RADICALS HD published

[Chartreuse Wombat]

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Published on-line.

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)00549-X/fulltext

The endpoint is MFS. To my knowledge this endpoint has not been validated in the postop setting. The ICECAP paper from 2017 that used Prentice criteria for surrogacy did not include postop studies.

No difference in OS. Is it wrong to sentence treat men with 24 months instead of 6?

Discuss

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[ramsesthenice]

Published on-line.

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)00549-X/fulltext

The endpoint is MFS. To my knowledge this endpoint has not been validated in the postop setting. The ICECAP paper from 2017 that used Prentice criteria for surrogacy did not include postop studies.

No difference in OS. Is it wrong to sentence treat men with 24 months instead of 6?

Discuss

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As I suspected from the beginning with radicals, it would be outdated before we ever got the results. Knowing what we know now, the duration of ADT in the adjuvant setting (which was almost half of the population) is probably irrelevant. The Forrest plot (based on PSAs) supports the idea any differences you see (validated or not) are less with an undetectable PSA. Which, since many will not fail even without any treatment, is not a shock. On top of that, we now have better imaging (PYL) that can potentially help you decide.

My bias, at the end of the day, it confirmed what we already know (or should have known at least). Even in the high risk post op or biochemically recurrent groups, risk of PCa death is low. Upfront longterm ADT may do a better job of delaying/preventing recurrence. But delaying additional ADT until that time probably doesn’t compromise cancer-specific survival. I personally don’t feel strongly about one over the other. My current practice is unless someone has PET positive disease or really scary features (like DT < 6 months) I typically do short term.

 

[Palex80]

And why do short-term at all?

These resuls (from Radicals-HD), reported at ESMO 2022, challenge the GETUG-findings.

Perhaps 24 months only for the high risk population after careful counselling and 0 months for the rest?

 

[ramsesthenice]

As I suspected from the beginning with radicals, it would be outdated before we ever got the results. Knowing what we know now, the duration of ADT in the adjuvant setting (which was almost half of the population) is probably irrelevant. The Forrest plot (based on PSAs) supports the idea any differences you see (validated or not) are less with an undetectable PSA. Which, since many will not fail even without any treatment, is not a shock. On top of that, we now have better imaging (PYL) that can potentially help you decide.

My bias, at the end of the day, it confirmed what we already know (or should have known at least). Even in the high risk post op or biochemically recurrent groups, risk of PCa death is low. Upfront longterm ADT may do a better job of delaying/preventing recurrence. But delaying additional ADT until that time probably doesn’t compromise cancer-specific survival. I personally don’t feel strongly about one over the other. My current practice is unless someone has PET positive disease or really scary features (like DT < 6 months) I typically do short term.

To clarify...I typically do short term if any. I don't cart blanc give ADT to every salvage patient I see. I will fully admit we are getting into a data free zone and I don't think we know what the right cutoff is but Shipley's data pretty strongly suggested the returns diminish with decreasing PSA. My totally made up system based on everything we know about prostate cancer in general is to construct a list of high risk variables (time to failure (I like >/< 2 years post- surgery), absolute PSA, PSA doubling time, + vs - margin, pathologic staging, etc). Rapid doubling time or very short disease free interval pretty much buys some duration of ADT for me. Opposite is also true. If they went 7-8 years between surgery and biochemical recurrence with a doubling time > 12 months, I don't care what the initial pathology was, I don't see ADT adding much. For everyone else, I typically think 0-1 risk factors, there is almost no chance ADT will do much and 2+ it is probably worth at least considering.

This kind of free-wheeling probably makes some people uncomfortable. The alternative makes me uncomfortable. The randomized data we have clearly suggests we have not figured this problem out yet. It will be many years before we get more clarity and just doing something because its what they did in the trial (when said trial its self implies that is overly simplistic) doesn't always feel right to me either. Part of the issue is that I now write trials and have a much better understanding of the process. There is a lot of haggling, negotiating, and hemming and hawing that goes on and eventually you just have to pick something deliverable. They are not magic and it is rarely (if ever) possible to design one in a way that gives a clear, easy to follow clinical blue print. Even though many people try to use them that way.

 

[evilbooyaa]

MFS is not a useless endpoint on its own. Metastasis generally means lifelong (Even if intermittent) ADT +/- ARSI/Chemo, etc.

It's hard for me to recommend 24 months of ADT in a node negative (on PSMA PET/CT) recurrent setting. For a patient that was maximally motivated, maybe. Most of my patients are maximally motivated to avoid ADT.

Despite interaction p-value not being isgnificant, I could see 24 month ADT being an option for pre-salvage RT PSA > 0.5. An argument could be made for pre-salvage RT PSA 0.3 - 0.5 as well given similar HR (although not sufficiently powered to show a benefit). I'm less sold on 24 months ADT for PSA < 0.3, and generally I don't give any ADT (as was shown to be OK on RADICALS-RT IIRC) for PSAs < 0.3.

Fortunately, I am very rarely seeing prostate cases at that high of PSA as our Urologists have understood the importance of early salvage.

 

[Palex80]

Most of my patients are maximally motivated to avoid ADT.

You cannot have an erection if you are dead.

Michael Bolla, ~ 2009

[add wonderful french accent to it]

 

[medgator]

MFS is not a useless endpoint on its own. Metastasis generally means lifelong (Even if intermittent) ADT +/- ARSI/Chemo, etc.

It's hard for me to recommend 24 months of ADT in a node negative (on PSMA PET/CT) recurrent setting. For a patient that was maximally motivated, maybe. Most of my patients are maximally motivated to avoid ADT.

Despite interaction p-value not being isgnificant, I could see 24 month ADT being an option for pre-salvage RT PSA > 0.5. An argument could be made for pre-salvage RT PSA 0.3 - 0.5 as well given similar HR (although not sufficiently powered to show a benefit). I'm less sold on 24 months ADT for PSA < 0.3, and generally I don't give any ADT (as was shown to be OK on RADICALS-RT IIRC) for PSAs < 0.3.

Fortunately, I am very rarely seeing prostate cases at that high of PSA as our Urologists have understood the importance of early salvage.

You cannot have an erection if you are dead.

Michael Bolla, ~ 2009

[add wonderful french accent to it]

Orgovyx claim to fame is rapid T/🦴 recovery (maybe because of poor compliance, but not hard to draw T levels while they are on it).

 

[evilbooyaa]

You cannot have an erection if you are dead.

Michael Bolla, ~ 2009

[add wonderful french accent to it]

For most of the salvage folks they're not having erections anyways b/c of the RALP

The other stuff, fatigue, loss of muscle mass, etc. is a significant concern for a big chunk of older men (at least American ones). It seems like old guys in the US just LOVE talking about their prostates at all times, and given the commonality and non-lethality of prostate cancer, they all seem to 'know a guy' who had basically like everything in regards to prostate cancer (surgery, EBRT, SBRT, LDR brachy, short term ADT, long-term ADT, Abiraterone, etc.) and thus come in frequently with reservations about ADT.