created AS guidelines that have some variability between them. And there are many things for both clinicians and patients to consider when implementing an AS protocol.

These variations and multiple decision points make this a rather complicated process to follow, even with adequate guidance by an experienced clinician. Studies show that in non-academic (real-world) settings, the frequency of adherence to AS professional guidelines is low.

UCLA researchers examined the records of men diagnosed with prostate cancer from 2004 to 2007 and found that only 4.5% of 3656 men on AS were monitored according to professional guidelines.

In another study, of 5192 men on AS over 5 years, 11.1% met Sunnybrook/PRIAS surveillance standards, and only 5% met Johns Hopkins surveillance standards. Repeat biopsies were the weak link.

Another real-world study monitored 546 men diagnosed with prostate cancer from 1995 to 2022. These men were enrolled in AS and had at least one biopsy after diagnosis. When followed over three decades, only 11.1% were adherent to AS guidelines.

When researchers dug into the details of this last study, they found some surprising and not-so-surprising things:

• Repeat prostate biopsies were the sticking point (no pun intended) and the main reason for nonadherence.

• Most men kept up with annual PSA monitoring but balked at undergoing biopsies as frequently as the guidelines suggest.

• For most men, nonadherence did not result in poor outcomes. For most men who didn't follow biopsy guidelines and had stable PSA levels over a median follow-up of 9.3 years, deaths caused directly by prostate cancer were a reassuringly low 1.6%, consistent with outcomes in landmark AS trials.

• Black men were significantly less likely to adhere to AS protocols compared to white men, consistent with known racial disparities in healthcare.

• Men with higher tumor stages (cT2) or men with more comorbidities were more likely to follow the guidelines.

Researchers summarized these findings by saying,

"Our findings highlight a fundamental truth about AS: while guidelines provide an important framework, they don't always align with the realities of clinical practice—or with what patients are willing to tolerate. This is where we, as a community, need to bridge the gap between trial-based protocols and real-world practice. Perhaps the future lies in more personalized monitoring strategies—ones that respect both the science and the individual patient experience."

The clinician's role

Patient characteristics alone aren't the only determinants of initiating and maintaining AS. There is a high variability in AS practices across different geographic regions, healthcare systems, and even among urologists in the same practice.

According to one study, the clinic where an eligible man seeks urological care is a primary predictor of whether his prostate cancer management plan includes active surveillance.

Matt Cooperberg, M.D., of the University of California, San Francisco, discussed the findings of a study on active surveillance at the American Urological Association's (AUA) 2022 annual meeting.

He said that AS use ranges from ~7% to ~80% depending on the practice and 0–100% depending on the clinician. Who you see truly matters.

He also said that in his UCSF program, "about 95% of men diagnosed with low-risk prostate cancer are put on active surveillance."

This wide variation indicates that local practice culture, clinician philosophy, and institutional priorities are key drivers of the type of care patients receive, often outweighing standardized national guidelines.

Why clinicians adapt the guidelines

Clinicians don't view professional guidelines as rigid rules but rather as templates to base decisions upon, given the unique context of each patient.

Urologists often exercise significant discretion, tailoring the frequency and type of monitoring based on their professional judgment, their personal comfort level with uncertainty, and their assessment of a patient's individual risk profile.

However, doctors often worry about missing signs that the disease is getting worse, and they're also concerned about potential lawsuits if something goes wrong.

These fears can create significant obstacles that push physicians toward doing more frequent testing and following strict monitoring guidelines, or even recommending that patients switch from active surveillance to active treatment.

Organizational influences on individual practice patterns

Where a clinician practices highly influences their decision-making, including whether to follow AS professional guidelines. Urologists who work in highly structured and hierarchical settings such as academic medical centers are more likely to follow AS national guidelines.

Whereas, urologists who practice in less structured settings, such as small community-based practices, may rely more on individual preferences. All of these factors lead to greater variability in the care of men who are eligible for active surveillance.

Ultimately, almost all studies indicate that the most critical factor influencing patient acceptance of AS is the doctor's opinion.

Not surprisingly, the physician's influence can also be a strong reason why patients decline AS.

Problems with acceptance and adherence to AS involve doctors, patients, and the healthcare system in which they practice.

Knowing the AS professional guidelines isn't enough to standardize care in AS.

Change requires the adoption of AS protocols at the institutional level, along with quality improvement initiatives, financial incentives, and performance feedback at the practice level.

Why some men drop out of AS despite stable disease

A fascinating study out of the United Kingdom looked at why some men who had been on AS for prostate cancer dropped out to undergo active treatment despite no signs of disease progression.

Researchers interviewed 14 men from diverse socio-cultural backgrounds in the London area who fulfilled this criterion. I found this paper particularly interesting because it included quotes from these men regarding the reasons why they chose to drop out of AS and pursue active treatment.

I took the quotes, without alterations, directly from the paper so you'd understand how these men felt.

Keep in mind that these were men in a universal healthcare system, the United Kingdom's National Health Service (NHS), which includes some private healthcare options. Regardless, I think many prostate cancer patients will find their reasons relatable.

Regarding the participants in the trial:

• Had been diagnosed and managed at the same clinic and by the same clinical team.

• Mean age was 64 years.

• Mean time on AS was 39 months.

• Mean PSA was 5 ng/mL (2 to 8 ng/mL).

• 29% were of Asian, African, and Afro-Caribbean ethnicity.

A common theme in the interviews was the impact of negative experiences during diagnostic procedures, highlighted as among the most challenging aspects of their entire experience.

What men say makes active surveillance hard

Long waits at diagnosis often continued during surveillance; scheduling gaps and slow communications increased their stress.

"…At diagnosis my scan took three weeks and my biopsy results took four weeks. I almost missed my appointment because the letter arrived the morning of the appointment by which point I was climbing the walls…It was just the same once I'd started on active surveillance—I couldn't deal with it…

Shared decision-making felt limited.

"…It was confusing. I read that there were new guidelines on active surveillance and the doctor told me they weren't relevant to me as I was part of an active surveillance trial. I just wanted to discuss the implications of the guidelines, was it better or worse than the care I was getting…"

Patients wanted real dialogue about evolving evidence. Human connection often provides more reassurance than handouts or links.

"…Whilst there was plenty to read on the internet, it's finding people that have been through it that I found most helpful. … Often you can read and read but, at the end of the day, talking to someone, is the most important part…"

Several men indicated that they had not been offered psychological support while on AS, though they felt it would have helped them cope or adjust to their diagnosis.

"…I just needed someone to off-load on. I couldn't get through on the phone…when I did, my nurse asked me what I was fussing over. I heard about the hospital psychological support services during my radiotherapy… Too little, too late!..."

Many men felt that their clinical team lacked enthusiasm for AS.

"…I asked the doctor for some references to the latest active surveillance research. He said there wasn't anything useful, he sounded so bored by the question. I did my own research; there was lots that interested me. I'm an engineer; I like to know how these things work. In my line of work if an engineer isn't engaged and interested in what he's doing mistakes happen, I couldn't risk it, it's my life…"

Men perceived more structured, visible support after switching to treatment than during AS.

"…I chose radiotherapy, from that moment I was introduced to my Nurse specialist and a support worker, I also met a specialist radiographer who was going to see me every week during my treatment. They sent me to a seminar…where I met more of the team and lots of other patients…that was to prepare me for treatment. I couldn't have felt more love and support. I didn't feel nervous about the treatment at all. If they had done the same for surveillance I might not have had treatment…"

Many men described the significant influence their partners had on their decision-making as the most challenging element to balance while remaining on AS.

"…My wife wanted me to have treatment, she never wavered. To be honest, she wore me down. I went for surgery because she wanted it, not because I did. If I'd been on my own I'd still be monitored…"

Researchers' conclusions

• A negative experience during the initial diagnosis can adversely affect both uptake and long-term adherence to AS.

• Clinical teams need to find ways to expedite the results of diagnostic testing and subsequent surveillance procedures to reduce the psychological stress associated with waiting for test results.

• Specialists and GPs (primary care providers) need to coordinate ways to check on patients' mental well-being during the diagnostic phase and minimize the psychological burden associated with adhering to AS protocols.

• More than two-thirds of participants indicated that the clinical team failed to respond to men's changing needs as a reason for opting out of AS. To help patients stick with their treatment plan, healthcare teams need to adjust how they make decisions together with patients as the patients' needs change over time during active surveillance.

• Researchers suggest mimicking the best parts of chronic care models, such as those for treating diabetes: Easy access to a multidisciplinary team to improve the quality of life for men on AS. One that provides ongoing education for self-care, stress reduction, community support, and the timely delivery of information.

• Based on the interviews, researchers recommend providing peer support for men on AS. Some clinics, both academic and non-academic, offer this.

Reasons for leaving AS for active treatment despite no disease progression

• Negative experiences at diagnosis.

• Delays and inflexibility at follow-up appointments.

• Inaccessibility of the healthcare team.

• Lack of information and support.

• Not being able to connect with peers.

• Being excluded from shared decision-making.

• Perceptions of being considered a low-priority patient.

The psychological burden of AS

The study based in London brought to light some of the psychological stressors prostate cancer patients face.

Besides the cumbersome aspects of monitoring, deciding to remain on AS is highly influenced by a man's psychological state. Research shows that men who undergo AS have higher rates of anxiety and depression.

Another paper discusses the factors that draw patients toward or away from AS. It focused on the psychological aspects of how men decide on active treatment or active surveillance.

It found that men will make decisions influenced by their prior experiences with cancer, their willingness to accept risk, and how they perceive their disease, which is highly influenced by others.

In almost all studies that examine the issues influencing a man's decision-making in prostate cancer, a prominent driver is cancer control and eradication.

A man's concern over cancer control is a driver toward surgery and a barrier to acceptance of AS. They want "physical removal of the cancer."

Researchers noted that this desire for action and control creates an internal conflict with the passive monitoring of AS.

For many, definitive treatment is perceived as a way to resolve this conflict, eliminating uncertainty and restoring a sense of control, despite the known risks of treatment-related side effects.

Proper education in shared decision-making is key

A meaningful way to help men make balanced decisions is to properly educate them about the overall safety of active surveillance as proven by multiple robust clinical trials.

Another way is to give men accurate and honest estimates of risks associated with aggressive treatment, such as radical prostatectomy and radiation. Include a discussion of their risks for urinary, sexual, and bowel symptoms.

Then it is up to each individual to decide how much concern they have regarding those possible side effects.

Factors associated with adherence

This same paper discussed factors associated with adherence and nonadherence to AS, and some findings were surprising.

It's less "general anxiety" and more about decisional confidence and uncertainty. If confidence erodes, men are more likely to exit AS without progression.

Factors associated with nonadherence to AS:

Uncontrolled anxiety may drive them towards definitive treatment.

Men who are undecided about treatment early on experience more psychological stress than those who are confident about their choice.

Ways to buffer anxiety and support AS adherence include:

Discussing the safety of AS.

Discussing ways for men to maintain "control" during AS, such as making choices related to maintaining a healthy diet and lifestyle.

The role of support systems is essential, especially in the context of family, as healthy family involvement seems more beneficial than peer support groups.

Men's experiences with peer support groups during active surveillance varied significantly. Some found these groups genuinely helpful, while others felt they weren't valuable or even made things worse.

Several men in this study reported feeling criticized or judged by other group members who had chosen more aggressive treatments like surgery or radiation.

Cancer progression versus social and psychological triggers

Whether certain patients stick with active surveillance doesn't just depend on how their cancer progresses medically. Psychological and social aspects play a huge role, too.

Men who feel confident about their decision, have good strategies for managing their own care, and receive strong support from their families tend to do better staying on active surveillance.

On the flip side, men who struggle with ongoing doubts about their treatment choice, encounter unhelpful support groups, or can't resolve their uncertainty are more likely to switch to active treatment even when it's not medically necessary.

What actually helps men stay on AS?

Make surveillance tolerable, predictable, and personalized.

• MRI-guided, risk-adapted follow-up: Use MRI to triage who truly needs a repeat biopsy now vs later, aligning testing intensity to risk. Growing evidence supports MRI-first strategies and protocols are evolving.

• Fast results + clear ownership: Tell patients exactly who calls with results and when. Delays magnify anxiety.

• Shared decision-making that evolves: Revisit the plan as needs change; decisional confidence is dynamic, not one-and-done.

• Peer support: Offer vetted communities early. Men repeatedly report that talking to someone on AS is more reassuring than reading another PDF.

  • Active Surveillance Patients International (ASPI)

  • AnCan Prostate Cancer programs

• Address disparities head-on: Track adherence by race & ethnicity at the clinic level and proactively reach out when surveillance milestones are missed.

PSA levels and biopsy results alone cannot measure the success of active surveillance. It hinges on our ability to support these men who are dealing with uncertainty while trusting us to help them.

The path forward requires a comprehensive model of care. One that integrates psychological support, prioritizes the patient's experience, and treats decisional confidence as a clinical outcome. Only then can this medically sound strategy become a truly sustainable and humane one.

