Episode 137: PEACE1 overall survival in prostate cancer

Dr. Karim Fizazi describes the OS benefit of the triplet.

  Brian: Hey everyone. Welcome to another ESMO 2021 podcast. Tom and I here with Karim Fizazi. We have some exciting new PEACE-1 data being presented. We did a podcast with Karim after the last presentation, the initial presentation of PEACE-1, which showed an rPFS advantage and there’s data being presented at this ESMO to update. It has been an area of debate and we’ve had other guests on sort of commenting on this. So Karim, welcome. If you just want to briefly re-introduce yourself and then maybe just start off by sort of summarizing where we were before ESMO in terms of the PEACE-1 data. Dr. Karim Fizazi: Sure. Thank you, Brian and Tom for giving me this opportunity. So I’m Karim Fizazi, medical oncologist here at Institut Gustave Roussy in Villejuif, France. So PEACE-1 is a phase three trial which is looking at whether we should combine different active treatments in men with de novo metastatic prostate cancer. As I guess we all know, the field has changed dramatically in the last five years with the demonstration that docetaxel, abiraterone, other hormonal agents, and actually also radiation therapy directed to the prostate oligometastatic disease. All are associated with overall survival improvement in these men with de novo metastatic prostate cancer. Dr. Karim Fizazi: [inaudible 00:01:46] know before PEACE-1 is whether we should actually combine these new treatments on top of androgen deprivation therapy. So the design of the trial is a large phase three trial, two-by-two design, and we are randomizing patients to receive ADT or ADT plus docetaxel. So standard of care treatment, depending on the time, plus or minus abiraterone and plus or minus radiation therapy directed to the prostate. Dr. Karim Fizazi: Regarding the radiation therapy question, the jury is out as I’m speaking, it’s too early. And I’m saying that because we want to focus on men with oligometastatic disease. So men who have better outcomes, and obviously for these men, we need a longer follow-up. The number of events remains low for these men, which is of course a great thing for them because it means most of them are alive. So I won’t speak about radiation too much today. Dr. Karim Fizazi: But regarding the second question, which is that of abiraterone on top of ADT plus docetaxel, what we reported before ESMO, so mainly at ASCO three months ago, was that adding abiraterone on top of ADT plus docetaxel very clearly prolongs progression-free survival. And I’m speaking about radiographic progression-free survival. So an objective way to assess PFS, with medians of two years in the control arm with ADT docetaxel, and four and a half years for men receiving abiraterone one on top of that. So an absolute delta in medians of two and a half years, which is really impressive I think. So this was really the situation before ESMO. Brian: Thanks, Karim. Thanks for that summary. So I think probably some of the most traumatic rPFS effects that have been seen in this setting, if I’m not mistaken, but there seem to be some controversy. You sort of presented it in a strong fashion about triplet therapy being standard. We’ve talked to others who were sort of less convinced that triplet was standard, but of course everybody was waiting for the survival signal. So can you update us on what you’re going to present at ESMO? Dr. Karim Fizazi: So basically what we’re showing here at ESMO is that indeed overall survival is also significantly improved when adding abiraterone on top of ADT plus docetaxel with 25% reduction in the risk of death. Hazard ratio is 0.75, and the difference is indeed significant. The median of overall survival in the control arm with ADT docetaxel is as expected, approximately four and a half years. And it’s not even reached in the triplet arm when abiraterone is added, which of course is just great. Tom: And Karim [crosstalk 00:04:57]. Dr. Karim Fizazi: Now, when looking at the two main subgroups that people are paying most attention to, which is the high volume and low volume patients, we see that for patients with high volume, the difference is very evident. 3.5 years as a median for standard of care with ADT docetaxel, versus 5.1 years. So more than five years for probably for the first time when abiraterone is added up on top of the doublet. And again, the difference is very significant with 28% reduction in risk of death. Dr. Karim Fizazi: On the other hand, for patients with low volume disease, the number of events is very low, actually the subgroup is also smaller. So we will need a longer follow-up to see whether overall survival is also improved for these men with better prognosis. Brian: Karim, remind us the definition of high and low volume for this study. Dr. Karim Fizazi: Right. We actually use the charted definition, but regardless of a definition, we also looked at the risk definition by latitude. We basically find the same trends. Big difference for patients with high volume, too early to say for patients with low volume, simply because most of these men were alive when we performed the analysis. Tom: Karim, are there any other subsets that are significant? Dr. Karim Fizazi: Pardon me, Tom? Brian: He was asking if there are any other subsets that are significant or clinically noteworthy. Dr. Karim Fizazi: Well, actually we serve as the same trend across the board for patients with and without radiation therapy, for patients with good performance status zero, versus those with performance status one or two. Also, we looked at the way people were using castration, LHRH agonist versus LHRH antagonist versus surgical castration. It’s really the exact same trend as compared to what we saw in the overall population. So no specific subgroup. I think the only subgroup which is really major is the low burden disease subgroup. Again, just because the number of events is just too low for this- Tom: And Karim, what about the shapes of the curves? Do they go apart and stay apart? Dr. Karim Fizazi: Brian, I think you