That was some excellent evidence based information. I had a bad feeling regarding bicalutamide long term, and this confirms that for a percentage of patients. It would be interesting to see studies on the effects of Orgovix (relugolix) for 16-24 months after or concommitant IMRT/ HDBT therapy. The side effects were minor, appart from libido
Hi Joe. Thanks! And I'm very happy to hear about your relatively good experience with relugolix. It's a fairly new drug, and when I come across interesting data on it, I'll write about it.
Keith is it wise to ask for the ctDNA test before the psa starts rising during lupron therapy? My husband has taken lupron shots for 5 years he could not tolerate xtandi or the biaculamide Treatment too. He is gleason 4+3. He is wanting to take a break from the shots we talked to an oncologist about it. He said to express this to his urologist. We have been told he must take shots for rest of his life. He will be 61 this year. His psa is stable right now. It is do hard to express how is fighting cancer but scans don’t really show metastatic disease now. I just wondered if the liquid biopsy would give any helpful information about what is going on now thru his treatment? Thank you for this enlightening article. We knew that the therapy at some point can stop working but I did not understand it could potentially fuel it.
Melissa, when you say his PSA is stable, I'm assuming you mean undetectable. ctDNA testing in patients with an undetectable PSA is unreliable, and the NCCN specifically recommends against it. The lower the PSA when testing ctDNA, the less reliable the test. While men on Lupron can develop mutations, there is no evidence that Lupron can develop the antagonist-to-agonist switch mutation, so Lupron cannot mutate to fuel prostate cancer. Since the oncologist does not want to recommend a break from therapy, your best bet is to discuss this with the urologist. I wish you and your husband the very best.
Yes… the L702H/prednisone trap is the one that keeps me up at night clinically. It's not just that the mutation makes prednisone activating, but it's that the system essentially mandates the fuel delivery. You can't stop prednisone abruptly after prolonged abiraterone use without risking adrenal insufficiency, so patients end up in a window where the oncologist knows the steroid may be feeding the cancer but can't simply yank it. The dexamethasone substitution pearl is clinically important and underused; the differential affinity data are there but most community oncologists haven't internalized it.
The 5α-abiraterone metabolite piece deserves more attention than it gets. The fact that abiraterone can be reduced in vivo to a partial AR agonist, independent of any acquired mutation, means the drug carries an intrinsic resistance mechanism baked into its own metabolism. That's not a side effect. That's a structural limitation of the molecule that probably contributed to some of the efficacy ceiling we see in the real-world data.
On the ctDNA testing gap you cite: 15% serial testing is staggering given how much the mutation landscape shifts between lines. Part of the problem is that ordering ctDNA at progression still feels optional to many oncologists in community practice, not standard of care. Until it's embedded in the workflow the way PSA monitoring is, it will remain underutilized.
The PLATO sequencing data (4% PSA response rate switching enza → abi) should have closed the ARPI-switch debate. That it hasn't reflects how much treatment inertia exists when docetaxel is the alternative and patients and sometimes clinicians aren't ready for that conversation.
One addition worth flagging: in patients with concurrent homologous recombination repair mutations (BRCA2 especially), the AR-directed therapy failure timeline and the mutation acquisition pattern may differ. The biology is genuinely different in those tumors, and ctDNA profiling in that context should also be prompting PARP inhibitor evaluation in parallel, not sequentially after yet another ARPI attempt.
Exceptionally well-referenced piece. The four clinical scenarios framework is exactly how this material should be taught.
Thank you for helpful article although as a lay person a lot of it was over my head! My husband has appointment with his oncologist (UCSD) this month and I will ask about genetic testing. He was on abiraterone/prednisone for almost two years and has been on “vacation” for almost a year. He has PSA tested every 3 months and it’s been undetectable. Should he get genetic testing now or when his PSA starts to rise and the doctor tells us what treatment is recommended. Besides this question is there anything else we should ask? Thank you.
Hi Laurel. You guys have an oncologist at UCSD so you are likely in good hands. Being off abi/pred for a year with an undetectable PSA sounds fantastic. Based on the limited information you gave me, I don't see a reason for molecular testing at this point. My advice is to simply "enjoy" his undetectable PSA and follow his oncologist's lead, which sounds like is doing him good.