Questions to ask your clinician

• What is our confirmatory plan? (timing, MRI vs systematic + targeted biopsy)

• If my PSA goes up, what exactly happens next? (MRI + biopsy triggers)

• Who calls me with results, and by when? (set a 7–day expectation)

• How often will MRI replace biopsy for me if my PSA and imaging stay stable?

• Can you recommend an AS peer support group? (local vs ASPI vs AnCan)

• What's my personalized risk profile? (include PSA density and, if used, a genomic score)

  • Can you review my UCSF-CAPRA risk score with me and explain what it means?

  • Can you review my MSKCC risk score with me and explain what it means?

If your clinician can’t satisfy your expectations, always opt for a second, and even a third opinion if necessary, preferably at a prostate cancer center of excellence.

I hope you enjoyed this post.

Until the next one, I wish you good health.

And much love,

Keith

I'm dedicating today's newsletter to my friend and neighbor Mike, who is a two-time cancer survivor, and who just lost a second sister to cancer. Mike works in the oncology field, is dedicated to his work, and is an inspiration to those who know him.

Lab anxiety

There was the usual low-grade anxiousness in the past two weeks, which is typical for me in the lead-up to getting lab results, specifically, PSAnxiety. It's associated with some low-grade catastrophizing, such as what if I'm anemic or what if the labs suggest bone metastases?

The anxiety is intermittent, but overall, not as severe as it used to be; it still rears its ugly head at test time.

The results

First, the good news. My complete blood cell count (CBC) is normal, and my comprehensive metabolic panel (CMP) is normal, except for a mildly low globulin level. More on the globulin level later.

Testosterone:

• Nov 2021: 633 ng/dL

• Dec 2023: 870 ng/dL

• Jul 2025: 606 ng/dL

And the bad news:

PSA:

• Feb 2025: 369.14 ng/mL

• Apr 2025: 316.33 ng/mL

• Jul 2025: 361.69 ng/mL

My PSA has bumped back up. As a friend put it, "...worst case scenario, your PSA has been level now for six months." That is a good way to look at it.

How did I feel seeing the PSA results? I didn't feel anger, sadness, or fear. I feel a mixture of curiosity, disappointment, and relief.

Curious about why my PSA dropped 53 points and disappointed that it bumped up 45 points. Yet, I'm relieved I don’t have any symptoms or other lab evidence of metastases.

The hardest part was telling Mike, my husband, and seeing him cry. I gave him a tight hug until he stopped crying. After so many years of dealing with this issue, I sometimes forget the stress it places on him.

I'd love to figure out what caused the 53-point drop in PSA so I can take whatever necessary steps to facilitate it.

Analyzing the PSA results

I don't think the PSA drop was due to testosterone in the 600 range, though I have no idea what the testosterone level was in April. Testosterone levels fluctuate with peaks typically occurring between 7 and 10 am, though that diurnal variation appears to be blunted as men age. My labs were drawn closer to noon.

I don't think the prior PSA, which showed a drop, was a lab error because if it were, the current one should be significantly higher than it is. I say that because my PSA had been doubling every 8.4 months from January 2019 to February 2025.

I use Memorial Sloan Kettering's PSA doubling time calculator to track my doubling times.

My lowest PSA ever was 0.9 in January 2019, which was after a radical prostatectomy and salvage radiation to my pelvis. My highest PSA was 369.14 in February 2025, and then it dropped 53 points to 316.33 in April 2025.

The only thing I did differently between February and April 2025 was to start high-dose ivermectin and fenbendazole. And then I increased the dose of ivermectin from 102 mg per day to 136 mg per day and changed the dosing of fenbendazole from 500 mg every other day to 500 mg 7 days on and 7 days off.

If the PSA drop were solely due to the ivermectin and fenbendazole, you would have expected to see a continued drop, not an increase. The problem with viewing things that way is that the body and lab values have numerous variables, making it impossible to account for all of them.

Regardless, there has been a recent significant drop and a subsequent slowing of the doubling time. If the most recent rise in PSA of 45.36 points over the last 3 months remained steady and were multiplied by four, we'd expect a PSA of 497.77 a year from now, which would reflect a much improved PSA doubling time of 18.3 months.

But I'm only speculating.

My point is that something caused my PSA to drop and then slowed the short-term PSA doubling time. Could it be related to the ivermectin and fenbendazole? I cannot unequivocally say these medications caused the April drop or the slower short‑window PSA doubling time.

Correlation doesn't establish causation.

However, it is an extraordinary coincidence that the PSA drop coincided with the start of those medications. If you are a doctor with a traditional view of ivermectin and fenbendazole, you probably rolled your eyes after reading that last sentence.

I understand where you are coming from because I used to do the same thing. However, I'd venture a bet that if you were diagnosed with an incurable cancer and couldn't tolerate the standard of care drug therapy, you'd be exploring all your options, no matter how slim they might appear.

That’s called the will to live, which has served me well since my diagnosis 7.5 years ago.

The low globulin level

The only lab abnormality, other than the high PSA, that stands out is the low globulin level.

In a comprehensive metabolic panel, globulin is a calculated value: total protein 6.4 - albumin 4.7 = 1.7 L (Reference range: 1.9 - 3.7 g/dL). Total protein levels include immunoglobulins (Ig) like IgG, IgM, and IgA.

The low globulin level, or hypoglobulinemia, has been a longstanding issue for me, at first occurring intermittently and now persisting since October 2024. A prior workup with an immunoglobulin panel in 2023 revealed a mildly low immunoglobulin A level, which was normal when later retested.

There are other causes for a low globulin level besides an immunoglobulin deficiency, though my labs don't suggest any of those causes. Even if I do have an intermittent IgA deficiency, there is no treatment for it.

Selective IgA deficiency

Selective IgA deficiency is the most common primary immunodeficiency, but it is highly variable in its expression. Most people are asymptomatic their whole life, while others develop frequent infections such as pneumonia and sinusitis.

Some have highly variable IgA levels ranging from normal to undetectable.

In some individuals, IgA deficiency causes a distortion of microflora in the gut, resulting in an increased incidence of gastrointestinal parasites and small intestinal bacterial overgrowth, which I’ve had before. See More Gut Drama - 034.

Some people with IgA deficiency can show blunting of the small intestinal villi, or lining, which was present on the biopsy of my small intestine in December 2023. Additional testing ruled out celiac disease.

While I have not been formally diagnosed with IgA deficiency, it could help explain some things, like why I had blunting of the villi of my small intestine and why I developed small intestinal bacterial overgrowth.

Gut dysfunction and immune health

I’m discussing this because I’ve recently had a flare of symptoms suspicious for small intestinal bacterial overgrowth (SIBO) - post-meal bloating and intermittent morning loose stools. Sorry - TMI!

When I started training with The Institute for Functional Medicine in 2009, they were well ahead of the curve, teaching the importance of a healthy microbiome for a healthy immune system.

A healthy gut and microbiome are essential for a healthy immune system because the gut-associated lymphoid tissue (GALT) is the largest immune organ in the body. Here is a really good YouTube video explaining the kind of immune functions that occur in the lining of the gut.

Because of this flare of gastrointestinal (GI) symptoms, Dr. Kessler has suggested I undergo stool testing again. While breath testing is the typical way to test for SIBO, obtaining a comprehensive digestive stool analysis gives you a lot more information about the overall function of your GI tract.

When we last did that stool test in the fall of 2023, it showed multiple abnormalities. See Immune Compromised - 028. We addressed each one, and I got better. The problem is that SIBO often recurs, especially in someone with IgA deficiency.

If your gut microbiome is in chaos, chances are your immune system is too. Recent studies have shown the association of the gut microbiome and prostate cancer.

In addition, other studies have shown that immunotherapy for cancer works better when there is a higher diversity of bacteria and a relative abundance of Ruminococcaceae bacteria.

My immune system is probably going to do a better job attacking the prostate cancer cells when my gut is optimally functioning with a healthy microbiome.

The plan

I met with my radiation oncologist and we discussed the lab results. Here is the plan:

• I will continue the ivermectin and fenbendazole for now, as I'm not having any side effects or liver enzyme elevation.

• My primary care provider will order a serum protein electrophoresis to assess the type of proteins in my serum and another IgA level.

• We’ll hold off on a PET/CT scan for now since I’m asymptomatic and all other labs are normal.

• I’ll order another Genova Diagnostics’ comprehensive digestive stool analysis to see where we stand with my overall gut function.

• If the SIBO symptoms persist, we’ll treat empirically for that.

• I’ll continue my current supplement regimen and intensive self-care.

• I’ll follow up with my radiation oncologist in three months with labs.

I remain optimistic as we continue working to piece everything together in an effort to strengthen my immune system and keep the cancer under control.

Until the next newsletter, I wish you good health.

Much love,

Keith

Disclaimer

While preclinical research has shown some intriguing anti-cancer properties of drugs like ivermectin and fenbendazole, there is currently no high-quality clinical evidence proving their safety or effectiveness in treating cancer. As such, any claims suggesting that these drugs are effective cancer therapies are not supported by randomized controlled trials or regulatory approval. Fenbendazole has documented drug‑induced liver injury in self‑medicating patients.

This Substack is intended solely for educational and informational purposes. This information is not intended as medical advice or a recommendation for any specific treatment. I do not endorse or advise the use of any drug discussed here, including those I may personally choose to take. Always make medical decisions in consultation with a qualified healthcare professional.

Despite prostate cancer being one of the most common causes of cancer in men, prostate cancer screening with the prostate-specific antigen (PSA) blood test remains a hot topic of debate.

The PSA blood test is a biomarker that detects abnormalities of the prostate, from enlargement (BPH) to inflammation (prostatitis) to prostate cancer. Most labs reference "normal" PSA levels of 0-4.0 ng/mL; however, PSA levels tend to increase with age.

According to Johns Hopkins Medicine:

• For men in their 40s and 50s: A PSA score greater than 2.5 ng/ml is considered abnormal. The median PSA for this age range is 0.6 to 0.7 ng/ml.

• For men in their 60s: A PSA score greater than 4.0 ng/ml is considered abnormal. The normal range is between 1.0 and 1.5 ng/ml.

• An abnormal rise: A PSA score may also be considered abnormal if it rises a certain amount in a single year. For example, if your score increases more than 0.35 ng/ml in a single year, your doctor may recommend further testing.

Why PSA Screening Remains Controversial

To make things even more complicated, one study found that 15.2 percent of men with a PSA 4.0 ng/mL or less had biopsy-proven prostate cancer. The vast majority of these had a Gleason score of 6, though 2.3 percent in this range had a Gleason score of 7 or higher.

Another study examined the prevalence of undiagnosed prostate cancer through a review of 19 autopsy studies encompassing over 6,000 men. It showed a high prevalence of asymptomatic and undiagnosed prostate cancer, even in men as young as 30, with prevalence increasing with age.

Among men aged 70-79, 36% of Caucasians and 51% of African Americans had previously undetected prostate cancer.

So, at this point, you are starting to see the incredible diversity and complexity associated with prostate cancer and PSA screening.

Balancing Early Detection with Overdiagnosis

While PSA screening has the potential for early detection and can reduce prostate cancer deaths in some men, it carries a high risk of causing overscreening, overdiagnosis, and overtreatment.

That's because PSA screening detects a high proportion of men with prostate cancer that grows slowly and rarely, if ever, metastasizes.

Overscreening causes unnecessary, risky prostate biopsies. Overdiagnosis results in overtreating indolent cancers that would never cause harm.

This overtreatment includes radical prostatectomy and radiation, resulting in life-altering complications of urinary incontinence, erectile dysfunction, and bowel dysfunction.

Thankfully, as the adoption of active surveillance of prostate cancer has increased, doctors and patients are much less likely to overtreat insignificant cancers. But in the past, this wasn't the case, and overtreatment was common.

Even choosing active surveillance comes with its own anxieties, with repeat biopsies carrying risks including bleeding and, rarely, urosepsis. And God forbid a man with an insignificant cancer gets treated with androgen deprivation therapy, but it has happened.

A substantial percentage, estimated to be between 23% and 60%, of prostate cancers detected through prostate-specific antigen (PSA) screening are considered indolent.

The reason for the wide range is that different studies included men of varying ages, races, and nationalities, as well as different diagnostic criteria.

But for those men with early PSA detection of clinically significant prostate cancer, it can be a lifesaver.

From the 'PSA Boom' to the 2012 Bust

In 1986, the United States (U.S.) Food and Drug Administration (FDA) approved the use of a serum PSA test for monitoring response to prostate cancer therapy and relapse.

PSA-based prostate cancer screening began in 1991 after studies showed PSA testing helped find localized prostate cancer. Its use in screening progressively increased, and in 1994, the FDA approved it as a screening test.

PSA-based prostate cancer screening took off, and healthcare providers using it as a screening tool in the early days were unaware of all the nuances and hazards later shown by the studies mentioned above.

