PEACE-1 Discussion

[Palex80]

If this was a trial of Gem +/- elective hip arthroplasty and had the same results, Stryker would already have bill boards on every high way in America.

Meanwhile in rad onc land: But.... the chemo, while standard then, is no longer standard. Would not bang.

I am going to repeat myself. It‘s an unplanned subgroup analysis. And it‘s a systemic treatment no longer offered to the majority of patients.

We faced the same argument in prostate cancer,
In a much bigger trial with a prespecified subgroup analysis and adequate power, RT was able to raise the OS in M1-oligo-mHSPC (Stampede Arm H). Yet, when that trial ran, s.o.c. was ADT only and less than a quarter of the patients had additional treatment.

When the question was asked, if people would still offer RT to the primary for a patient with M1-oligo-mHSPC getting an ARPI on top of ADT, opinions were split. The majority would still do it, but the general feeling was, that we don‘t really know if the OS benefit is still there. When PEACE-1 came out last year, we had evidence that the OS benefit was gone. In PEACE-1, patients had Abi / Docetaxel on top of ADT.

The bottom line is: The role and net-benefit of RT changes, when systemic treatment changes. It is likely the reason, numerous trials will continue to come out negative.

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[RickyScott]

I am going to repeat myself. It‘s an unplanned subgroup analysis. And it‘s a systemic treatment no longer offered to the majority of patients.

We faced the same argument in prostate cancer,
In a much bigger trial with a prespecified subgroup analysis and adequate power, RT was able to raise the OS in M1-oligo-mHSPC (Stampede Arm H). Yet, when that trial ran, s.o.c. was ADT only and less than a quarter of the patients had additional treatment.

When the question was asked, if people would still offer RT to the primary for a patient with M1-oligo-mHSPC getting an ARPI on top of ADT, opinions were split. The majority would still do it, but the general feeling was, that we don‘t really know if the OS benefit is still there. When PEACE-1 came out last year, we had evidence that the OS benefit was gone. In PEACE-1, patients had Abi / Docetaxel on top of ADT.

The bottom line is: The role and net-benefit of RT changes, when systemic treatment changes. It is likely the reason, numerous trials will continue to come out negative.

The unplanned sub group is what is disturbing. These almost never work out in subsequent trials.

 

[grenz]

I am going to repeat myself. It‘s an unplanned subgroup analysis. And it‘s a systemic treatment no longer offered to the majority of patients.

We faced the same argument in prostate cancer,
In a much bigger trial with a prespecified subgroup analysis and adequate power, RT was able to raise the OS in M1-oligo-mHSPC (Stampede Arm H). Yet, when that trial ran, s.o.c. was ADT only and less than a quarter of the patients had additional treatment.

When the question was asked, if people would still offer RT to the primary for a patient with M1-oligo-mHSPC getting an ARPI on top of ADT, opinions were split. The majority would still do it, but the general feeling was, that we don‘t really know if the OS benefit is still there. When PEACE-1 came out last year, we had evidence that the OS benefit was gone. In PEACE-1, patients had Abi / Docetaxel on top of ADT.

The bottom line is: The role and net-benefit of RT changes, when systemic treatment changes. It is likely the reason, numerous trials will continue to come out negative.

When you narrow PEACE 1 down to the low volume subset that got Abi, the N is way too low to say RT no longer improves OS.

 

[evilbooyaa]

I am going to repeat myself. It‘s an unplanned subgroup analysis. And it‘s a systemic treatment no longer offered to the majority of patients.

We faced the same argument in prostate cancer,
In a much bigger trial with a prespecified subgroup analysis and adequate power, RT was able to raise the OS in M1-oligo-mHSPC (Stampede Arm H). Yet, when that trial ran, s.o.c. was ADT only and less than a quarter of the patients had additional treatment.

When the question was asked, if people would still offer RT to the primary for a patient with M1-oligo-mHSPC getting an ARPI on top of ADT, opinions were split. The majority would still do it, but the general feeling was, that we don‘t really know if the OS benefit is still there. When PEACE-1 came out last year, we had evidence that the OS benefit was gone. In PEACE-1, patients had Abi / Docetaxel on top of ADT.