That was some excellent evidence based information. I had a bad feeling regarding bicalutamide long term, and this confirms that for a percentage of patients. It would be interesting to see studies on the effects of Orgovix (relugolix) for 16-24 months after or concommitant IMRT/ HDBT therapy. The side effects were minor, appart from libido
Hi Joe. Thanks! And I'm very happy to hear about your relatively good experience with relugolix. It's a fairly new drug, and when I come across interesting data on it, I'll write about it.
Keith is it wise to ask for the ctDNA test before the psa starts rising during lupron therapy? My husband has taken lupron shots for 5 years he could not tolerate xtandi or the biaculamide Treatment too. He is gleason 4+3. He is wanting to take a break from the shots we talked to an oncologist about it. He said to express this to his urologist. We have been told he must take shots for rest of his life. He will be 61 this year. His psa is stable right now. It is do hard to express how is fighting cancer but scans don’t really show metastatic disease now. I just wondered if the liquid biopsy would give any helpful information about what is going on now thru his treatment? Thank you for this enlightening article. We knew that the therapy at some point can stop working but I did not understand it could potentially fuel it.
Melissa, when you say his PSA is stable, I'm assuming you mean undetectable. ctDNA testing in patients with an undetectable PSA is unreliable, and the NCCN specifically recommends against it. The lower the PSA when testing ctDNA, the less reliable the test. While men on Lupron can develop mutations, there is no evidence that Lupron can develop the antagonist-to-agonist switch mutation, so Lupron cannot mutate to fuel prostate cancer. Since the oncologist does not want to recommend a break from therapy, your best bet is to discuss this with the urologist. I wish you and your husband the very best.
Thank you.
Yes… the L702H/prednisone trap is the one that keeps me up at night clinically. It's not just that the mutation makes prednisone activating, but it's that the system essentially mandates the fuel delivery. You can't stop prednisone abruptly after prolonged abiraterone use without risking adrenal insufficiency, so patients end up in a window where the oncologist knows the steroid may be feeding the cancer but can't simply yank it. The dexamethasone substitution pearl is clinically important and underused; the differential affinity data are there but most community oncologists haven't internalized it.
The 5α-abiraterone metabolite piece deserves more attention than it gets. The fact that abiraterone can be reduced in vivo to a partial AR agonist, independent of any acquired mutation, means the drug carries an intrinsic resistance mechanism baked into its own metabolism. That's not a side effect. That's a structural limitation of the molecule that probably contributed to some of the efficacy ceiling we see in the real-world data.
On the ctDNA testing gap you cite: 15% serial testing is staggering given how much the mutation landscape shifts between lines. Part of the problem is that ordering ctDNA at progression still feels optional to many oncologists in community practice, not standard of care. Until it's embedded in the workflow the way PSA monitoring is, it will remain underutilized.
The PLATO sequencing data (4% PSA response rate switching enza → abi) should have closed the ARPI-switch debate. That it hasn't reflects how much treatment inertia exists when docetaxel is the alternative and patients and sometimes clinicians aren't ready for that conversation.
One addition worth flagging: in patients with concurrent homologous recombination repair mutations (BRCA2 especially), the AR-directed therapy failure timeline and the mutation acquisition pattern may differ. The biology is genuinely different in those tumors, and ctDNA profiling in that context should also be prompting PARP inhibitor evaluation in parallel, not sequentially after yet another ARPI attempt.
Exceptionally well-referenced piece. The four clinical scenarios framework is exactly how this material should be taught.
Thank you! And Thanks for the information about ctDNA testing in the context of concurrent HRR mutations and PARP inhibitors.
Thank you for helpful article although as a lay person a lot of it was over my head! My husband has appointment with his oncologist (UCSD) this month and I will ask about genetic testing. He was on abiraterone/prednisone for almost two years and has been on “vacation” for almost a year. He has PSA tested every 3 months and it’s been undetectable. Should he get genetic testing now or when his PSA starts to rise and the doctor tells us what treatment is recommended. Besides this question is there anything else we should ask? Thank you.
Hi Laurel. You guys have an oncologist at UCSD so you are likely in good hands. Being off abi/pred for a year with an undetectable PSA sounds fantastic. Based on the limited information you gave me, I don't see a reason for molecular testing at this point. My advice is to simply "enjoy" his undetectable PSA and follow his oncologist's lead, which sounds like is doing him good.