After reviewing the data in clinical trials and seeing the harm of overdiagnosis and overtreatment caused by PSA-based prostate cancer screening, the U.S. Preventive Services Task Force (USPSTF) called a halt to routine PSA-based screening in 2012 with a landmark "D" rating.

The expert panel concluded that screening caused more harm than the small number of lives it might save. This significant policy change upset urologists, who believed the panel had dismissed the value of catching cancer early and saving lives.

What happened next was troubling but not surprising. Doctors began seeing more aggressive, advanced prostate cancers that had spread beyond the prostate. It appeared the drop in screening was causing cancers to be caught too late.

Shared Decision-Making (SDM): A Modern Imperative

In response to this new evidence, the USPSTF revised its recommendation in 2018, stating that men aged 55 to 69 should make individual screening decisions after consulting with their doctors about both the potential benefits and risks.

They acknowledged that the right choice depends on each man's specific situation and values and that screening isn't right or wrong for everyone.

Instead, it requires honest conversations between patients and doctors about what matters most to each individual.

The American Urological Association (AUA) had already adopted shared decision-making into its prostate cancer screening guidelines in 2013, and now the USPSTF was coming on board, followed shortly by the National Comprehensive Cancer Network (NCCN).

As a direct consequence of decades of conflicting evidence, shared decision-making has become a key component of responsible screening. However, this change in their guidelines has placed an enormous responsibility on doctors and other healthcare professionals.

However, SDM is crucial for an issue like PSA-based prostate cancer screening to help balance some of the uncertainty and potential harms.

Shared decision-making occurs when doctors and patients collaborate to determine the best healthcare options. It's not just the doctor telling the patient what to do or the patient making decisions alone without medical input.

Instead, both people bring something meaningful to the table.

The doctor brings their medical training, experience with similar cases, and knowledge of what the research has shown to work. The patient brings their life situation, what matters most to them, their fears and hopes, and their personal health goals.

When you combine these, you get decisions that are both medically sound and personally meaningful.

What makes this approach special is that it recognizes there's usually more than one reasonable path forward. Sometimes, the "right" choice for one person may be entirely wrong for another, even if they have the same medical condition.

That's because each person's life circumstances, values, and priorities are different.

If the clinician and patient choose to skip a treatment or avoid a screening test, they're not giving up or being careless. Instead, they're being thoughtful about what truly serves the patient best.

Every medical intervention carries risks, side effects, or burdens that might outweigh the benefits for a particular person's situation.

This approach requires doctors to really understand their patients as whole people – their values, fears, goals, and what makes life meaningful to them. It's about practicing medicine with both scientific knowledge and deep human wisdom, recognizing that the "right" choice isn't always the most aggressive one.

Sometimes, the most compassionate thing clinicians can do is step back and allow the person's own healing capacity and life choices to guide the decision. Doing this honors what matters most to each patient and recognizing that good medical care sometimes means choosing restraint over action.

The goal is to ensure that patients understand their options clearly and feel confident that their final decision reflects both sound medical judgment and their values and circumstances.

SDM is more than just a doctor providing you with information, and then you make a decision. A robust SDM protocol is a well-informed collaboration between the healthcare provider and you.

And it's especially useful when the outcomes aren't clear-cut or when weighing the benefits and risks involves some really subjective judgment calls.

This collaboration intends to come up with a quality decision based on these components:

• Information from the healthcare provider in the form of facts, including risks versus benefits.

• All the viable paths or alternatives you could take.

• Your personal preferences and values - what matters most when considering the risks, side effects, and quality of life.

Doctors are usually good at providing hard facts and alternatives. However, understanding patient preferences is more complicated because it requires a fundamental shift in thought.

Doctors must listen to you and move from just delivering information to diagnosing preferences, actually understanding what makes you tick.

It's about the doctor fully understanding your priorities. And they can only accurately understand your priorities if they present the correct facts and ask the right questions.

A Four-Step SDM Blueprint in Practice

Here's an example of a 4-step SDM discussion:

Potential Benefits of PSA Screening:

• Mortality Reduction: For men aged 55-69, screening about 1,000 men over ~13 years may prevent approximately 1.35 deaths from prostate cancer.

• Prevention of Metastatic Disease: Screening may prevent approximately 3 out of 1,000 men from developing metastatic prostate cancer.

• Psychological Reassurance: For some men, knowing their cancer status can provide peace of mind and a sense of control.

Potential Harms of PSA Screening:

False-Positive Results: A positive PSA test may not indicate cancer and can lead to anxiety, additional tests, and potentially unnecessary biopsies.

Biopsy Complications: Prostate biopsies, while rarely serious (e.g., urosepsis in 0.5%), can cause discomfort, bleeding, or rectal hemorrhage in about half of men.

Overdiagnosis: This is a major concern, as screening can detect "indolent cancers" that would never have caused symptoms or shortened a man's life. Estimates suggest overdiagnosis may occur in 20%-50% of screen-detected cancers.

Overtreatment: Overdiagnosis often leads to overtreatment with surgery or radiation, resulting in unnecessary exposure to side effects.

Treatment Complications: Radical prostatectomy or radiation can cause long-term side effects such as urinary incontinence, erectile dysfunction, and bowel problems, negatively impacting quality of life.

Psychological Harms: The "labeling" of a cancer diagnosis, even for low-risk disease, can cause anxiety, depression, and uncertainty, irrespective of treatment.

Mitigating Harms with Active Surveillance (AS):

For men diagnosed with low-risk prostate cancer, AS is a recommended and increasingly accepted option. It involves monitoring the cancer with regular tests and interventions only if progression occurs, allowing men to avoid or delay invasive treatment and its side effects.

The second step involves eliciting a patient's values regarding prostate cancer screening, active surveillance, and treatment.

The clinician presents the patient with a list of competing values that are central to the screening decision. For example:

• Maximizing Lifespan: "My top priority is to do everything possible to live as long as possible, even if it involves risks or side effects."

• Maintaining Current Quality of Life: "My top priority is to preserve my current lifestyle, including sexual and urinary function, and avoid medical interventions unless absolutely necessary."

• Achieving Peace of Mind: "My top priority is to reduce uncertainty and anxiety. I want to know for sure if I have cancer."

• Avoiding Medical Procedures: "My top priority is to avoid invasive tests like biopsies and treatments like surgery."

The patient ranks or prioritizes these statements, providing the clinician with a concrete, patient-generated framework to guide the rest of the conversation.

The third step moves the conversation from generic statistics to personalized risk information.

Clinicians might use a validated, interactive risk calculator, such as the Prostate Cancer Prevention Trial (PCPT) Risk Calculator 2.0, which incorporates multiple variables to generate a more precise risk profile.

During the visit, the clinician inputs the patient's data, including their age, race, family history, PSA level, and digital rectal exam (DRE) findings, into the tool. This calculator provides a preliminary assessment of the risk of prostate cancer if a clinician performs a prostate biopsy.

This step transforms the talk into a review of the patient's situation, making the risks real and relatable.

The fourth step completes the decision-making process by bringing together everything the clinician and patient have learned about the patient's personal risk and what matters most to them.

Here, the clinician shifts into the role of a decision coach rather than simply telling the patient what to do. It's the clinician's job to help connect the dots between the patient's risk numbers and their priorities.

The conversation may become very direct and personal:

"Mr. Smith, you told me that maintaining your current quality of life is what matters most to you right now. When we look at your specific risk calculator results, your chance of having a high-grade, aggressive cancer is quite low, around 5%. Since your main goal is to avoid treatment side effects, and your risk of dangerous cancer is relatively small, it makes sense that skipping the biopsy and simply rechecking your PSA in two years would best match what you've shared with me about your priorities. How does that feel to you?"

This method ensures that whatever they decide isn't something the clinician is imposing on the patient but rather a natural conclusion that flows from their values combined with their medical data.

The patient drives the decision. The clinician is just helping them see how their priorities and their numbers fit together logically.

Once they reach an agreement, the clinician documents both the plan chosen (such as "Patient will defer screening and return for PSA recheck in 1 year") and the key patient values that led to this decision (such as "prioritizing quality of life preservation").

This process creates a clear record of not only what they decided but also why they chose it, based on what matters most to this particular patient.

Beyond PSA: MRI, Biomarkers, and Genetics

I presented a fairly simplified example of SDM, as there are many more variables to consider in a modern practice. Such as:

• The results of any multiparametric magnetic resonance (mpMRI) study, including the PI-RADS score and PSA density.

• The results of any liquid biomarker testing, such as 4kScore, percent-free PSA, or SelectMDx.

• The results of any germline genetic testing.

Decision Aids: The Missing Ingredient

All of this information is too much to discuss in a 15-minute time slot with patients who inevitably have other medical conditions to address.

The optimal approach is to provide decision aids in the form of brochures or online material to read and/or watch before attending their appointment.

Unfortunately, these preappointment decision aids are not very prevalent.

The Future: Personalised, Data-Driven, Human-Centered

Nevertheless, the days of blanket screening recommendations for every man are behind us. The future of prostate cancer detection needs to be deeply personal, combining cutting-edge technology with meaningful conversations between doctors and patients.

Better tools will sharpen the data, but the final call should rest on what matters most to the patient. Bringing that level of personalization into everyday practice isn’t simple, yet it’s precisely the kind of challenge that can move the field forward.

Until the next newsletter, stay healthy.

Much love,

Keith

This newsletter is a rebuttal to an article, “What’s the Truth About Prostate Cancer,” posted by Howard Wolinsky on his Substack, The Active Surveillor. Dr. Bert Vorstman, a urologist, and Ron Piana, an investigative reporter, wrote the article.

If you haven’t read it, I encourage you to do so. My rebuttal will make a lot more sense if you read it first.

Role of the contrarian

Although many of my Substack posts take a contrarian stance, I strive to provide a balanced perspective, even when I selectively choose data to support my viewpoint.

One-sided stories present a subtle danger, especially when discussing a cancer diagnosis.

The article by Vorstman and Piana points out legitimate concerns in prostate cancer screening and care. I agree with their remarks about:

• The risk of overdiagnosis and overtreatment.

• The limitations of a 12-core systematic blind prostate biopsy.

• Patient anxiety linked to diagnostic processes.

• Treatment complications.

• A flawed healthcare system easily influenced by financial incentives.

However, in their effort to offer a strong critique, they overlooked nuance. In prostate cancer, nuance is crucial.

My response is not just about offering a counterargument but a balanced perspective because men facing this diagnosis need clear information, not increased frustration.

If Vorstman and Piana were right about everything in their paper, then recommendations from my physicians that I've agreed to and the subsequent actions I've taken on my journey with advanced prostate cancer could be considered a waste of time.

But, I can tell you, without a doubt, had I not undergone a prostatectomy or radiation therapy twice, I wouldn’t be here today.

Fighting yesterday's battle

The article is a polemic, framing the entire field of prostate cancer management as a financially driven "hoax." The problem in portraying it that way is that the authors are attacking a caricature of urology from 20 years ago.

Their accusations don't match the reality of how urologists practice prostate cancer screening and management today.

According to them, treatment is often worse than the disease, the prostate-specific antigen (PSA) blood test is useless, and surveillance doesn't save lives.

That kind of narrative might feel empowering to some. But for men who are interested in screening, are in active surveillance, or who are living with a diagnosis of advanced prostate cancer, it's like deleting the map while we're still deep in the woods.

Nuance is crucial

Let's look at where Vostman and Piana's paper lacks nuance.

Vorstman and Piana state that "most prostate cancers are outlived." This concept applies to a specific subset of cases. Yes, indolent, slow-growing Gleason 6 cancers seldom become life-threatening.

But that statement doesn't represent the complete picture. It definitely doesn't represent the 394,200 men who died from prostate cancer globally in 2022.

Prostate cancer appears in very dangerous forms, such as high-grade Gleason 8–10 tumors. Without treatment, aggressive prostate cancer can rapidly spread to bones, damage organs, and shorten lives.

To suggest that treatment is "commonly worse than the disease itself" without discussing breakthroughs in therapy for men with advanced prostate cancer is misleading. Such a statement might unintentionally encourage inaction in men who urgently require treatment.

Breakthroughs in therapy

Treatments for metastatic hormone-sensitive prostate cancer (mHSPC) had shown dramatic improvements in median overall survival since 2010, when monotherapy with androgen deprivation therapy (ADT) was the standard of care.

The CHAARTED trial demonstrated that for men with high-volume mHSPC, the median overall survival was 51.2 months when docetaxel was added to ADT, compared to 34.4 months with ADT alone.

Triplet therapy in mHSPC shows the deepest survival curves reported to date:

• In ARASENS, adding darolutamide to ADT + docetaxel lifted the 4-year overall-survival from 50.4 % to 62.7 %.

• In PEACE-1, median overall survival for the abiraterone triplet remains unreached after 68 months’ median follow-up, whereas ADT + docetaxel alone reaches ~53 months.

