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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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@heavyphil
I wouldn’t call it just as effective. That it is not.
The placebo will just allow whatever is going to happen happen. I know in my case, it would cause my PSA to rise excessively and quickly, I mean in a matter of a few months.
When it comes to this doesn’t happen to everyone. I suspect those with more severe cases would have their PSA rise significantly.
Guess I will get a CT scan soon!!!
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1 Reaction@jeffmarc well, again, ‘everyone is different’!
Jeez, somebody should write that song already🤮!
Phil
@northoftheborder Yeah, but they did not even use PSMA PET scans to draw these conclusions, so perhaps the numbers in reality were much higher.
They stated that they could not detect anything below 10ng/ml, which is a HUGE number.
So basically, they’re saying to scan ‘periodically’ hopefully using PET PSMA and then once they find all these lesions….Chemo??
It’s almost complimentary - yet contradictory - to Dr Wasserug’s theory. He claims early and prolonged ADT does not cause castrate resistance, but that clones bombarded by cosmic rays will bring about this change. However, it seems that these ARSI drugs do just that – give rise to these super clones that do not even produce PSA yet freely metastasize. Thankfully, this phenomenon does not occur in a high percentage of individuals, which probably account for the 230,000 or so prostate deaths each year.
Truly scary all around.
Phil
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3 Reactions@jeffmarc Probably a PSMA PET , Jeff…according to the author’s limitations impacting the study.
@heavyphil
More like "Everybody is different, and nobody knows a thing " lol
There should be a disclaimer on any proposed PC treatment protocol at the bottom of paper with an asterisk : *Before proceeding please consult your personal astrologer lol
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2 Reactions@surftohealth88 Yeah, new treatments are definitely shifting the centre of the bell curves dramatically to the right on the survival scale, but still, no individual knows exactly where they're going to land on the bell curve.
It must be cold comfort to find out that the majority of people with advanced prostate cancer are living 5, 10, 20++ years longer if you're not one of them. 😢
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3 ReactionsMy experience:
Last year was diagnosed with prostate cancer metastatic to two lymph nodes. Had IMRT radiation to prostate, lymph nodes and surrounding area with SBRT booster to a Gleason 8 prostate with intraductal and squamous differentiation. Also present were ECE and perineural invasion.
ADT with Orgovyx was started immediately, and ARPI with Nubeqa was added a month later. PSA and Testosterone were undetectable at 3, 6, 9 and 12 month checkups.
At 12 months FDG PET/CT scan was done because of the squamous differentiation. This showed a mid uptake (SUV 3.8) with a lesion measuring 26 x 17 mm.
A follow-up PSMA PET/CT scan showed mild uptake in the same area.
A bone biopsy was done last week and was positive for adenocarcinoma consistent with prostate origin with negative PSA staining. SBRT is scheduled for that lesion.
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3 Reactions@heavyphil That's back to my point that this was a restrospective study, so it was stuck reanalysing data from previous trials which weren't designed with its goals in mind (or may have been designed before newer imaging tech was available).
Retrospective studies are an inexpensive way to spitball new ideas using old research (that's already been paid for), but, as I've mentioned before, at the patient level we probably shouldn't be paying much attention to them, except maybe "that's interesting, lets see if anything emerges in 5 years."
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4 Reactions@pcscott I'm so sorry to hear that, and it's very much in line with what the study @jeffmarc shared ended up recommending: that it's still important to do imaging, even when PSA is low or undetectable on ADT + an ARPI. I'm glad they caught it.
If you don't mind my asking, was your PSA undetectable on the ultrasensitive test (e.g. < 0.01) or the regular PSA test (e.g. < 0.1)? I'm asking only because I have not yet been able to find an example of the former in the papers I've read, while I have found (a few) examples of the latter.
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1 Reaction@northoftheborder
< 0.1
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2 Reactions