The Most Controversial Therapy for Advanced Prostate Cancer - 046
And it's not androgen deprivation
Before discussing today's topic, I'd like to thank Howard Wolinsky, who writes the Substack newsletter, The Active Surveillor. Howard is a seasoned journalist who serves the prostate cancer community with his wealth of knowledge, especially about active surveillance for low-risk prostate cancer.
Most of my subscribers come my way through his newsletter, and I'm thankful for that. If you're not a subscriber to The Active Surveillor, I highly recommend his newsletter. If you already are, please consider becoming a paid subscriber. The wisdom and information he imparts is valuable.
Reasons I consider this advanced prostate cancer therapy controversial:
In 2007, the FDA rejected the therapy on its first attempt, with pooled data from two clinical trials showing only a 4.3-month improvement in median overall survival.
In 2010, the FDA approved the therapy based on the IMPACT clinical trial, showing only a 4.1-month improvement in median overall survival.
It lacks a biomarker to measure efficacy because it rarely causes the PSA to drop.
It doesn't slow disease progression in imaging studies such as PET CT or bone scans.
An invasive central venous catheter is sometimes necessary if a patient lacks adequate peripheral veins.
The FDA approved this therapy in 2010 when there were no other drugs available to treat metastatic castrate-resistant prostate cancer except for docetaxel (Taxotere), a chemotherapy agent. This approval is an example of when desperate times call for desperate measures.
A cumbersome therapy
While relatively short-lived, the treatment process is quite cumbersome. The patient must undergo a 2-4 hour leukapheresis, during which blood is extracted and run through a machine. A small amount of immune cells, platelets, and red blood cells are removed, and the rest of the blood is returned to the body.
Three days later, you return to receive an infusion of your treated blood cells, which takes about an hour and a half. You repeat this process twice, two weeks apart, for six visits. The treatment cost depends on your insurance and the pharmacy you use, but in 2011, the wholesale price was $93,000.
Sipuleucel-T (Provenge)
As some of you may have figured out, this therapy is called sipuleucel-T (Provenge) by Dendreon Pharmaceuticals. It's FDA-approved for men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer without visceral metastases.
It's an autologous cellular immunotherapy designed to stimulate a patient's immune system to target prostate cancer cells. A manufacturing facility combines the patient's immune cells with a mixture of prostatic acid phosphatase (PAP) and granulocyte-macrophage colony-stimulating factor (GM-CSF).
PAP is an antigen expressed in most prostate cancer cells, and GM-CSF is an immune cell activator. While sipuleucel-T's exact mechanism of action isn't fully understood, doctors think it works by stimulating the patient's T-cell immune responses against PAP-expressing prostate cancer cells.
A therapy and company that struggles
Not surprisingly, the year after it was approved, sales for sipuleucel-T weren't good. As Sandy Srinivas,D, a professor of medical oncology at Stanford Cancer Center, puts it,
"Patients are used to PSA. It was a total change in our approach and in our ability to convince patients that you have to take this drug: 'It may not drop your PSA, it may not make your bone scans get better, but it will make you live a little bit longer, by about 4 months.' That was a little bit of a tough sell."
Then, in 2012, a paper published in The Journal of the National Cancer Institute proposed that Dendreon's IMPACT trial was flawed and that this flaw explained the survival benefit of sipuleucel-T rather than the therapy itself. The writers stated,
"Because two-thirds of the cells harvested from placebo patients, but not from the sipuleucel-T arm, were frozen and not reinfused, a detrimental effect of this large repeated cell loss provides a potential alternative explanation for the survival "benefit."
Of course, Dendreon refuted this, but the paper only added doubts about the efficacy of sipuleucel-T. Combined with its expensive manufacturing process and many doctors not buying into sipuleucel-T, Dendreon filed for bankruptcy in 2014.
Like a hot potato, Dendreon rapidly changed owners three times in three years, eventually landing in the hands of its current owner, Nanjing Cenbest. This Chinese department store chain, branching into healthcare, bought it for 886 million dollars.
How Pharmaceutical Companies Promote Their Products
As I read journal articles to write these newsletters, I’ve noticed a disturbing trend.
Pharmaceutical companies have figured out how to create papers that nuance data so that their products appear to have specific advantages. They frequently conduct retrospective (post hoc) analyses of clinical trial data to extract findings beyond the study's original objectives and then publish these findings in peer-revewed journals.
Inevitably, pharmaceutical companies pay for these "studies,” and the physicians who write these papers are usually either employees or on the company's advisory board or its speaker's bureau. This incestuous relationship creates a very high risk for bias. The way to know if this is occurring is by looking at the bottom of a research paper in the "financial disclosure" section.