Fear-based statistics or reality

The authors state, "Regrettably, the frequency of this cancer is exploited through the marketing of fear-based statistics such as 1 in 8 men will be diagnosed with prostate cancer in their lifetime and that it's the second leading cause of death in men after lung cancer."

The article links to those statistics on the American Cancer Society's (ACS) webpage. How is this marketing? It is the ACS's job to provide accurate statistics about every cancer, regardless of what fear it might induce.

The fact that prostate cancer is the second leading cause of cancer deaths in men is significant. That statistic represents a lot of men and their families. Whether people read those statistics and develop fear or not is irrelevant.

Facts are facts, and people want the truth.

The 'false cancer' allegation and the reality of clonal evolution

The article claims that Gleason 3+3=6 "lacks the hallmarks of cancer, exhibits minor biochemical features,” and is a "false cancer." These claims are ignore the biological nature of some of these low-grade tumors and their potential to evolve.

First, let's establish the evidence that Gleason 6 is, by definition, a carcinoma. The authors claim it lacks cancerous features, but pathology and molecular biology tell a different story:

• Loss of basal cells is a fundamental characteristic that distinguishes prostate carcinoma, including Gleason 3+3, from benign glands. The absence of the outer basal cell layer is a key diagnostic feature of all prostate cancers. The exception to this would be intraductal carcinoma of the prostate (IDC-P) which retains the basal cell layer.

• Infiltrative growth pattern: Gleason pattern 3 glands exhibit an infiltrative growth pattern, haphazardly invading the surrounding prostatic stroma. Benign glands do not display this behavior, and this architectural difference serves as a crucial visual cue for pathologists.

Molecular changes: Even low-grade prostate cancers exhibit distinct genomics compared to benign tissue. These include:

• TMPRSS2:ERG gene fusions: Found in 40-50% of prostate cancers, though less frequently in Gleason 6. One study showed that ERG-positive Gleason 6 patients had significantly shorter cancer-specific survival. A "minor biochemical feature" doesn't shorten cancer survival.

• Copy number alterations (CNAs): Studies have shown that as the frequency of these chromosomal gains or losses increases in Gleason 6 tumors, the risk of recurrence and mortality also increases. A "minor biochemical feature" doesn't increase the risk of recurrence and death.

• PTEN loss: The loss of this protective gene, which is more common in high-grade cancers, is also found in a small subset of Gleason 6 tumors. This study shows “that PTEN protein loss in Gleason score 6 biopsies, although uncommon, is associated with an increased risk of tumor upgrading at radical prostatectomy.” A "minor biochemical feature" does not cause a pathologic upgrade at prostatectomy.

Second, the authors’ claim that higher-grade cancer must be an entirely new tumor and that tumors cannot upgrade ignores decades of cancer biology research.

The molecular features above are part of the reason tumors have a potential to evolve.

That's not theory. That's biology.

• A genomic study by Nurimen et al. analyzed DNA from 22 different tumor sites within two patients who had undergone radical prostatectomy and precisely mapped out how multiple prostate tumors in the same person originated from one rogue cell and evolved over several years.

• A 2013 study published in Cancer Research demonstrated that a small subset of Gleason 3 tumors can progress to Gleason 4 in a linear pattern of evolution, often driven by molecular features such as PTEN loss.

• A study by Bakbak et al. found that adjacent Gleason 3 and Gleason 5 patterns were often clonally related, meaning a pure Gleason 3+3 could represent an early stage of a lineage that can evolve into higher-grade disease.

Under the microscope. Gleason 3+3=6, also known as Grade Group 1(GG1) looks like cancer. It infiltrates local tissue and contains many of the same mutations found in higher-grade disease. Yet in practice it remains remarkably indolent in that pure GG1 almost never, if ever, metastasizes.

Across >17 000 contemporary radical-prostatectomy cases reread with modern criteria, not a single man whose entire gland contained only Gleason 3 cancer has developed nodal or distant metastases or died of the disease.

However, genomic testing shows that a minority of Gleason 3 foci can progress linearly to Gleason 4 by acquiring genomic aberrations such as biallelic PTEN loss.

More importantly, a biopsy revealing GG1 proves malignant transformation has occurred and does not exclude an unsampled higher-grade clone elsewhere in the prostate.

A new label won’t fix this because it risks creating complacency and slip-ups in active surveillance. Real progress will come when next-generation imaging and molecular profiling make the whole argument moot.

Using biomarkers to augment PSA and DRE

Attacking the Prostate-Specific Antigen (PSA) test and Digital Rectal Exam (DRE) as "wholly unreliable" disregards current diagnostic practices. No knowledgeable healthcare provider relies solely on these tests for diagnosis.

Clinicians following the National Comprehensive Cancer Network (NCCN) and American Urological Association (AUA) guidelines may use individual risk factors, mpMRI, and adjunct biomarkers to help decide who needs a biopsy and who doesn’t.

The authors reference "prostate cancer markers," saying there's no evidence that any of these markers "...are accurate enough to estimate which prostate cancers are potentially deadly or may become deadly so as to alter care."

However, a study published in European Urology showed that the four-kallikrein panel (used in the 4Kscore test) is accurate in predicting the long-term risk of prostate cancer death, particularly in men with an elevated PSA, where uncertainty is highest.

This level of accuracy enables practitioners to “alter care” decisions by reducing unnecessary biopsies.

Article claim:

“Amazingly, urologists' studies have concluded that at 12 years, 15 years and almost 20 years, radical prostate cancer surgery failed to save significant numbers of lives and had the same outcome as observation."

Evidence-based assessment:

To support this statement, the authors reference the Prostate Cancer Intervention versus Observation Trial (PIVOT) and the Prostate Testing for Cancer and Treatment (ProtecT) trial.

For the PIVOT trial, patient accrual occurred from 1994 to 2002, and for the ProtecT trial, patient accrual took place from 1999 to 2009. Both studies recruited men diagnosed using PSA testing and systematic, non-targeted TRUS-guided biopsies.

While these trials did accrue data over many years, their selection criteria and initial management strategies were based on the prevalent standards of their time.

Those standards differ significantly from current approaches that incorporate advanced imaging, targeted biopsies, and more refined risk stratification and active surveillance protocols.

It wasn't until the period between 2019 and 2023 that major international urological and cancer organizations incorporated multiparametric magnetic resonance imaging (mpMRI) into their guidelines for both the diagnosis and active surveillance of prostate cancer.

Today, when properly used, mpMRI acts as a critical filter. It improves the detection of clinically significant cancer (Gleason ≥3+4) and helps avoid the detection of insignificant cancer. A man with a high PSA and a negative (PI-RADS 1-2) MRI may avoid a biopsy altogether.

A man with a positive MRI (PI-RADS 4-5) will likely undergo a targeted biopsy, in conjunction with a systematic biopsy that is much more likely to find the aggressive cancer that benefits most from treatment.

Therefore, men recommended for surgery today represent higher-risk patients compared to those in the ProtectT and PIVOT trial populations.

Another issue to consider is that both trials included a very large proportion of men with low-risk disease.

• In the ProtecT trial, approximately 77% of participants had Gleason 6 cancer.

• In the PIVOT trial, after initial biopsy readings and a subsequent central pathological review, approximately 52% of men had Gleason scores of 6 or less.

It's no wonder the studies didn't show that treatment saved lives. The majority of men in both trials had cancer that was unlikely to be lethal.

These trials are not generalizable to today's clinical practice and cannot answer the modern question: After using mpMRI and biomarkers to filter out low-risk disease, does radical prostatectomy improve survival in men with well-characterized, clinically significant prostate cancer?

The authors failed to mention:

• An analysis of the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) clinical trial showed that for younger men (<65) and those with intermediate-risk disease, surgery provided a significant reduction in prostate cancer death.

• The ProtecT trial itself demonstrated that men who received treatment experienced a 50% relative risk reduction in cancer progression or metastasis compared to those on active monitoring. When translated to absolute risk reduction, the figure isn’t nearly as impressive, but:

  • While the ProtecT trial’s primary endpoint showed no significant difference in prostate-cancer–specific mortality at a median 15-year follow-up, radical treatment (surgery or radiotherapy) produced an absolute reduction of roughly 4.6–5 percentage points in the cumulative incidence of distant metastasis — a statistically significant secondary outcome (hazard ratio 0.47-0.48 vs active monitoring).

The purpose of active surveillance

The authors stated that "... there's no scientific evidence that active surveillance saves lives."

Their statement misrepresents the goal of active surveillance. Active surveillance aims to protect men from unnecessary treatment while monitoring the cancer for signs of progression. When that danger arises, that is the time to intervene.

Experienced and knowledgeable specialists, through consensus, design active surveillance protocols to detect signs of cancer progression at an early stage.

Large studies show that 5-year progression rates on active surveillance vary from 14% to 50%, depending on the specific criteria and monitoring intensity.

The most common cause of men transitioning off AS is a medical reason, either disease progression or recommendations from a doctor.

For those whose cancer does progress, timely treatment remains possible. When implemented correctly, active surveillance minimizes harm from overtreatment while preserving the option for curative therapy.

A dangerous rejection of modern medicine

In another interview, Howard Wolinsky asks, "Should men skip PSAs?" and Dr. Vorstman answers, "Absolutely."

There is no mention of caveats or exceptions.

Then Howard asks, "Should they not go on AS?" And Dr. Vorstman says, "Yes. Stop PSA testing and active surveillance."

Dr. Vorstman's reason? "There is no irrefutable and reproducible scientific evidence for safety or benefits - we're not saving significant numbers of lives."

I have some questions:

• What about the 47-year-old man whose father died of pancreatic cancer and his mother died of breast cancer, and he just found out he has a BRCA germline mutation? Should he get a PSA test?

• What about the 45-year-old African-American gentleman whose father died of prostate cancer in his fifties? Should he get a PSA test?

• What about the 53-year-old man on active surveillance whose last prostate biopsy showed an increase in Gleason pattern 4 from 10% to 20%, and his PI-RADS score increased from 2 to 3? Do you think he should stop active surveillance?

Should we disregard all individual risk factors because the science isn't yet perfect?

Medicine is the art and science of making the best possible decisions with the available data and tools rather than waiting for perfection while a disease progresses.

Patients want doctors who are savvy and innovative

The most savvy and innovative physicians work with what they've got and do their best to thread the needle for patients even when they know the science isn't yet optimal.

They combine individual risk factors with tests like PSA, mpMRI, PSA density, and liquid biomarkers to develop the most effective screening and management approach for each patient.

Professional guidelines incorporate risk stratification

A balanced assessment of the medical literature about prostate cancer supports a risk-stratified approach as recommended by the NCCN and AUA guidelines:

• Informed PSA-based screening based on individual risk factors.

• The use of adjunct biomarkers when appropriate.

• MRI-guided biopsy, when indicated.

• Active surveillance for Grade-Group 1 and many Grade-Group 2 tumors.

• Selective systemic therapy for higher-risk disease, when indicated.

Conclusion

I welcome critiques of medical overtreatment and inadequate screening measures. However, those critiques carry more weight if they are precise, like a scalpel, and not wielded like a sledgehammer.

Vorstman and Piana's article raises important points, but its sweeping generalizations risk creating unnecessary fear and confusion.

We must never lose sight of the man at the center of this journey, who faces a series of difficult decisions. The foundation for an informed choice is not based on outdated criticism, but accurate information rooted in modern clinical practice.

This means providing a clear understanding of today's rigorous, evidence-based guidelines from the NCCN and AUA. By delivering this information clearly, we effectively support the men who rely on our guidance, enabling them to make informed decisions about their next steps.

Until the next newsletter, I wish you good health and much love,

Keith

Multiparametric magnetic resonance imaging (mpMRI) is a special type of scan that combines several different imaging techniques to create detailed pictures of your prostate. It gives your healthcare provider both structural and functional information about your prostate.

This post mainly focuses on using mpMRI in prostate cancer detection and active surveillance.

Unlike regular MRIs, which take standard pictures, mpMRI uses multiple "parameters" or types of scans to gather more information.

• T1 and T2-weighted imaging show anatomy.

• Diffusion-weighted imaging shows how densely packed cells are.

• Dynamic contrast-enhanced imaging shows blood flow patterns.

These combined views help doctors identify suspicious areas that might contain cancer. The primary goal is to detect clinically significant prostate cancer, which is generally defined as Grade Group 2 (Gleason score 3+4=7) or higher, often with a tumor volume ≥0.5 mL or evidence of extraprostatic extension (EPE).

Importantly, mpMRI uses magnetic fields rather than radiation, so it doesn't increase the risk of developing other types of cancers.

When Is Multiparametric MRI Appropriate

The National Comprehensive Cancer Network (NCCN) and the American Urological Association (AUA) guidelines recommend mpMRI in several situations:

• If you have an elevated PSA level but a previous negative biopsy.

• Before a first prostate biopsy, to better target suspicious areas.

• For active surveillance of men with low-risk and favorable intermediate-risk prostate cancer.

• When deciding if you need a repeat biopsy.