The bottom line is: The role and net-benefit of RT changes, when systemic treatment changes. It is likely the reason, numerous trials will continue to come out negative.

What does PEACE-1 have to do with prostate RT?

Oligomet M1 prostate cancer receiving ADT and Abi should 100% receive prostate RT until a trial proves it is unnecessary. Why assume benefits are NOT additive across two different modalities (local vs systemic) when there are active trials accruing to give us an answer? Sure, if the trial is open at your instituion, then enroll in it.

Now, to the above line, I would 100% understand if a medical oncologist had an opposing opinion.

Palex, as a Rad Onc, why do you have such a negative opinion of our field and barrier for entry?

You'd rather advocate for patients to get combo Abi/Docetaxel rather than 55/20 prostate alone RT (+/- Abi)?

 

[TheWallnerus]

What does PEACE-1 have to do with prostate RT?

Oligomet M1 prostate cancer receiving ADT and Abi should 100% receive prostate RT until a trial proves it is unnecessary. Why assume benefits are NOT additive across two different modalities (local vs systemic) when there are active trials accruing to give us an answer? Sure, if the trial is open at your instituion, then enroll in it.

Now, to the above line, I would 100% understand if a medical oncologist had an opposing opinion.

Palex, as a Rad Onc, why do you have such a negative opinion of our field and barrier for entry?

You'd rather advocate for patients to get combo Abi/Docetaxel rather than 55/20 prostate alone RT (+/- Abi)?

Palex does a way better job of explaining/defending his logic than I ever could, but I don’t see a single thing he’s ever said as being a “negative opinion of our field.”

Carry on.

 

[evilbooyaa]

Palex does a way better job of explaining/defending his logic than I ever could, but I don’t see a single thing he’s ever said as being a “negative opinion of our field.”

Carry on.

Maybe the previous post was a bit harsh, but I feel like I'm seeing a trend that anything that supports radiation in any manner is immediately poo-poo'd. But seriously, if the trial is going to give us a result like this and we're not going to listen to it, while simultaneously ignoring, then why do we even run trials in the first place, if the first thing we're going to say is "well, it's out of date"?

 

[Palex80]

What does PEACE-1 have to do with prostate RT?

Peace-1 featured a 2x2 design,

One question was if ADT + Abi was better than ADT. The other question was if RT to the prostate in M1 mHSPC adds anything.

The second question was presented at ASCO 2023

ASCO 2023: Prostate Irradiation in Men with De Novo, Low-Volume, Metastatic, Castration-Sensitive Prostate Cancer (mCSPC): Results of PEACE-1, a Phase 3 Randomized Trial with a 2x2 Design

ASCO 2023 results from the phase III PEACE-1 trial, prostate irradiation in men with de novo low-volume metastatic castrate-sensitive prostate cancer (mCSPC), PEACE consortium, Prostate Cancer Consortium in Europe.

www.urotoday.com

Oligomet M1 prostate cancer receiving ADT and Abi should 100% receive prostate RT until a trial proves it is unnecessary. Why assume benefits are NOT additive across two different modalities (local vs systemic) when there are active trials accruing to give us an answer? Sure, if the trial is open at your instituion, then enroll in it.

Peace-1 does not show an OS benefit anymore with the addition of RT, unlike Stampede-Arm-H. The likely reason is that Abi eliminates this effect. It‘s only PFS that‘s better.

You'd rather advocate for patients to get combo Abi/Docetaxel rather than 55/20 prostate alone RT (+/- Abi)?

Treating mHSPC with ADT+RT only is no longer considered sound. These patients need an ARPI and high-volume disease benefits from triple therapy. The net benefit of RT in this scenario is unknown.

 

[Palex80]

Maybe the previous post was a bit harsh, but I feel like I'm seeing a trend that anything that supports radiation in any manner is immediately poo-poo'd. But seriously, if the trial is going to give us a result like this and we're not going to listen to it, while simultaneously ignoring, then why do we even run trials in the first place, if the first thing we're going to say is "well, it's out of date"?

