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ARPI use after radiation treatment may be an issue
Does being on an ARPI actually stop your cancer from growing after radiation. This article seems to show that it can cause your cancer to grow without your PSA rising.
PSA is Not the Whole Story
Rick asked me to review the JCO article (3/27/2026) published by Armstrong, et al., titled, Radiographic Progression With and Without Prostate-Specific Antigen Rise in Patients With Advanced Prostate Cancer Treated With Enzalutamide
https://ascopubs.org/doi/10.1200/JCO-24-02829
This post-hoc analysis covered two clinical trials – ARCHES and PROSPER.
Spoiler Alert: Both trials reported a significant minority of patients who had radiographic progression without PSA progression.
Ok, but my questions lingered. The ARCHES trial looked at patients with mHSPC and the PROSPER trial looked at patients with nmCRPC. What about studies in patients with mCRPC? And what about the other ARPIs, i.e., darolutamide and apalutamide?
Did they show similar percentages of radiographic progression without PSA progression?
This was a huge task, so I probed Microsoft’s AI software, Co-Pilot, to help me organize a digestible presentation of the data for the multiple trials involving all three ARPIs and covering all advanced disease states.
Incidence of Radiographic Progression Without PSA Progression — ARPI vs. Placebo/Control Arms
See attached photo
Across all four trials, the incidence of radiographic progression without PSA progression was consistently higher in the ARPI arms compared to placebo/control arms.
The highest incidence was observed in ARCHES (enzalutamide, 62%), while the lowest was in ARAMIS (darolutamide, 35%).
These findings underscore that PSA alone is an unreliable marker of disease control in ARPI-treated patients and that routine imaging surveillance is essential.
Keep in mind, the radiographic imaging done in all these trials was conventional (CT, MRI, bone scintigraphy/Tc-99M). One could easily imagine that radiographic progression rates would have been even higher if PSMA PET/CT had been used.
From the Table, you can see that even without ARPIs, some radiographic progression occurs without PSA progression. But ARPIs amplify this effect.
Surprisingly, the radiographic progression without PSA progression was most pronounced within the first 2 years of ARPI therapy. Armstrong et al. recommend imaging every 6-12 months in the first 2 years. After the first 2 years, if cancer dormancy ensues and there are no symptoms, he suggests imaging can be delayed every 12-18 months.
Why ARPIs cause more discordant progression
ARPIs suppress PSA production so effectively that:
Tumor clones can grow without producing PSA
AR‑independent or neuroendocrine biology emerges
Visceral metastases (especially liver) become more common, especially with enzalutamide
PSA becomes a less reliable biomarker of tumor activity
Key Takeaways:
Across all three ARPIs:
Radiographic progression without PSA progression is real, common, and clinically important.
It happens more often with ARPIs than with placebo/ADT.
Enzalutamide and apalutamide show the highest discordance; darolutamide shows the same pattern but to a lesser degree.
This is why routine imaging is essential, even when PSA looks excellent.
So you can take that to the Bank, i.e. your GU Medical Oncologist.
AnCan can also be your bank for deposits (donations) and withdrawals (sound medical information). See you all Monday.
Len/MS Co-Pilot
Abbreviations
JCO = Journal of Clinical Oncology
mHSPC - metastatic hormone sensitive prostate cancer
nmCRPC - non-metastatic castrate resistance prostate cancer
mCRPC - metastatic castrate resistance prostate cancer
ARPI - androgen receptor pathway inhibitor
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@jeffmarc
"Len Who wrote the article commented on the fact that Darolutamide Results were almost the same as placebo results, Much better than the other two drugs"...
I am a bit confused by this statement...
Nubeqa results almost the same as a placebo - then "much better than the other two drugs" ??
@xahnegrey40
The incidents of Cancer cell growth from Darolutamide was much lower than from Enzalutamide or apalutamide. Close to the amount of growth with just a placebo.
Check out the graph I included At the bottom of the article.
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3 Reactions@jeffmarc
Huh - OK 👍. So I should proceed with plan of asking for Nubeqa after all 😊 - couple of hours to go ... wish me luck ...
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2 Reactions@surftohealth88 I take it...Jeff takes it( I think Jeff only takes Nubeqa now?)
I started off ( July 11, 2025) with Orgovyx and Erleada ( love those names..;=) but jesus, they fucked me up at first..I stopped everything for about 2 weeks or so...then started back up with Orgovyx and added Nubeqa a month of so later...( early Sept)...my PSA dropped from 71 to .05 ( mid Sept) to < .02 ( late Oct) and after Christmas >.01 and most recent end of March, still < .01...
I think the first 30 days are a bit tough but your body adapts and then not too bad-hot flashes, chills, a bit sore and stiff..and you gotta take 5 pills/day 1 Orgovyx and 4 Nubeqas w/food.
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3 Reactions@surftohealth88
The only problem is that Nubeqa Is approved for metastatic, castrate sensitive Prostate cancer. If you are castrate sensitive, but don’t have metastasis than some doctors will not give you a prescription for it.
It looks like a lot more Doctors are opening up to the fact that it’s a better drug, and will prescribe it anyway.
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2 Reactions@surftohealth88 I wouldn't take a small retrospective study too seriously, especially in my choice of med. It's an important contribution to overall knowledge, but for deciding on treatment it's not even the bronze standard, much less silver or gold. Repurposing data collected for a different purpose — especially from more than one past trial — is always fraught.
All of the -lutamides (and even Abiraterone) combined with ADT have shown stunning improvement in overall survival compared to ADT alone for mCSPC, and that's based on massive Phase 3 trials that have done their own primary data collection.
In the end, of course, discuss with your partner's oncologist.
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3 Reactions@xahnegrey40
To answer The question asked above
I take Orgovyx and Nubeqa. I did stop Orgovyx for 8 months in 2024, but I had to go back on it when my Testosterone hit 50.
Not sure how long I can stay on it. My testosterone has started to rise, even though I’m on it and I may have to switch to Lupron if it keeps rising.
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3 Reactions@jeffmarc So taking a capsule filled with water or gelatin was just as ‘effective’ as the one drug that did NOT cause an increase in radiographic spread…
I just said that 3 times out loud and started laughing…WTF??
Phil
@heavyphil Unless I misunderstood the retrospective study, that was a percentage of a percentage, not an absolute number.
So the ARPI + ADT was still far more effective than the placebo + ADT for delaying or preventing cancer progression for mCSPC, but the percentage of progression without PSA rise was higher for the (few) cases with the ARPI than it was for the (many) cases with placebo.
Simple example: if 60 out of 100 people on placebo + ADT and 30 out of 100 on ARPI + ADT see cancer progression within the trial period, and that progression happens without a PSA rise for 5 on placebo and 3 on ARPI, then the *percentage* of people with progression on ARPI who didn't see a PSA rise was higher (10% vs 8.3%), even though the absolute number was lower (3 vs 5).
Yep, numbers are weird. 🙂
Sometimes, the stuff doesn't work anyway, so there's that. (insert unallowed emoji here)