• If your doctor suspects prostate cancer despite a normal or low PSA level.

Details from the guidelines

The AUA's 2023 guidelines on early prostate cancer detection say that clinicians may use mpMRI before an initial prostate biopsy to improve the detection of clinically significant cancer, more aggressive cancers that truly need treatment.

If the mpMRI shows something suspicious, the AUA recommends a targeted biopsy of that area, typically combined with a systematic biopsy. A systematic biopsy uses ultrasound guidance to sample the prostate in a grid-like pattern taking 10 to 12 cores from both lobes of the gland.

Combining mpMRI-targeted and systematic biopsies increases the detection of clinically significant cancer while reducing the chance of missing tumors not visualized by the MRI.

Suppose the mpMRI looks normal, but there are other signs that the risk is still high, such as a persistently high PSA or high PSA density. In that case, the guidelines advise not to rely on MRI alone, but recommend considering a systematic biopsy despite a normal mpMRI.

PSA density is calculated by dividing the PSA level by prostate volume as measured by MRI or transrectal ultrasound. The NCCN and AUA guidelines acknowledge that a PSA density >0.15 ng/mL/g suggests a higher cancer risk.

mpMRI may also be helpful for men who have had a prior negative biopsy but still have an elevated PSA or cancer suspicion. In such cases, the guidelines strongly recommend getting an mpMRI before doing another biopsy.

An mpMRI might show a lesion that the first biopsy missed. The AUA recommends an mpMRI for patients with a negative initial biopsy but ongoing suspicion. If the mpMRI shows a suspicious area, as indicated by a PI-RADS score of 3–5, a doctor can perform an mpMRI-targeted repeat biopsy.

This approach can yield clinically significant prostate cancer by avoiding another blind sampling of the prostate.

An abnormal digital rectal exam (DRE), like a lump, irregularity, or firmness felt on the prostate, is another trigger for an mpMRI in many cases. NCCN's early detection guidelines highlight the role of mpMRI, particularly for men with an elevated PSA or an abnormal DRE.

If your doctor recommends an mpMRI, they should discuss why with you. This could be to avoid an unnecessary procedure or ensure a biopsy is as accurate as possible.

Overall, an mpMRI is about personalizing prostate cancer screening. It helps zero in on clinically significant tumors and gives more peace of mind when results are normal.

Understanding the PI-RADS Reporting System

After your mpMRI, a radiologist will use the Prostate Imaging-Reporting and Data System (PI-RADS) to score any suspicious areas. This standardized 5-point scale helps doctors understand how likely an area is to contain clinically significant cancer.

The radiologist examines the multiple MRI sequences and gives each lesion a score from 1 to 5. The higher the score, the more likely that area is a clinically significant cancer, meaning a cancer that would likely need treatment.

Your doctor will use the PI-RADS score and other factors like your PSA level, PSA density, age, family history, and prior biopsy results to decide the next steps. In general:

• PI-RADS 4 or 5 lesions are considered suspicious for clinically significant prostate cancer and usually warrant a targeted biopsy.

• PI-RADS 1 or 2 lesions are considered unlikely to be cancer, and active monitoring may be appropriate, especially if other risk factors are low.

• PI-RADS 3 is indeterminate and may lead to biopsy depending on additional risk factors like PSA density or prior biopsy history.

For example, your report might say, "PI-RADS 5 lesion in the left apex," which tells the urologist that there's a very suspicious area at a specific location worthy of targeted biopsy. Or it might say, "PI-RADS 1 – no abnormal lesions," which indicates that nothing on the MRI raises concerns.

Limitations of Multiparametric MRI

While mpMRI is a powerful tool, it’s not perfect:

• Small tumors (less than 0.5 cm) may be missed.

• Studies show mpMRI can miss 10–15% of clinically significant cancers, particularly in the anterior or transition zones or smaller-volume lesions.

• Some aggressive cancers don’t form a clear mass or show restricted diffusion, making them hard to detect.

• Scan quality depends on the equipment: 3T MRI is preferred over 1.5T.

• Reader expertise matters: Interpretation can vary significantly between radiologists, especially for PI-RADS 3 lesions. Centers with experienced radiologists generally have higher diagnostic accuracy.

• False positives are possible, especially with inflammation, prostatitis, or benign nodules, which may lead to unnecessary biopsies.

• Not all men can undergo MRI, especially those with metal implants, severe claustrophobia, or advanced kidney disease.

• Insurance coverage varies, and out-of-pocket costs can be high.

It's important to remember that a "normal" mpMRI doesn't completely rule out cancer. It just means the radiologist didn't see any suspicious areas on the scan.

Multiparametric MRI may miss certain cancers

The PROMIS study, published in The Lancet in 2017, looked at the diagnostic accuracy of mpMRI compared to transrectal ultrasound-guided biopsy for detecting prostate cancer in men with clinical suspicion, before any biopsy.

The PROMIS study had a primary definition for clinically significant cancer as:

• Gleason score 4+3 = 7, OR

• A maximum cancer core length of 6 mm (of any Gleason grade).

The PROMIS results indicated a Negative Predictive Value (NPV) of 89% for mpMRI for this primary definition. This means that 11% (1 in 9) of men with a negative MRI were found to have clinically significant cancer.

When the study used a broader definition of clinically significant cancer—a Gleason score of 3 + 4 = 7 or a maximum cancer core length of 4 mm—28 % (roughly 1 in 4) of men with a negative MRI had a clinically significant cancer.

This study is a good reason why the guidelines recommend considering all risk factors and possibly using liquid biomarkers when deciding to perform a prostate biopsy, and not just relying on mpMRI results.

Multiparametric MRI can be pretty reliable

Other studies are more promising.

A pooled review of 21 studies covering almost 4,000 men showed that multiparametric MRI (mpMRI) guided by PI-RADS scores has a sensitivity of about 89 % and a specificity of about 73 % for detecting prostate cancer. This study shows that mpMRI finds roughly nine out of ten clinically significant cancers while limiting false alarms.

Another study of 207 men undergoing active surveillance underwent MRI-ultrasound fusion biopsy with a concurrent systematic biopsy. 14% of the men experienced pathologic upgrading of their tumor that was otherwise undetected by systematic biopsy.

A study of 85 men who initially qualified for active surveillance underwent mpMRI with MRI/Ultrasound fusion-guided prostate confirmatory biopsy. Adding mpMRI resulted in 29% of the men no longer meeting criteria for active surveillance.

In another study, 281 men qualified for active surveillance based on systematic ultrasound-guided prostate biopsy. Subsequent mpMRI-targeted biopsy resulted in 10% of the men no longer being eligible for active surveillance.

Variability in Radiologist Interpretation

The accuracy of mpMRI results depends partly on who reads your scan. Studies have shown that interpretation can vary between radiologists due to:

• Different levels of experience with prostate MRI.

• Subjective judgment in assigning PI-RADS scores.

• Variations in image quality between different MRI machines.

• Different medical centers use different protocols.

This variability is why it's beneficial to have your mpMRI interpreted by a radiologist with special training and experience in prostate imaging. Some medical centers now have dedicated "prostate MRI experts" who interpret these scans.

Studies have shown that the accuracy of mpMRI interpretation improves with the radiologist's experience and specialized training. Prostate cancer centers of excellence have radiologists with this experience and training.

Combining mpMRI with Liquid Biomarkers for Better Accuracy

To improve screening accuracy and avoid unnecessary biopsies, doctors are increasingly using mpMRI with biomarkers, including tests called liquid biomarkers, which I discussed in a prior newsletter. This approach creates a more complete picture of your prostate health.

Biomarkers, including liquid biomarkers, used in conjunction with mpMRI include:

• PSA density (PSA level divided by prostate volume measured on MRI)

• Free-to-total PSA ratio

• Prostate Health Index (PHI)

• 4Kscore test

• SelectMDx

• ExoDx urine tests

• PCA3 urine test

When these tests are combined with mpMRI results, doctors can better determine who needs a biopsy. For example, if your mpMRI shows a PI-RADS 3 lesion (intermediate suspicion), biomarker tests help decide whether you should proceed to biopsy or continue monitoring.

NCCN guidelines support a more comprehensive approach to detecting prostate cancer. Instead of relying on a single test, this “multiparametric” strategy combines different types of information to give a more accurate picture of a man’s risk.

What This Means for You

If your doctor recommends an mpMRI, it's a valuable tool that can provide important information about your prostate health. The test is most helpful when used as part of a comprehensive approach to prostate cancer detection, considering your PSA history, other biomarkers, family history, and overall health.

By combining mpMRI with other tests, your doctor is taking an intelligent approach that aims to find significant cancers while avoiding unnecessary procedures. Always talk with your doctor about how the results of your mpMRI influence their decisions about your care.

NCCN Position Regarding mpMRI:

• Recommends consideration before biopsy.

• Strongly recommend before repeat biopsy.

• Supports MRI-targeted fusion biopsy approach.

AUA Position Regarding mpMRI:

• Acknowledges utility but takes a slightly more conservative stance.

• Recommends consideration, particularly for men with prior negative biopsy.

• Less prescriptive about routine pre-biopsy MRI for initial evaluation.

Questions to Ask Your Provider

1. What is my PSA density and PI-RADS score on my mpMRI, and what do they mean?

2. Would an mpMRI of my prostate be appropriate at this stage?

3. Would additional blood or urine biomarker tests, like PHI or 4Kscore, help clarify whether I need a biopsy?

4. Could imaging, such as an mpMRI, be combined with these biomarker tests to improve accuracy?

5. How much experience does the radiologist who read my prostate MRI have with these specific types of scans, and do they have any special qualifications for interpreting them?

Conclusion

As a physician who believes in patient empowerment, I encourage you to have meaningful conversations with your healthcare provider. Ask about your PSA density, PI-RADS score, and whether additional biomarker tests might help clarify your situation. Your prostate health journey should be personalized to your specific circumstances, risk factors, and concerns.

The future of prostate cancer detection and active surveillance lies not just in better technology but also in more innovative and individualized approaches that find dangerous cancers that need treatment while sparing men from unnecessary procedures.

mpMRI is an important step in that direction, but it still requires the skilled interpretation and judgment of experienced healthcare professionals.

Until the next newsletter, stay healthy.

Much love,

Keith

It had been six months since my last prostate-specific antigen (PSA) level, and I knew it was time for another set of labs. I arranged to have them done at my radiation oncologist's office. As the day of the blood draw drew near, I started feeling that low-grade anxiousness I call PSAnxiety.

I try not to let the anxiety build by reminding myself that I feel fine. I've been having fantastic gym workouts, which is how I grade my overall health.

Still, anxious thoughts crept in. What if my PSA had doubled? Will I do another positron-emission tomography (PET) contrasted tomography (CT) scan after I get my lab results?

Radiation exposure

I’d just read the study published in JAMA Internal Medicine reporting that 103,000 lifetime cancers are expected to result from CT scans performed in 2023. The most frequent types projected are lung cancer, colon cancer, leukemia, bladder cancer, and, in women, breast cancer.

I have had so many CT scans that I’ve honestly lost count. From the first CT scan in January 2018 as part of a cancer staging protocol to my last PET scan in October 2024, I’d estimate I’ve had ten CT scans.

That doesn’t count the numerous planning CT scans for my radiation therapy from August to November 2018, and for proton therapy from January to February 2023. With all the radiation I’ve absorbed, I could probably light up a small city.

PSA results

On Friday, I drove to my radiation oncologist’s office after work and had my blood drawn. I was already scheduled to meet with my favorite nurse practitioner, Katrina, on Tuesday to discuss the results.

I got through the weekend okay, but when Monday rolled around, the anxiousness started creeping in again. Since I knew the anxiousness was mainly about me not knowing the results, I emailed Katrina on Monday afternoon, asking her to send me a copy of the labs, and told her I’d see her in the morning.

My last PSA on February 4, 2025, was 369.14, reflecting a doubling time of 9 months.

Please, God, don’t let it be much higher than that.

Within an hour, I got a notification on my phone that her office staff had emailed me. My heart started racing as I opened the email and clicked the secure link to access my labs.

I clicked on the PDF containing my labs and slowly started scrolling down. I first saw a comprehensive metabolic panel with normal liver enzymes (no liver metastases), including a low normal alkaline phosphatase (ALP), which can be high with bone metastases.

The second thing I saw was a normal complete blood cell count, which can be low with metastatic bone marrow infiltration.

I slowed my scrolling, unsure if I really wanted to see the PSA.

316.33. What? At first, I didn’t realize it had dropped, probably because I was so used to seeing my PSA go up each time. Then I looked at it again and realized it had fallen 52.81 points! Thank God!

It’s so strange to be in shock, preparing for bad news, and then seeing good news but not feeling like it was good news. I don’t know how to describe it other than it literally took about an hour to kick in that my PSA had dropped 53 points. Then I started feeling happy about it.

When I told Mike the results when he got home from work and saw the look of incredible happiness on his face, I began to feel ecstatic. It was very strange how my emotions rolled out over time like that.

