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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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@pcscott
Actually, your case with squamous differentiation it’s not the same as what we’re discussing here. That particular problem can lead Metastasis without PSA rise. It’s also resistant to standard treatments. That makes it difficult to find if it gets worse. The intraductal Also makes it a lot more aggressive.
Must admit I’ve never heard of a case with this problem before. I attend nine online, advanced prostate cancer meetings every month and Attend a lot of talks about prostate cancer and this has just never come up, It is so rare.
Sounds like this is something where they need to do regular SBRT scans, So they can zap metastasis as they come up. The PSA is really irrelevant.
I wish you luck on finding the latest problem and treating it.
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3 ReactionsThanks, Jeff. I'm wondering where Abiraterone fits in this discussion as it's an ARPI, as well? Here's Google's AI view:
Radiographic progression (rPD) during abiraterone/ARPI treatment without a corresponding rise in Prostate-Specific Antigen (PSA) occurs in roughly 20% of patients and often indicates tumor evolution into a more aggressive, neuroendocrine phenotype. While PSA usually tracks with treatment efficacy, this discordant, non-PSA-driven progression is associated with worse survival outcomes. (Wiley Online Library)
In July, 2022, I was Dx with Gleason 9 with mets to surrounding lymph and one spot on the RT Iliac crest. I was on ADT (Degarelix) with Abiraterone plus prednisone for over 2 years along with and following IMRT. My PSA has been undetectable since early on in the process. The last imaging I had was an MRI done in January, 2024 ... one year F/U after IMRT. I have never had a PSMA-PET and have asked my OncMD to order one just for my peace of mind. He hasn't responded, yet.
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1 Reaction@tjs911
16 years ago I had surgery. 3 1/2 years later my PSA started rising so when it hit .2 I was put on Lupron for six months and two months later had salvage radiation. 2 1/2 years later, my PSA started rising again And I was put on Lupron. 2 1/2 years later, I became castrate resistant and was put on casodex for over a year, When my PSA hit 1, I was put on Zytiga With prednisone. In the 2 1/2 years, I was on it my PSA was only undetectable for one month.. It did keep it below .5 most of the time. It caused me to have four afib events, severe hot flashes and high blood pressure which I still have today, and I have to take three different drugs twice a day for it.
I do know people that had many years of Zytiga With success. I was working with one guy who had extreme fatigue from it, Helped by increasing prednisone from 5 mg to 10mg. But it never went away completely and he finally got off of it.
For a long time Zytiga Was recommended over the lutamides for first use with ADT. It did work well for many, but some had serious issues. We Now have Darolutamide Which causes no side effects for most people, So it is being used more and more instead of a Zytiga. Apalutamide is used for those that are not metastatic and castrate sensitive, unfortunately, Daro has not been approved for them yet.
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3 Reactions@tjs911
I forgot to mention. After 2 1/2 years on Zytiga I switched over to Darolutamide And have now been undetectable for the last 29 months, Something Zytiga really failed me at.
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2 Reactions@jeffmarc
Jeff thank you for your postings.
Do you happen to know what studies are used to justify using the Apalutamide for for metastatic castrate sensitive cancers, and the Darolutamide for metastatic castrate resistant cancers only? .
@klein505
Darolutamide has been FDA approved for mCSPC not CSPC yet. I think there are studies looking into it at this time. All CRPC types are approved.
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1 Reaction@klein505 The phase III TITAN trial in 2018 demonstrated Apalutamide's effectiveness with ADT (doublet therapy) for treating mCSPC, and is the basis of its regulatory approval for that in the U.S., Canada, and elsewhere.
The ARANOTE trial, which concluded in late 2024, demonstrated the same thing for Darolutamide, but might be too recent to have made it through regulatory approval yet.
On the bright side, no trial has demonstrated that Apalutamide has any more side-effects than Darolutamide — the difference is purely theoretical and anecdotal at this point.
One retrospective study suggested that Apalutamide actually has *fewer* side-effects than Darolutamide, but it's even less reliable than most retrospective studies, so I wouldn't read too much into that.
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3 Reactions@northoftheborder
Bayer sued Johnson and Johnson over its claims that Erleada patients with CSPC lived longer than those that took Nubeqa.
Bayer Claims the study was biased.
Available comparative data indicates that Nubeqa generally has a more favorable safety profile, particularly regarding fatigue, falls, and rash.
Journal of Hematology Oncology Pharmacy
Lots of differences of opinion.
@jeffmarc Yes, I know that Bayer sued to get ahead of the news cycle (probably a good move, since J&J's study was a little hastily-assembled).
Still, while I know that Bayer predicts fewer side-effects, based on Darolutamide being less likely to cross the blood/brain barrier in-vitro, I haven't (yet) seen a head-to-head trial with other -lutamides establishing that the theory pans out for humans (just retrospective comparisons across different trials done at different times for other purposes with varying methodologies, much as J&J did with their iffy study).
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1 ReactionThanks for this detailed analysis. This is really good information to be aware of.