Because we are running the wrong trials, quite often. This is my personal opinion.

 

[evilbooyaa]

Peace-1 featured a 2x2 design,

One question was if ADT + Abi was better than ADT. The other question was if RT to the prostate in M1 mHSPC adds anything.

The second question was presented at ASCO 2023

ASCO 2023: Prostate Irradiation in Men with De Novo, Low-Volume, Metastatic, Castration-Sensitive Prostate Cancer (mCSPC): Results of PEACE-1, a Phase 3 Randomized Trial with a 2x2 Design

ASCO 2023 results from the phase III PEACE-1 trial, prostate irradiation in men with de novo low-volume metastatic castrate-sensitive prostate cancer (mCSPC), PEACE consortium, Prostate Cancer Consortium in Europe.

www.urotoday.com

Peace-1 does not show an OS benefit anymore with the addition of RT, unlike Stampede-Arm-H. The likely reason is that Abi eliminates this effect. It‘s only PFS that‘s better.


Treating mHSPC with ADT+RT only is no longer considered sound. These patients need an ARPI and high-volume disease benefits from triple therapy. The net benefit of RT in this scenario is unknown.

I have not done a deep dive on PEACE-1 previously, but read through the website you linked.

Median f/u of 6-years to assume that OS would be benefited by 32% (goal HR of 0.68) in the experimental arms (in the MAIN group, NOT this tiny subset analysis you are quoting)? Not a realistic goal! Study massively underpowered to actually detect differences in the group that is. HR 0.77 adding RT to SOC + ABI, p=0.21.

I would say PEACE-1 is underpowered to tell us anything definite about SOC+Abi vs SOC+Abi+RT. Even if the goal was expecting radiation to cause a 32% relative improvement in OS, in prostate cancer, at a 6-year time point, I'd say that's a stupidly optimistic goal of what local therapy can add, especially in metastatic disease!

How do you reconcile that RT did not show benefit in the ADT (+/- docetaxel) alone arm?

Which of the curves would you rather be on, both for bPFS AND OS?

We all heard about the reduced prostate events thing, which I was not overtly excited about.

How about Castration/resistance free-survival? Again, which curve would you rather be on?

Yes, at 6-year f/u, RT did not show a statistically significant OS benefit (again, goal was HR 0.68?!) to SOC+Abi. A trial that is not powered to look at subset analyses or has completely insane ideas of how RT will benefit a patient is a trial that is underpowered, NOT a trial that is negative. Especially when looking at such a small sample size (126 patients in each arm for OS analyses!). And that's not even looking at the rPFS/CRFS benefits that are still seen.

So, we'll see when PEACE-1 patients actually start dying in the SOC + Abi arm that are low-volume. For the time being, I would have no qualms of continuing to recommend prostate RT in a low volume metastatic patient getting ADT + Abiraterone.

 

[Palex80]

I have not done a deep dive on PEACE-1 previously, but read through the website you linked.

I was under the impression that you didn‘t even know that Peace-1 had a radiotherapy question based on your previous comment

What does PEACE-1 have to do with prostate RT?

But thank you for taking the time to read it up. That’s what we are here for, to learn new stuff.


All fair points. I would merely like to remind you, that the absolute OS benefit in Stampere-Arm-H at 5 years was more than 5% with a HR of 0.68.

That‘s pretty much in line with what Peace-1 tried to prove, and failed. Yes, that‘s not how statistics work, but one would have expected to see the curves separating meaningfully But they did not.

And the reason is likely Abi.

 

[evilbooyaa]

I was under the impression that you didn‘t even know that Peace-1 had a radiotherapy question based on your previous comment

But thank you for taking the time to read it up. That’s what we are here for, to learn new stuff.


All fair points. I would merely like to remind you, that the absolute OS benefit in Stampere-Arm-H at 5 years was more than 5% with a HR of 0.68.

That‘s pretty much in line with what Peace-1 tried to prove, and failed. Yes, that‘s not how statistics work, but one would have expected to see the curves separating meaningfully But they did not.