The next day, I met with Katrina and discussed the results. She had already addressed my labs with Dr. Stroud and Dr. Ackerman. She said Dr. Ackerman had immediately asked her what I was doing, and she told him she didn’t know yet.

We laughed, and then I told her what I had been doing differently - the new drug and supplement regimen I was on. I told her I would increase the doses and see them again in three months with labs.

As I was writing this part, I looked up at the clock and it was 2:22. Since I work with angels in my spiritual life, I looked up Angel Number 222 and it says:

“Number 222 concerns balance and manifesting miracles. The message is to keep the faith and stand strong in your personal truths. Angel Number 222 also reminds you to keep up the good work you are doing, as the evidence of your manifestations is coming to fruition.”

The hard part

I know I promised I’d tell you the new regimen I’m taking if my PSA dropped, and it did. But I’m nervous about telling over 1,000 people what I’m taking. That’s because I’m very science-oriented when it comes to medicine.

Yes, I believe in Functional Medicine and angels, but my core is deeply rooted in science. Yet, I also recognize that science doesn't hold all the answers. My belief stems from the tangible impact these experiences have had on my life, which is my truth.

Some doctors are touting drugs in this regimen as the cancer cure we have all been looking for. And even though my PSA dropped more than fifty points taking them, I want to be cautious and not seem like I’m promoting a panacea for cancer.

Correlation does not establish causation. Could this current PSA be a lab error? It’s possible, but unlikely. Could this current PSA be lower because my testosterone level is lower? It’s possible, but unlikely, given that my workouts are as strong as ever and I’m not taking anything that would lower my testosterone.

My last testosterone level was 870 on December 10, 2023.

What could be the cause of this PSA drop? The new regimen may be working.

Could it be a placebo effect? I’m not sure. I have taken these drugs before, but not together, and not in unison with this specific protocol I’m on. And my PSA didn’t drop then.

The placebo effect often requires prior exposure to a drug or therapy for the body to learn a physiologic response. But, open-label studies in which people know they are taking a placebo have been effective, such as with irritable bowel syndrome, chronic low back pain, and migraine headaches.

Studies show there is a placebo effect inherent in every therapeutic encounter and in every medication we take. To date, no placebo-controlled study has demonstrated the ability to lower a cancer tumor marker like PSA. If such an effect exists, it would challenge many current assumptions in oncology. Are scientists ready for that? I’d say, probably not.

So, what do I think caused my PSA to drop? As always with the human body, I’d say a combination of many things, possibly including this most recent regimen.

Everything I’ve done thus far on this cancer journey - every prayer, affirmation, alternative therapy, and traditional therapy. Also, the multitude of things I’ve done to make my body less favorable to letting cancer take hold - drinking a liter of green tea daily, regular juicing and detoxification shakes, the variety of supplements I’ve taken and continue to take to shore up my body’s systems, regular exercise, and most importantly, a positive mindset.

If I could take a survey of five hundred doctors who work with prostate cancer patients and ask them if they ever treated a patient whose PSA went from 63 to 369 with no signs or symptoms of prostate cancer, and had three normal PET scans in a row. I’d bet their answer would be “no.”

I am an enigma, and am this way because of everything I believe and do to stay this way.

A warning

So, as I reveal this regimen, I do so with a word of caution for my readers. Please do not assume that this regimen is effectively treating the prostate cancer and thus lowering my PSA. While that could be so, nothing I write about here proves this.

I say that because there is the risk that someone could misinterpret what I’m writing here as a cure for prostate cancer, and then take the same regimen and harm themself. This regimen is risky, especially for someone who is already very ill and on multiple other medications.

This regimen has drugs and substances in it that can have dangerous side effects when combined with other medications. Please discuss this regimen with your doctor if you are considering taking it, and don’t go out on your own and start taking it.

Strangely, these drugs and substances can be obtained on the internet without a doctor’s prescription. That is the world we live in today. And this is why I’m so cautious about revealing the regimen.

But I have been candid and transparent with you since I started writing this Substack. Some would say to a fault. TMI! I’ve told you everything I’ve done on this prostate cancer journey and will continue to do so.

The origin of the regimen

I had seen some of the drugs in this regimen on the internet and briefly subscribed to a doctor’s Substack who touts this medicine as a potential cure for cancer. I read many of his “case examples” and wasn’t impressed, from a scientific standpoint, by any of them.

In the vast majority of the case examples, people were concomitantly on proven anticancer drugs or therapies, or had recently stopped them. In other case examples, there wasn’t enough detail to know exactly what else the patient was taking or the timing of the traditional and alternative therapies.

I’m all for people having choices, especially when their lives are on the line, but we must use caution when experimenting with potentially harmful medications and substances.

I’m not naming this doctor because I don’t want minions of keyboard warriors coming after me as if I’ve said or done something wrong. I’m as open-minded as the next person, but people can lose their ability to think critically when highly passionate about something.

I had discussed some of those case examples with my friend and physician, Dr. Kessler. He told me his friend from medical school was practicing in Arizona and using these medications to treat his cancer patients. He offered to arrange a three-way Zoom call for us to hear about what Dr. X is using with his cancer patients.

Dr. X came across as very intelligent and compassionate. I immediately liked him. He told me he hadn’t heard of the doctor I had mentioned earlier.

He had developed his regimen based on years of practice and research, and as he noted what other physicians were using in their integrative oncology practices. He then created a “best of” regimen for his cancer patients.

He told me about several successful case examples of using these drugs in various cancers, including prostate cancer.

In addition, Dr. X had been an advocate for Ivermectin during the COVID-19 pandemic and told me some pretty impressive statistics about his COVID-19 patients. I didn’t get the impression he was exaggerating.

The regimen

Here is Dr. X’s regimen:

• Ivermectin 0.4-2 mg/kg/day

• Fenbendazole 500 mg seven days on/seven days off

• B17 500 mg daily

• Methylene Blue 12 mg twice daily

On February 13, 2025, I began the following regimen:

• Ivermectin 34 mg three capsules daily on an empty stomach in the morning.

• Fenbendazole 500 mg one capsule Monday, Wednesday, Friday

• Methylene Blue 12 mg one capsule twice daily

I also increased my melatonin from 140mg to 200 mg at bedtime. Melatonin is not FDA approved to treat any medical condition.

[Update to this post: Taking 200mg of melatonin disrupted my sleep, and I dropped the dose to 160 mg, which is my sweet spot.]

I continue to take CuraMed 750mg (curcumin) two capsules three times a day with meals. If I'm fully absorbing it, this supplies me with 3 grams of pure curcuminoids daily. CuraMed (curcumin) is not FDA approved to treat any medical condition.

I’m no longer taking itraconazole or valacyclovir.

I am getting the ivermectin from a compounding pharmacy and the others from various internet sources, including Amazon.com.

Risks of this regimen

All drugs and supplements come with risks. Click on the links to learn more about the potential side effects of taking these drugs.

I decided not to take B17 (amygdalin) after reading about potential side effects, including cyanide toxicity. Ivermectin is not FDA-approved for treating cancer, and fenbendazole is not FDA-approved for treating human diseases, but is used to treat animal parasites. Both have the potential for dangerous side effects, especially at higher doses.

Methylene blue as an intravenous formulation is FDA approved to treat a limited number of conditions and has a multitude of potential drug interactions as it is a monoamine oxidase inhibitor, which can cause a dangerous serotonin syndrome in people also taking antidepressants and opioids.

Oral methylene blue is not FDA approved to treat any condition. In addition, methylene blue is contraindicated in individuals with a common inherited enzyme deficiency, G6PD deficiency, due to the risk of hemolytic anemia and methemoglobinemia.

Ironically, intravenous methylene blue is FDA approved to treat methemoglobinemia, but in people with G6PD deficiency, it can paradoxically worsen the condition by inducing hemolysis (breakdown of red blood cells) and oxidative stress.

Methylene blue is thought to act as an electron carrier within the mitochondria's electron transport chain, generating ATP, the cell's primary energy currency. By potentially improving electron flow, methylene blue may enhance energy production and reduce the generation of reactive oxygen species, unstable molecules that can cause cellular damage (oxidative stress).

Why would I do this?

Why would I take these medications when there are no clinical trials that show efficacy in prostate cancer? I decided to take this regimen because I've run out of options.

I will not retake any testosterone blocker or inhibitor because of the terrible quality of life I had when I did do that. Chemotherapy has never been proven to offer any long-term benefit in men not on androgen deprivation therapy (ADT) or androgen -signalling inhibitors.

I’ve endured eight weeks of intensity-modulated radiation therapy to my pelvis and five weeks of proton therapy to my peri-aortic lymphatic chain. Those radiation treatments have resulted in long-term side effects, which I choose not to discuss because they are too personal.

Based on my last three PET scans showing no evidence of disease despite a PSA over 300, the prostate cancer has lost all PSMA expression, so I’m not a candidate for PSMA radioligand therapy, even if I wanted to go to Germany for off-label treatment.

After my last proton therapy, my PSA continued to climb, doubling every nine months. In my mind, I had nothing to lose starting these medications because if I didn't do something, the cancer would eventually manifest in detectable tumors in my body, and at some point, kill me.

So, it is literally an act of desperation for me to take ivermectin and fenbendazole.

But I’m glad I did, because based on the drop in my PSA, this regimen may be helping me. Either that or I just experienced a statistically unlikely drop in my PSA after over seven years of a rising PSA with a fairly rapid doubling time.

If my PSA continues to drop on this regimen, and especially if the cancer goes into remission, I will write it up as a case study and submit it for publication in a peer-reviewed journal. Whether it would be accepted is not in my control.

Doctors and scientists want “proof” from a scientific perspective. Sometimes people forget that not everything can be proven by the scientific method. Examples include the many documented cases of spontaneous remission of cancer:

Lung cancer

Colon cancer

Multiple types of cancers

Disclaimer

While preclinical research has shown some intriguing anti-cancer properties of drugs like ivermectin and fenbendazole, there is currently no high-quality clinical evidence proving their safety or effectiveness in the treatment of cancer. As such, any claims suggesting that these drugs are effective cancer therapies are not supported by randomized controlled trials or regulatory approval.

This Substack is intended solely for educational and informational purposes. It is not medical advice, nor is it a recommendation for any specific treatment. I do not endorse or advise the use of any drug or supplement discussed here, including those I may personally choose to take. Always make medical decisions in consultation with a qualified healthcare professional.

I’m encouraged

So, the plan is set. I’m increasing the dose of ivermectin and adopting the seven-on/seven-off fenbendazole cycle. As always, this decision comes after careful consideration, research, and weighing the potential risks and benefits for me.

While correlation isn't causation, this result inspires me to continue integrating evidence-based medicine with complementary experimental approaches. As always, I pay unwavering attention to my mental and spiritual well-being.

The real test, of course, lies ahead with the next set of labs in three months. I remain committed to transparently sharing my experiences.

Until next newsletter, I wish you good health and much love.

Keith

What if there was another way to understand what's really going on inside your body, something other than PSA alone?

There is.

It's called liquid biomarker testing, and it's changing the way we think about prostate cancer screening.

Why just a PSA isn't enough anymore

PSA (prostate-specific antigen) is a protein made by the prostate. When it is high, it may mean prostate cancer. However, it can also be high due to benign conditions like an enlarged prostate (BPH) or an inflamed prostate (prostatitis).

Most men with an elevated PSA don't have clinically significant prostate cancer — the kind that actually needs treatment. So, while PSA is a helpful starting point, it lacks precision.

That's where liquid biomarkers come in. These blood or urine tests add detail to the PSA picture, helping to answer whether we need to act right now or can safely wait and watch.

What the guidelines say

Both the National Comprehensive Cancer Network (NCCN) and the American Urological Association (AUA) recognize the value of using multiparametric magnetic resonance imaging (mpMRI) or a validated biomarker, and sometimes both, to refine biopsy decisions.

So, how does this look in practice?

• Step 1: PSA is high.

• Step 2: A biomarker may be ordered before any biopsy, specifically when MRI access is limited or the MRI results are equivocal.

• Step 3: If either a liquid biomarker or mpMRI shows high risk or if both are borderline, you might then proceed to biopsy.

Some experts argue for a liquid biomarker-first approach, especially in men with PSA in the gray zone (2–10 ng/mL), to reduce anxiety and avoid an unnecessary MRI or biopsy.

Others favor doing an mpMRI first, especially in practices with easy MRI access or in men with prior biopsies. The reality? There's no one-size-fits-all. What matters most is combining these tools thoughtfully to personalize your care.

A Simplified Approach

For the average urologist, probably the most straightforward approach is:

1. Obtain a detailed family history to help stratify risk for prostate cancer. Consider discussing germline testing in men with high‑risk family history per NCCN.

2. Always repeat the PSA after considering any factors that may have caused or contributed to the high reading.

3. Wait an appropriate amount of time before repeating PSA testing.

4. Always add a percent-free PSA with repeat PSA testing. Lower is better, with a 25% or less cutoff of free PSA recommended for patients with PSA values between 4.0 and 10.0 ng/mL.