have to repeat. I could not hear. Brian: So Karim’s having trouble hearing Tom, everyone, so I’m interpreting Tom, which is something I do for a living. I feel like I interpret Tom. But Karim, he was asking you about shapes of the curve, whether they go apart and stay apart, come together. And is there a plateau of the curve, a higher tail of the curve? I think that’s what the question was. Dr. Karim Fizazi: Sure. So we start to separate after one year and a half or two years say, and the more time of a greater of a difference for these patients with ADT docetaxel as with standard of care. The plan is eventually to reanalyze the data with more events. This was obviously pre-planned, this was a local primary endpoint and we needed at least 250 death events to run this analysis in the ADT docetaxel population. But by protocol, we will be able to reanalyze the data in some years from now and to see really how the curve really separates or not in the very long term. But to address your question, Tom, yes, the curve separates nicely starting after two years or so. And the more time, the more of a separation. Brian: Do you have data on what percent of the control arm ultimately received abiraterone or a similar drug? I assume it’s the majority. Dr. Karim Fizazi: You’re very right. And this is really what impressed me in this trial also. More than 80% of men received at least one life-prolonging agent, and actually more than 80% of them received either abiraterone or enzalutamide or darolutamide or apalutamide. But that’s really [inaudible 00:09:25] it’s really quite unique amongst the trials we saw in the past. It’s really testing early versus deferred. And it’s really showing us that early is indeed better for both rPFS, but also by overall survival, which I think is key. Tom: Karim, there’s been some criticism of the trial design, particularly people- Dr. Karim Fizazi: Pardon me? Tom: There’s been some criticisms of the trial design, particularly the control arm not having- Dr. Karim Fizazi: I really couldn’t hear. I’m sorry. Tom: Brian, you might have to ask that for me. I’m really sorry. Brian: Yeah. It’s okay. Tom was asking about the control arm because the control arm is hormones, chemo. And I think at least, well, at least I know the US patterns, most people are getting sort of hormones abi or hormones enza. And the question is about adding chemotherapy. So I think that was the impetus of the question. Dr. Karim Fizazi: Yeah. So remember that the trial accrued patients between 2013 and 2018. So this was before basically abiraterone and enzalutamide, apalutamide were approved for use in the M1 castration-sensitive disease. So at this time, ADT alone at the beginning of a trial, and then starting in 2015 ADT plus docetaxel was the standard of care. So this is of course why we use this as the standard of care, because it was simply what was approved and recommended by guidelines at this time. Dr. Karim Fizazi: The next generation of hormonal agents came afterwards. And this is why it’s really not a part of the control arm. But actually this is not an exception. If you think about other diseases, this is what we’re doing all the time. If you take, I don’t know, GI cancer, colorectal cancer, people started with [inaudible 00:11:19] alone, and then continuous infusion, and then folinic acid on top of that, and then mixing the two and then adding bevacizumab, et cetera, et cetera. But every time you’re adding something on top of your previous standard of care, you keep the standard of care as it was. So this is exactly what we did in this trial. The trial is not addressing the question whether docetaxel adds something on top of ADT plus abiraterone, it was not the goal of this trial. And actually at the time we did the trial, it would have been probably just unethical to do it because abiraterone was not proven overall survival in these men. Brian: I guess the question is practically, probably nobody’s going to go back and do that trial. That nobody’s going to go back and do LHRH abi plus minus docetaxel. Do you agree? My sense is with a survival benefit that we’ve moved to triplet therapy, and nobody’s going to go back and test the different permutations of doublet versus triplet. Dr. Karim Fizazi: Well, at least I don’t think I would do it to be honest. People might consider doing it. If I’m trying to put this data in the context of all what we’ve learned in the last five years. For example, for patients with de novo high volume disease, these men had a life expectation of less than three years in the mid 2010s. So with ADT alone. So let’s start with three years. Dr. Karim Fizazi: ADT plus docetaxel was associated with a median overall survival of approximately 43 months in these men when you take into consideration all the randomized trials. Now, ADT plus abiraterone probably did better approximately 53 months median overall survival. And we’re now seeing 61 months for these men using the triplet. So it truly seems of course that every time you’re adding one of these agents on top of the previous standard or on top of a doublet, whatever it is, you’re getting some additional life for the patient. Of course we don’t have all the answers, and for sure PEACE-1 is only addressing whether abiraterone adds anything on top of ADT plus docetaxel, not the reverse question. But I think indirectly, we have part of the answer and I strongly believe that we should change our practice, at least for patients with de novo high volume disease. Brian: So Tom texted me a question. How do you reconcile these data with ENZAMET? There was no overall survival advantage in ENZAMET. And I realize they’re different trials, but what are your thoughts on that? Dr. Karim Fizazi: Correct. I think probably for ENZAMET the jury’s out for the triplet question. And I hope Chris and his colleagues will be able to show their data as soon as possible. And I think he will. Because when he first reported the data two years ago, I think the trial was made sure regarding the addition of enzalutamide on top of ADT. Like in this one, these men were first