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ARPI use after radiation treatment may be an issue

Posted by Jeff Marchi @jeffmarc, Apr 20 12:48pm

Does being on an Androgen Receptor Pathway Inhibitors (ARPIs) 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

Interested in more discussions like this? Go to the Prostate Cancer Support Group.

Profile picture for Mrs K
Mrs K | @klein505 | Apr 23 9:16pm
In reply to @northoftheborder "@klein505 The phase III TITAN trial in 2018 demonstrated Apalutamide's effectiveness with ADT (doublet therapy) for..." + (show)
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@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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@northoftheborder Thank you! Would have taken me hours and hours to find those.
Lol, Just when I think there can't be anymore named trials, here are two more to read :):)

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overage | @overage | May 14 11:50am
In reply to @jeffmarc "@surftohealth88 The only problem is that Nubeqa Is approved for metastatic, castrate sensitive Prostate cancer. If..." + (show)
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@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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@jeffmarc Getting a proscription may be one problems but getting reimbursed from your insurance could be another problem if your insurance plan follows FDA approvals.

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Jeff Marchi | @jeffmarc | May 14 12:49pm
In reply to @overage "@jeffmarc Getting a proscription may be one problems but getting reimbursed from your insurance could be..." + (show)
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@jeffmarc Getting a proscription may be one problems but getting reimbursed from your insurance could be another problem if your insurance plan follows FDA approvals.

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@overage
Not sure what you mean. Once I hit that $2100 prescription limit, I have never paid another dollar for prescriptions for the rest of the year.

Part B can fall under your annual medical deductible amount.

Part D Does end at $2100.

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overage | @overage | May 14 4:47pm
In reply to @jeffmarc "@overage Not sure what you mean. Once I hit that $2100 prescription limit, I have never..." + (show)
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@overage
Not sure what you mean. Once I hit that $2100 prescription limit, I have never paid another dollar for prescriptions for the rest of the year.

Part B can fall under your annual medical deductible amount.

Part D Does end at $2100.

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@jeffmarc I am not familiar with the Medicare plans since I do not live in the United States and did not sign up for Medicare Part B when I was 65. I do have a United States Blue Cross plan that covers me in most countries. That plan uses the FDA approvals to determine what ARPI drugs they will approve for each condition. Also ADT with a LHRH agonist or antagonist or a dual orchiectomy is required when an ARPI drug is used.

For example for Metastatic CSPC they will approve Erleada or Nubeqa with ADT. For Non-metastatic CRPC the will approve those same drugs. Once you reach Metastatic CRPC the approved drugs with ADT are Xtandi or Zytiga. To be able to take only Nubeqa requires that you not only have to have a doctor that is willing to prescribe that and an insurance plan that will override FDA approved standard of care.

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mrkoji | @mrkoji | May 16 6:55pm
In reply to @jeffmarc "@tjs911 16 years ago I had surgery. 3 1/2 years later my PSA started rising so..." + (show)
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@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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@jeffmarc Unfortunately some insurance plans in the US will often not approve of Nubeqa or Xtandi. They will approve of Zytiga because it's a cheap generic.
My insurance last week approved of Nubeqa and my MO was surprised as she sees far more denials than approvals.

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Jeff Marchi | @jeffmarc | May 17 11:19am
In reply to @mrkoji "@jeffmarc Unfortunately some insurance plans in the US will often not approve of Nubeqa or Xtandi...." + (show)
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@jeffmarc Unfortunately some insurance plans in the US will often not approve of Nubeqa or Xtandi. They will approve of Zytiga because it's a cheap generic.
My insurance last week approved of Nubeqa and my MO was surprised as she sees far more denials than approvals.

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@mrkoji
If you are castrate sensitive, then you cannot be prescribed Nubeqa Unless you have a metastasis.

I think the vast majority of people that get prostate cancer are in that situation. The drug that is recommended at that point is Erleada. You did not mention that one. Not saying it wouldn’t be rejected, but it is the one recommended for those people.

For a long time, Zytiga has been a choice for the first drug to use. If it causes somebody problems, then I’m pretty sure insurance would allow a lutamide.

Yes, it’s a difficult thing. People can’t always get what they want because insurance is looking at the bottom line. I think one of the biggest problems is that once somebody on Medicare hits the $2100 limit, which happens quickly with a lutamide, the insurance company has to pay for any increase costs not the government. This really can become prohibitively expensive. The government sets a limit, they should pay for it. That would make it a lot easier to get an expensive prescription.

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