5. If the PSA remains high, obtain a mpMRI of the prostate and ensure the radiologist calculates the PSA density by dividing the PSA level by prostate volume. A PSA density >0.15 ng/mL/g suggests a higher cancer risk.

By this point, most urologists will have enough information to help patients make informed decisions about whether to proceed with a prostate biopsy. If there is still a question of whether to biopsy, that's the time to consider using NCCN-recommended liquid (blood or urine) biomarkers.

Access Isn't Universal

One challenge is that not every physician is familiar with all these tests. Clinicians often learn about them through industry reps, conferences, or continuing education courses.

That means they might feel confident using just one or two tests they've worked with before. In addition, insurance coverage varies widely.

Some insurers cover tests like the PHI or 4Kscore. Others may not, or require prior authorization or documentation that the test will change management.

That's why having an open conversation with your treating physician is crucial. You may find that the test you're most interested in isn't accessible, but a similar one is. What matters most is that the test is used in the proper context to guide thoughtful, personalized decisions.

Conclusion

An elevated PSA is just the opening bell. Liquid biomarkers and, where available, mpMRI let you target biopsies at cancers that matter, spare men from unnecessary procedures, and bring genuine precision to prostate cancer screening.

If your doctor hasn’t mentioned liquid biomarkers or an mpMRI, ask about them. The conversation may be the difference between an unnecessary biopsy and the early detection of a cancer that deserves immediate attention.

Understanding your options helps you make better-informed decisions, which is always good.

Until the next one, I hope you stay healthy.

And much love,

Keith

References:

• Kawada et al. "Diagnostic Accuracy of Liquid Biomarkers for Clinically Significant Prostate Cancer Detection: A Systematic Review." European Urology Oncology, 2024​

• NCCN Clinical Practice Guidelines in Oncology – Prostate Cancer, Version 4.2024​

• Liu et al. "Liquid Biomarkers in Prostate Cancer Diagnosis." World Journal of Men's Health, 2025​

• Vickers & Lilja. "Five Things You Need to Know About Prostate Cancer Diagnostic Tests." Asian Journal of Urology, 2024​

Disclaimer: This post is for informational purposes only and does not constitute medical advice. Always consult with your healthcare provider for any health concerns or before making any decisions related to your health or treatment.

Many in the U.S. hailed this targeted radioligand therapy as revolutionary, promising a new weapon in the fight against mCRPC.

Germany a step ahead of the U.S.

As is sometimes the case in medical therapies, the U.S. was several years behind Europe regarding PSMA radioligand therapy. Germany had widely adopted PSMA radioligand therapy for mCRPC as early as 2013 under a compassionate use program. Before its approval in the U.S. in 2022, some American men with mCRPC were traveling to Germany and paying cash for treatment.

In some instances, German physicians are also using it to treat metastatic castrate-sensitive prostate cancer (mCSPC), including men from the U.S. who pay cash for treatment. It is only FDA-approved for mCRPC, and no clinics in the U.S. are using it, outside of clinical trials, to treat mCSPC.

Prostate-specific membrane antigen (PSMA)

PSMA stands for prostate-specific membrane antigen, which is a misnomer. This protein also exists on the cell surface of other cancers and some healthy tissues, such as the salivary glands and small intestine. However, it is found on prostate cancer cells and not on healthy prostate cells.

Yes, its name makes things confusing. However, it is a reliable marker for prostate cancer cells in that 90% of prostate cancer cells, both CSPC and CRPC express it.

PSMA radioligand therapy is part of a theranostics system. The diagnostic part is the PSMA positron emission tomography (PET) scan, and the therapeutic part is the PSMA radioligand therapy (Pluvicto). The PSMA PET scan detects the expression of PSMA on prostate cancer cells, and Pluvicto treats it.

Precision radiation

Pluvicto is a precision type of radiation in which a radioisotope is injected into the bloodstream. The radioisotope then locates and binds to the PSMA antigen on the prostate cancer cell surface.

Once the radioisotope binds to the cell surface antigen, it releases a two-millimeter radiation burst, killing the tumor cell. It's such a small burst of radiation that it tends to spare healthy tissue, unlike typical radiation therapy.

However, despite such a small burst of radioactivity, collateral damage can occur to healthy tissue. Because the salivary glands express PSMA, their damage can result in a dry mouth, which is rarely severe and permanent.

Patients with extensive bone metastases, especially those with prior chemotherapy, can develop bone marrow suppression with low red blood cells (anemia), low platelets (thrombocytopenia), and low white blood cells (neutropenia).

Yet another example of how Germany outshines the U.S. is using prophylactic ice packs on the salivary glands to induce vasoconstriction, reducing blood flow and PSMA ligand uptake in the salivary glands, thereby lowering radiation exposure.

In Germany, a low-cost ice pack applied to the salivary glands during PSMA-radioligand therapy is the standard of care due to observational data and real-world evidence of its effectiveness.

Infuriatingly, most clinics in the U.S. don't bother using ice packs during treatment to prevent dry mouth. Why? Because no one in the U.S. has done a U.S. phase 3 clinical trial to prove it works. Ridiculous! Just look at the data from Germany.

So, if you are a patient in the U.S. getting Pluvicto, bring your own ice packs to help avoid getting dry mouth!

The VISION trial

Speaking of infuriating, let's discuss the phase 3 VISION trial that got Pluvicto approved in the U.S.

The study showed that Pluvicto when added to standard care, did indeed help men live longer than standard care alone. Success!

But here's where we need to put on our critical thinking caps.

What did "living longer" actually mean in the trial that paved the way for Pluvicto's approval? The VISION trial showed Pluvicto extended median overall survival by four months, meaning the midpoint of survival was extended—but this still reflects a grim prognosis for many participants.

Let me be clear. In the face of mCRPC, any extension of life is precious. For the men and families receiving that extra time, it's invaluable.

Pluvicto also demonstrated benefits in delaying disease progression and improving quality of life, which are hugely important. It represents real, tangible progress and a valuable addition to treatment options for mCRPC.

A critical look

But let's step back from the initial celebratory fireworks. Did a four-month median overall survival advantage live up to the 'game-changer' narrative often given to new therapies?

This isn't just about Pluvicto. It's about a broader pattern I see time and again in the development of treatments for heavily pre-treated men with mCRPC.

Honestly, achieving big leaps in survival at this late stage of the disease is incredibly difficult. By the time men qualified for the VISION trial, their cancer had already outsmarted multiple lines of therapy, including androgen deprivation therapy (ADT), potent androgen receptor pathway inhibitors (ARPIs), and taxane-based chemotherapy.

Their disease was, by definition, highly resistant. So, maybe the 'secret' isn't that Pluvicto's benefit was only four months, but rather that achieving even that much is a significant accomplishment in such a challenging setting.

The surprise might be less about the result and more about how it contrasts with the hope and hype often surrounding new drug approvals. Is it possible that we, as patients, physicians, and observers, sometimes set high expectations only to feel let down by the current reality of mCRPC research? I admit that I do.

Looking at other therapies approved for mCRPC, you'll see a similar pattern - relatively low median overall survival benefits.

I still have high hopes for Pluvicto and am looking forward to seeing what it can do in clinical trials involving men with castrate-sensitive prostate cancer.

VISION’s unethical trial design

While I'm disappointed in the VISION trial's results, I'm very unhappy with its design. Here's why.

The VISION trial's control arm (standard-care therapies) was poorly designed and limited the use of pharmaceuticals with a survival benefit. In other words, it allowed suboptimal treatment options.

This was a disservice to the men in the control arm, who might otherwise have received the real standard of care outside this clinical trial. Some might say it was malpractice.

For example, 50% of men in the control arm were eligible for cabazitaxel, which showed a survival benefit over androgen receptor pathway inhibitors (ARPIs) in the CARD trial. But they couldn't get it because of the VISION trial rules.

Nor could men in the control arm with only bone metastases get systemic radioisotopes like radium-223, which has shown a median overall survival of 15 months.

In addition, 55% of men in the control group had already received one ARPI, and 39% had already received two. This significantly limits hormone therapy options in the control group because the clinical efficacy of switching one ARPI to another is not very good at all.

A control group should always get therapies that are the prevailing standard of care, and in the VISION trial, men in the control group did not receive the prevailing standard of care. That is unethical.

In addition, this phenomenon of a suboptimal control arm is widespread in pharmaceutical-sponsored clinical trials. Why? Poorly designed control arms that don't allow life-prolonging therapies potentially make the study (drug) look better than it is.

The VISION trial designers tried to rationalize excluding certain treatments by saying that the safety profile of these therapies had not been established with Lu-PSMA-617. However, that is no excuse for designating a terrible control arm. They could have allowed men in the control arm to receive cabazitaxel.

High rate of dropout in the control arm

If I were enrolled in a clinical trial that prevented me from taking a standard of care therapy that has the potential to prolong my life, I would be angry and drop out of the study. And that appears to have happened in the VISION trial.

After the trial started, the control group had an extremely high incidence of withdrawal—56%—mainly attributed to patient disappointment. This is an example of cutting off data too early in the control group, which messes up the trial results and makes later measurements less trustworthy.

When the trial designers saw this, they implemented “trial-site education measures” to reduce the incidence of withdrawal—basically, they convinced patients to stay in a poorly designed control arm. That is simply wrong.

I've discussed poorly designed clinical trials with suboptimal control arms before. Please read that Substack post if you haven't already done so. It is eye-opening.

Conclusion

Even modest survival gains are meaningful in clinical trials involving heavily pre-treated men with mCRPC. Still, these gains should not be overhyped or come at the cost of ethical compromise in trial design.

Men with mCRPC considering enrolling in a clinical trial should understand the importance of an ethical control arm. Even if you consult with a physician at a prostate cancer center of excellence, sometimes these physicians are biased, especially if their center participates in the clinical trial.

Until the next one, I hope you stay healthy.

Much love,

Keith

However, just because your data isn't being used for training doesn't automatically mean it's confidential. In the regular version of NotebookLM, it's possible for others to see your information in some situations.

Avoid giving feedback.

• If you click the thumbs up or thumbs down on a response, you are choosing to provide feedback.

• Google's privacy policy says human reviewers may look at your questions, uploads, and the AI's responses if you provide feedback.

• If you want to prevent this, don't click the feedback buttons

It's crucial to read the privacy policy to understand exactly how your data is handled and decide if you are comfortable with it.

With NotebookLM, you can have up to 100 notebooks, each containing up to 50 sources. Each of those sources can be up to 500,000 words long. All users start with up to fifty chat queries and three audio (podcast) generations per day. Let me know in the comments if you’d like more videos like this.

Correction: I called the National Cancer Comprehensive Cancer Network in this video the National Cancer Center Network. Whoops:-))

Until the next one, stay healthy.

Much love,

Keith

Today’s newsletter is exclusively for paid subscribers, and as a thank you, I’m offering you free access to my Udemy.com course.

Read more

Before we tackle today’s topic, I’m letting you all know that I’ve decided to stop accepting paid subscriptions. This means that if you are on a monthly paid subscription plan, Substack will no longer charge your account. If you‘ve already paid in full, thank you! I sincerely appreciate those of you who chose to become paid subscribers.

I’m stopping because Substack’s payment processor does not automatically remit state tax payments or Value-Added Tax (VAT) to other countries when a subscriber becomes a paid subscriber. Because Substack doesn’t do this like other content creator platforms like Patreon or Etsy, it puts the onus on Substack writers to collect and remit state and VAT for paid subscriptions.

That can get extremely complicated, and I choose not to add that to my plate.

All subscribers will continue to receive Prostate Cancer Secrets newsletters, whether paid or not. I plan to sell ebooks about various prostate cancer topics eventually and will use my newsletter to inform subscribers about their availability.

In the meantime, continue to enjoy my newsletters.

Introduction

I chose today’s topic when I researched the guidelines for testosterone replacement therapy (TRT) in men with a history of prostate cancer and was pleasantly surprised by what I found.

When I was in med school and residency, this was forbidden territory - we wouldn't even consider it. The conventional wisdom was absolute: testosterone would fuel any existing cancer cells like throwing gasoline on embers.

Now? The evidence has pushed us to rethink everything. It’s these types of fundamental shifts in medicine that consistently renew my commitment to advancing medical education

In addition, based on this emerging evidence, the 2018 American Urological Association guidelines provide cautious yet evolving recommendations, which I’ll detail later in this article.

Testosterone replacement in men on active surveillance

Active surveillance (AS) is the standard of care for monitoring low-grade, low and intermediate-risk localized prostate cancer. The goal of AS is to monitor for possible progression while preventing or delaying therapy with inherent side effects.

Several retrospective studies have examined the safety of TRT in AS:

• Morgentaler et al. (2011): This study followed 13 men with prostate cancer on active surveillance who received TRT. The median follow-up period was approximately 30 months. Twelve men had low-risk disease, and one had intermediate-risk prostate cancer. All men had a follow-up biopsy as a part of their protocol, and no upgrading or prostate cancer progression was reported.