And the reason is likely Abi.

I was not aware that it had a true RT randomization. All I had heard about the trial was the benefits but potential toxicities of adding Abi to ADT + Docetaxel (triple therapy), and the fact that RT maybe helped reduce major GU events (but one of the 'major GU events' was receipt of RT, so does that really count). My impression was that it was a ADT + Docetaxel +/- Abiraterone arm, and hey btw, some of the patients got some RT.

So, always happy to learn more, and I certainly have.

Good point about final result of HR 0.68 in STAMPEDE H in the RT arm. That being said, the benefit of RT (I suppose, if present) will be less dramatic , especially at an earlier time point, in patients already getting ADT + Abi +/- Docetaxel, than it would be expected for a population that only got Docetaxel 18% of the time (in STAMPEDE H), while 710/1172 (~60%) of PEACE-1 patients got Docetaxel (without even considering whether they got Abi or not)

I guess I'm struggling to figure out this subset analysis of 250 patients (125 in each arm) telling me that RT doesn't benefit. I find it hard to believe that 250 patients is sufficient to reach statistical power that they report in the abstract/presentation, when STAMPEDE arm H needed 2000 patients (1000 in each arm) to feel confident about finding HR 0.75 in their original trial - https://www.sciencedirect.com/science/article/pii/S0140673618324863?via=ihub

But, maybe, in patients getting triple therapy with ADT, probably Docetaxel, and Abi, prostate RT might not have a benefit.

Not sure how routinely I'm seeing that for low-volume metastatic disease as opposed to ADT + Abi + ablate all sites of disease.

I think I'll move this discussion to its own thread. It's a good one (IMO).

 

[yesmaster]

I don’t like 2x2 trials with stratifications for additional treatments (docetaxel). It muddies the waters.

My read of PEACE-1 is that patients are getting too much systemic therapy on trial, more than they’d get in the real world. After 2017, patients were mandated to get docetaxel and 50% of patients with mHSPC with low volume disease got docetaxel. That is way higher than I see in practice, for questionable benefit.

Radiation therapy still has PFS benefit and castration resistance free survival benefit. There’s a trend towards better OS for the most relevant subgroups (ADT/abi/RT vs ADT/abi) and my guess is that in the absence of docetaxel and with higher patient numbers, OS survival benefit would emerge as in STAMPEDE.

Finally, PEACE-1 low volume disease +/- XRT is also a subset analysis. Likely unplanned — I do not have the original protocol — regardless, the patient numbers are less than STAMPEDE by 30%. Plus if we take PEACE-1’s subset data at face value, prostate directed XRT should have MORE survival benefit with background of ADT/abi, versus background of ADT alone.

Sadly, I don’t get referrals for prostate directed XRT for low-volume mHSPC as an attending, as some of my med onc’s and urologists are behind the times. This may change soon.

 

[yesmaster]

One other thought — how did PEACE-1 treat oligomets for low metastatic burden subset of patients? If oligomets are untreated, the trial would overestimate the benefit of systemic therapy, since these oligomets could drive morbidity and mortality, without maximal systemic therapy. PEACE-1 would be a better and a more honest study (in terms of addressing benefit of prostate-directed XRT) if oligomets in the low metastatic burden subset were mandated to undergo SBRT, if safe.

 

[Palex80]

Finally, PEACE-1 low volume disease +/- XRT is also a subset analysis. Likely unplanned — I do not have the original protocol — regardless, the patient numbers are less than STAMPEDE by 30%. Plus if we take PEACE-1’s subset data at face value, prostate directed XRT should have MORE survival benefit with background of ADT/abi, versus background of ADT alone.

Why do you think so?
The HR in PEACE-1 (0.81) with the addition RT is not as good as in STAMPEDE (0.68) for the low-volume subgroup.

One other thought — how did PEACE-1 treat oligomets for low metastatic burden subset of patients?

No local treatment to mets.
STAMPEDE-2 will be looking into that.

 

[evilbooyaa]

I don’t like 2x2 trials with stratifications for additional treatments (docetaxel). It muddies the waters.