Here is an online searchable database that shows you exactly how much pharmaceutical companies pay individual doctors.
Problems with post hoc analyses
What is wrong with this practice, which essentially all pharmaceutical companies do?
When pharmaceutical companies fund post hoc analyses, this creates an inherent conflict of interest. They have a financial stake in finding positive results, which can lead to biased interpretations of data.
Post hoc analyses aren't designed with the same scientific rigor as the original clinical trials. They look at data in new ways after the study's conclusion, which can lead to cherry-picking of results.
Positive findings from post hoc analyses can be used in marketing materials, potentially misleading healthcare providers and patients about a product's true efficacy.
Post hoc analyses are exploratory and hypothesis-generating rather than conclusive evidence.
Doctors may perceive post hoc analysis findings in a journal article as definitive, which may inappropriately influence clinical practice.
Researchers, clinicians, and the public should consider post hoc analyses with caution, especially when they are funded by pharmaceutical companies that stand to benefit from positive results.
Dendreon's post hoc analysis
The IMPACT clinical trial published in 2010, which got sipuleucel-T FDA-approved, showed a small but statistically significant 4.1-month improvement in median overall survival.
A post hoc analysis of the IMPACT trial published in Urology in 2013 concluded,
"The greatest magnitude of benefit with sipuleucel-T treatment in this exploratory analysis was observed among patients with better baseline prognostic factors, particularly those with lower baseline PSA values. These findings suggest that patients with less advanced disease may benefit the most from sipuleucel-T treatment and provide a rationale for immunotherapy as an early treatment strategy in sequencing algorithms for metastatic castration-resistant prostate cancer."
An editorial comment from an outside physician reminded everyone,
"It should be appreciated that these are retrospective, exploratory analyses, and that before being translated to routine clinical practice, any marker(s) identified would likely need to be validated in a prospective manner."
Registry studies
Another practice in the medical literature is for pharmaceutical companies to publish registry studies involving their products. Compared to post hoc analyses, registry studies are less problematic, but they are not free from potential problems
Registry studies are observational studies that collect data on patients using a particular drug or treatment. They are often called "real-world" studies, but I find the term misleading. "Real world" means existing or occurring in reality, which implies how things actually happen in life.
When pharmaceutical companies use the term "real world" to describe these registry studies, they imply that the study potentially explains how efficacious their products are outside a clinical trial. That is misleading for several reasons.
Potential problems with registry studies include:
Unlike randomized controlled trials, observational registry studies cannot establish causation between a therapy and outcomes.
The inability to infer causation is often inadequately address in the study report and associated media coverage.
Registry studies produce hypothesis-generating data, which some patients and doctors may misinterpret as definitive.
Observational registry studies often overestimate treatment effects.
Dendreon's PROCEED registry study
Dendreon published a registry study in the journal Cancer in 2019. It suggested as much as a 30 percent reduction in the risk of death for black patients compared to white patients who underwent sipuleucel-T therapy.
That data was eye-opening for clinicians who treat advanced prostate cancer since it is well-known black men have much worse outcomes than white men.
However, this registry study had several significant limitations.
It couldn't assess a survival benefit because there was no comparator group—in other words, no group that didn't receive sipuleucel-T for comparison.
77.1% of patients in this study received other life-prolonging therapies, including abiraterone, enzalutamide, docetaxel, cabazitaxel, and radium-223, in addition to the androgen deprivation therapy drug they were already on.
Of those 77.1%, 17.8% of patients had received those other life-prolonging therapies before receiving sipuleucel-T.
So, you can see how other therapies significantly muddy the water when assessing the survival benefit of sipuleucel-T.
Unfortunately, the average lay reader and even some physicians don't understand the difference between a registry study and a randomized, double-blind clinical trial. If one were only to read parts of the study or clipped sentences from the registry study, one might consider the results definitive.
For example, here is some wording taken directly from the published study.
"PROCEED also offers confirmation of correlative findings noted in prior phase 3 studies (of sipuleucel-T). Patients in the lowest baseline PSA quartile (PSA ≤ 5.27 ng/mL) had significantly longer OS [overall survival] (median survival, 47.7 months) than those in higher PSA quartiles."
That sounds definitive to me! All pharmaceutical companies play these games.
Dendreon’s active surveillance study
Finally, Dendreon hopes to capitalize on another segment of the prostate cancer community - those on active surveillance. Their ProVent phase III clinical trial of sipuleucel-T was completed on February 28, 2024.
This clinical trial aims to assess the efficacy of sipuleucel-T in reducing histologic progression in men under active surveillance. I'll let you know when I see any preliminary or final data.
Until the next newsletter, stay healthy.
Much love,
Keith