• Kacker et al. (2015): A retrospective study of prostate cancer progression rates in testosterone-deficient men on active surveillance. There were 28 men in the treatment arm and 96 men in the control arm who went untreated. Biopsy proven progression rates were similar between both groups over a 3-year follow-up period.

• Ory et al. (2016): A retrospective study examined eight men on active surveillance with low-volume Gleason 6 who received TRT for a median of 27 months. Six of the eight men had follow-up biopsies. None of the eight showed clinical or pathologic progression, and none moved on to definitive treatment.

• Kaplan‐Marans et al. (2024): A retrospective study of men with prostate cancer on active surveillance comparing 167 patients receiving testosterone therapy with 6658 patients not receiving testosterone. The median follow-up was 5.2 years for the testosterone group and 4.7 years for the no-testosterone group. There were 28 (17%) conversions to active treatment in the testosterone group and 1455 (22%) in the no-testosterone group. There were no prostate cancer-specific deaths in the testosterone group compared to 39 (0.6%) prostate cancer-specific deaths in the no-testosterone group.

• Applewhite et al. (2025): This recent retrospective analysis involved 43 men on active surveillance. With follow-up periods of 44.3 and 79.5 months, the study found stable PSA levels and similar progression rates compared to the general AS population.

TRT in men previously treated for prostate cancer

In men who have undergone treatment for prostate cancer, the decision to initiate TRT for testosterone deficiency is complex.

Studies that have examined the safety of TRT in men treated for prostate cancer:

• Pastuszak et al. (2013): This retrospective study evaluated the safety of transdermal TRT in 103 hypogonadal men who had undergone radical prostatectomy for prostate cancer, comparing them with 49 non-hypogonadal men post-surgery. Over a median follow-up of 27.5 months, the testosterone-treated group experienced a modest rise in PSA. However, these PSA changes were not consistent with cancer recurrence, and the rate of biochemical recurrence was lower in the treatment group, even among those with high-risk disease.

• Kaplan et al. (2016): A literature review of multiple studies reported that TRT in men with a history of prostate cancer did not lead to higher recurrence rates or worse oncologic outcomes.

• Ory et al. 2016: A retrospective analysis of TRT-treated men observed no biochemical recurrence in 22 men treated with radical prostatectomy, although 3 of 50 (6%) treated with radiation therapy experienced biochemical recurrence. Of those, two were high-risk patients, and one was intermediate risk.

• Jones and Snyder (2023): A retrospective study of 16 men who were testosterone deficient before radical prostatectomy for organ-confined disease and resumed TRT after surgery. There was no biochemical recurrence during a median follow-up of five years.

Limitations of these TRT studies in men with a history of prostate cancer:

While these studies are promising, it is crucial to keep in mind their limitations:

• Retrospective studies generate hypotheses; prospective randomized controlled trials would be needed to confirm the results.

• Active surveillance protocols used by different providers may vary, affecting the study groups' comparability.

• Many lacked data such as testosterone serum levels, testosterone dosage, and treatment indications.

• Lack of randomization can introduce bias and limit the studies’ viability.

• Many of the studies had small sample sizes, which can undermine the validity of the results.

In addition, the lack of robust data in these studies reflects the most recent American Urological Association and European Association of Urology guidelines reporting:

There is insufficient evidence to determine the risk-benefit ratio of testosterone therapy for men with a history of prostate cancer.

A paradigm shift

Despite the lack of robust data to support the use of TRT in hypogonadal men with a history of prostate cancer, modern data also doesn’t suggest that TRT contributes to the development of prostate cancer. The American Urological Association guidelines go as far to say:

Clinicians should inform patients of the absence of evidence linking testosterone therapy to the development of prostate cancer. (Strong Recommendation; Evidence Level: Grade B)

The 2018 American Urologic Association guidelines offer insight and guidance for the treatment of men with a history of prostate cancer.

Patients with testosterone deficiency and a history of prostate cancer should be informed that there is inadequate evidence to quantify the risk-benefit ratio of testosterone therapy. (Expert Opinion)

“It is the opinion of this Panel that the decision to commence testosterone therapy in men with in-situ prostate cancer on active surveillance or previously treated prostate cancer is a negotiated decision based on the perceived potential benefit of treatment weighed against the limited knowledge of potential risks.”

Post-radical prostatectomy

“Testosterone therapy can be considered in men who have undergone radical prostatectomy with favorable pathology (e.g., negative margins, negative seminal vesicles, negative lymph nodes), and who have undetectable PSA postoperatively.”

Radiation therapy

“Available studies evaluating the safety of testosterone therapy in men treated with RT have suggested that after RT patients (with or without a history of androgen deprivation therapy) do not experience recurrence or progression of prostate cancer and experienced either a steady decline in PSA values to <0.1 ng/mL or had non-significant changes in PSA.”

Active surveillance

“There are limited data on men on active surveillance who are candidates for testosterone therapy. Available literature indicate that patients with and without high-grade prostatic intraepithelial neoplasias who were on testosterone therapy did not experience significant increases in PSA or subsequent cancer diagnosis compared to men not receiving testosterone.”

Patient Selection

Ideal candidates for TRT are those with:

• Favorable pathology: Organ-confined disease, negative surgical margins, and undetectable PSA levels post-treatment.

• Significant symptom burden: Patients experiencing severe hypogonadal symptoms - fatigue, reduced libido, erectile dysfunction - refractory to lifestyle modifications.

• Informed decision-making: Uncertainty about long-term outcomes requires thoroughly discussing the risks, benefits, and alternative therapies between the patient and clinician.

General guideline recommendations regarding TRT

• Recommend that a prostate-specific antigen (PSA) level should be measured in men over age 40 before beginning testosterone therapy to help exclude a prostate cancer diagnosis.

• Practitioners should use a total testosterone level cutoff of 300 ng/dL to support a diagnosis of low testosterone.

• Diagnose “low testosterone” only after measuring two total testosterone levels taken on separate occasions, both drawn in the early morning.

• A clinical diagnosis of “testosterone deficiency” can only be made with a combination of low testosterone levels and symptoms +/- signs.

• Recommends using the minimal dosing necessary to bring testosterone levels to the normal physiologic range of 450-600 ng/dL.

• If patients do not have symptom relief after reaching the testosterone level target at three to six months, they should discuss stopping TRT with the patient.

• After reaching therapeutic targets, measure total testosterone every six to twelve months.

Conclusion

Testosterone replacement for men with a history of prostate cancer requires a careful, personalized approach based on the latest evidence.

If you're on active surveillance, the research isn't comprehensive yet, but current studies suggest TRT might not make your cancer worse. And if you've had treatment like a radical prostatectomy or radiation with good results, TRT could be an option if your doctor monitors you closely.

The American Urological Association updated its guidelines in 2018 to reflect this changing perspective. The association acknowledges that while recent data looks promising, we still lack high-quality controlled studies that would give us complete confidence.

Their recommendations make sense: carefully select appropriate patients, aim for moderate testosterone levels, and keep a close eye on PSA levels.

If you’re considering TRT and have a history of prostate cancer, having a thorough conversation with your doctor is crucial. You'll need to weigh potential benefits, such as better energy, sex drive, and mood, against the uncertainties that exist.

I hope this information helps you and your practitioner make an informed decision that aligns with your health needs and quality of life goals.

Until the next newsletter, stay healthy.

Much love,

Keith

I was stretching, doing a home exercise program for my back, and using the massager before bedtime. I had started seeing my friend for craniosacral therapy, a gentle, hands-on technique used on the skull and spine to promote pain relief by decreasing tension. My friend Nataya and my sister Dianne were doing long-distance healing on me.

Then, the Advil started upsetting my stomach, so I stopped it and went back to difficulty sleeping. I was pulling out all the stops, and nothing seemed to be helping. I finally called my radiation oncologist’s office to let them know, and they ordered a lumbar spine MRI.

Testing stress

As soon as the MRI was ordered, my stress level increased, and I began having dark thoughts about what we’d find. The thoughts were worse at night when I was trying to sleep. As I’ve mentioned before, unrelenting pain, especially at night when you are trying to sleep, makes your mind go down some dark alleys.

I was thinking things like,

Oh, this is where the cancer’s been hiding. It’s finally going to show itself.

I called the imaging center and scheduled the test for Sunday, January 26. As I was driving there, I thought, “We want to show you another miracle.” Then the thought came again, and again, and again, and was more intense each time. It was as if someone had told me that sentence a while before, and I remembered our conversation.

That thought was so loud and repetitive that I laughed to myself. People are going to think I’m crazy when I tell them this. And who is we? Intuitively, I knew this message was coming from the spirit realm. For some, “We” might be the Father, Son, and Holy Spirit.

I felt this message was coming from my angels and my parents, who are in spirit. My father had previously come to me when I was stressing about the results of my PET CT while getting the test done.

I arrived at the imaging center, checked in, and sat down. I felt compelled to type the message I had been hearing into my phone. As soon as I did that, I felt this sense of peace. I knew the scan wouldn’t show cancer.

Two days later, I got the results, and I was right. The scan showed multilevel spondylosis, which is degeneration of the vertebrae, and neuroforaminal stenosis at L5/S1. The findings matched my symptoms, and there was no evidence of malignancy.

Another miracle

This is yet another miracle in this long journey. After all, prostate cancer metastasizes to the bones in 60-90% of patients, and the majority of those have metastases to the spine. After over seven years of metastatic prostate cancer, the inability to tolerate androgen deprivation, and despite a PSA over 300, I have never been diagnosed with bone metastases. That is a miracle!

It reminded me that I’m being watched over and that everything I’ve done thus far has been right for me. It also reminded me to keep my faith and not give in to negative thinking.

It’s okay to have negative thoughts, but when those thoughts overwhelm you and you can’t relinquish them, that darkness starts to take over in the form of hopelessness and depression.

What do I do not to let fearful thoughts overwhelm me? I rely on my faith that no matter what happens, I’ll be okay. That is the ultimate faith.

I call upon my spiritual liaisons, which will be different for everyone. I also lean on those who love me and relinquish the thought that I’m a burden to them because I know I’d do the same for them if our roles were reversed.

I can’t imagine how terrifying this cancer journey would be without my faith and my loved ones. However, I’ve found that trusting my ability to heal is the most important thing to have faith in.

Whether the healing results in a cure or not, I have faith in my ability to resolve pain and release the fears, if not for a little while. And to remember the power of the mind over the body.

As soon as I got the MRI results, my pain immediately dropped fifty percent. We are a body-mind, and our perceptions of stressful events directly impact our physiology and can magnify whatever pain or fear we are experiencing.

No matter what challenges arise, don’t surrender to fear. Trust yourself to navigate the path ahead, making choices that bring relief and peace of mind.

That may mean seeing your physician for medication, speaking with your clergy, praying with your spiritual liaisons, speaking with a mental health counselor, leaning on your loved ones, taking a walk in nature, or all of the above. The key is to take action.

Full-court press

Before recommending an interesting article on Substack, I’d like to let you know that I’ve decided to initiate a full-court press regarding my persistently rising PSA.

I’ve begun a controversial three-drug regimen that isn’t FDA-approved for treating prostate cancer but has some anecdotal evidence to support it. I’m not going to name the three drugs unless my PSA drops while I’m taking them.

I will follow up with my radiation oncologist for labs and another PET CT scan in April. I figure two months is an adequate test of this regimen, and if it works, I will reveal the names of the drugs.

Keep your fingers crossed; I also appreciate the prayers and positive energy.

An interesting article

My friend Howard Wolinsky is a seasoned journalist, thought leader, and patient advocate for men with prostate cancer. He writes The Active Surveillor and Prostate Cores on Substack. He recently wrote an interesting article about the disparity in funding for research in breast cancer versus prostate cancer.

He wrote that the National Cancer Institute and the American Cancer Society’s (ACS) funding of prostate cancer has consistently lagged behind that of breast cancer.

In 2024, the ACS spent $121.1 million on breast cancer research, $37 million on prostate cancer, $67 million on lung cancer research, and $62 million on colorectal research. Howard points out this clear funding gap between breast and prostate cancer.

William Dahut, M.D., PhD. is the chief scientific officer for the ACS. In an article Howard wrote for Medscape last year, the ACS denied any gender bias in research funding. Dr. Dahut said the group makes funding decisions "based on finding the most impactful science regardless of tumor type.”

In my opinion, Dr. Dahut’s response—that funding is based on ‘the most impactful science’—sidesteps the real question. If the process were truly neutral, why does prostate cancer consistently receive far less funding than breast cancer? Simply stating the criteria doesn’t explain the disparity.

Howard suggests that if you’re considering donating to a cancer charity, you should ask what the charity has done for prostate cancer patients like you recently.

I'd like you to read Howard’s article. It’s eye-opening.

Until the next newsletter, stay healthy.

And much love,

Keith