My read of PEACE-1 is that patients are getting too much systemic therapy on trial, more than they’d get in the real world. After 2017, patients were mandated to get docetaxel and 50% of patients with mHSPC with low volume disease got docetaxel. That is way higher than I see in practice, for questionable benefit.

Radiation therapy still has PFS benefit and castration resistance free survival benefit. There’s a trend towards better OS for the most relevant subgroups (ADT/abi/RT vs ADT/abi) and my guess is that in the absence of docetaxel and with higher patient numbers, OS survival benefit would emerge as in STAMPEDE.

Finally, PEACE-1 low volume disease +/- XRT is also a subset analysis. Likely unplanned — I do not have the original protocol — regardless, the patient numbers are less than STAMPEDE by 30%. Plus if we take PEACE-1’s subset data at face value, prostate directed XRT should have MORE survival benefit with background of ADT/abi, versus background of ADT alone.

Sadly, I don’t get referrals for prostate directed XRT for low-volume mHSPC as an attending, as some of my med onc’s and urologists are behind the times. This may change soon.

As Palex also noted, I don't think the data supports the bolded. For some reason, it makes snese to me as well. We know there can be dramatic responses to ADT (with or without second generation ARSI) in the primary, to the point where people get ADT alone for curable prostate cancer and don't have catastrophe until years down the line. So I'm not surprised ARSI improved outcomes across the board, thus making the potential risk reduction with RT be less pronounced. I think docetaxel probably contributed as well, which is not commonly used (most de novo mCSPCs are getting Abi/Enza + ADT, not Chemo).

I believe the subset analysis is planned. I just don't know if 250 patients is powered enough to definitively say OS is not improved. I'm open to the idea that the benefit of RT may not be as strong in the Abiraterone era. But I'm not sold that there is NO benefit.

 

[ramsesthenice]

As Palex also noted, I don't think the data supports the bolded. For some reason, it makes snese to me as well. We know there can be dramatic responses to ADT (with or without second generation ARSI) in the primary, to the point where people get ADT alone for curable prostate cancer and don't have catastrophe until years down the line. So I'm not surprised ARSI improved outcomes across the board, thus making the potential risk reduction with RT be less pronounced. I think docetaxel probably contributed as well, which is not commonly used (most de novo mCSPCs are getting Abi/Enza + ADT, not Chemo).

I believe the subset analysis is planned. I just don't know if 250 patients is powered enough to definitively say OS is not improved. I'm open to the idea that the benefit of RT may not be as strong in the Abiraterone era. But I'm not sold that there is NO benefit.

Your instincts make perfect sense to me. I have always viewed that most likely way radiating the disease you know about in this situation is by delaying the emergence of castration resistance and prolonging responsiveness to ADT. That's surprisingly hard to prove but if you are like me and have those subjects we end up playing whack-a-mole every time the PSA starts to rise on ADT, there seems to be some evidence to support the general idea (in at least some situations). If I am right, that means radiation and Abi/Enza are probably doing the same thing to some extent. They may still do good things together but if anything, it probably would shrink any absolute improvements with RT.

 

[Chartreuse Wombat]

I believe the subset analysis is planned. I just don't know if 250 patients is powered enough to definitively say OS is not improved. I'm open to the idea that the benefit of RT may not be as strong in the Abiraterone era. But I'm not sold that there is NO benefit.

From the presentation slides the OS HR (95% CI) for the SOC + Abi + RT (referent SOC) arm is 0.81 (0.55-1.21). Judge for yourself whether this is sufficient to rule out an effect. It is not in my book.

 

[evilbooyaa]

From the presentation slides the OS HR (95% CI) for the SOC + Abi + RT (referent SOC) arm is 0.81 (0.55-1.21). Judge for yourself whether this is sufficient to rule an effect. It is not in my book.

As Palex educated me, HR was 0.68 in STAMPEDE, and the authors assumed HR of RT would be 0.68 again, even with Docetaxel/ADT. Maybe the HR of adding RT is 0.80-0.85 with addition of Abi/Docetaxel....