randomized in his trial, but for the ADT plus docetaxel plus or minus enzalutamide question, I think the follow-up was really too short, at least for overall survival. It was fine for PFS, and actually there was a benefit for PFS with a triplet. But for overall survival, when he reported the data, most men were alive. So we’ll see. I think he’s working with his colleagues on updating the data and we’ll see how it goes. Dr. Karim Fizazi: It might just confirm what we saw with abiraterone in PEACE-1. It may not. The safety might be an issue based on what he reported with a triplet with enzalutamide, which is not something we saw with abiraterone in all the triplets. The safety profile was really the one we were expecting with abiraterone, with classical stuff, additional hypertension, mild hypokalemia and sometimes [inaudible 00:15:41] increases, but nothing really bad. So we’ll see for ENZAMET. And this is also true for ARAMIS, which is testing the same hypothesis with darolutamide. Brian: And so you mentioned you think it’s the standard of care for high volume. What about low volume? It may take a while for all those events to play out of course. So if a low volume patient walks in tomorrow to your clinic, how are you going to treat them? Dr. Karim Fizazi: Well, I guess it depends what you think about RPFS versus OS. For men with low volume disease, there is also a very clear rPFS benefit. The hazard ratio was 0.58 and the median was 2.7 years for the control arm. And actually it was not reached for the abi arm, but you can tell by the curves that there is a strong benefit in rPFS. OS is really too immature. Dr. Karim Fizazi: So I guess I would speak with my patient if you’re asking me individually what I would do with my patient. I would just explain the situation and we’d probably make a decision together. Either I would start with ADT plus next-generation hormonal agent for these men, or for some of them, maybe I would consider using the triplet. Of course, the patient has to be fit. And maybe when it’s borderline low volume man, say extensive lymph node metastases and free bone metastasis, including some big ones or something like that. Those men, I would probably discuss strongly the data with them. But I fully understand also if colleagues are still using ADT plus a next-generation hormonal agent without chemotherapy for this man based on the available data. Brian: There’s no reason to think that the rPFS benefit in low volume won’t necessarily translate, right? It’s a pretty similar rPFS benefit. So there’s no biologic reason, I guess is what I’m asking, to think that it would be different. Dr. Karim Fizazi: I agree. It’s more a question of time. You may argue, depending on how long people live, wherever they might just die from other reasons. Because in low volume prostate cancer, the current overall survival expectancy is probably somewhere between five and 10 years. So also depending on the age and comorbidities, the patient might just die from something else. So, but otherwise I’m with you. I agree with you. If they live long enough, they will very likely benefit from the triplet as patients with high volume disease are. Brian: Sounds like it’ll, as you’re suggesting, at least for the time being, it may be forever be a personalized decision in that low volume patient. Whereas for the high volume or visceral mets, it might be a little more clear to use the triplet. Dr. Karim Fizazi: I would agree on that. I think this is reasonable. Yeah. But again, coming for the high volume patients, this remains a lethal disease. We have different mechanisms of action, different toxicities with no synergy between the toxicity and the data show better outcome by both PFS and OS. I think it just makes all sense to combine starting now and use as a triplet for these high volume men. Brian: So, Tom’s asking you about if the trial amendments had an effect on the results. I don’t remember exactly the details of the amendments that happened during the course of the trial. Dr. Karim Fizazi: Well, actually the amendments were mostly about effects when the data came out from the other trials, so that the next patients to come would receive appropriate standard treatment. So actually the main amendment was to allow for docetaxel use as part of standard of care in 2015, when CHAARTED and STAMPEDE came out. So this really what was the main one. Dr. Karim Fizazi: And then two years after that in 2017, docetaxel became mandatory for patients to be randomized in the trials because we didn’t want to randomize anymore ADT versus ADT plus abiraterone just because the LATITUDE and STAMPEDE abiraterone data were out, and we felt it was just unethical to randomize this question further more. So those were really the main amendments. The rest of the amendments were technical amendments to allow more countries, more European countries to [crosstalk 00:20:47] Brian: Sure. And did you see, when the more major amendment happened, did you analyze based on time of enrollment? Is there any sort of analysis based on that? Dr. Karim Fizazi: Well- Brian: To see if the effect size changed or something. Dr. Karim Fizazi: Sure. So of course you need to be cautious because those are sometimes small subgroups. The biggest of these small subgroups is the first one before the first amendment. So before we allowed for docetaxel. So the question was ADT versus ADT plus abiraterone. And we see exactly the same trend as in LATITUDE and STAMPEDE. The abi arm being better. So this is really the same thing. Brian: Any updates this year in terms of toxicity, obviously, as we get into more and more drugs for these patients? Dr. Karim Fizazi: Yeah, this was quite reassuring to me. When we reported the data at ASCO, we had only six first month for toxicity. So mostly chemo toxicity, and there was nothing bad. But I was feeling that in the longer term we might see worst data. Actually, it’s not the case. Again, the febrile neutropenia remains the same, 5% in both arms, but regarding long-term toxicity, it’s really reassuring. We saw 6% liver toxicity versus 1%, which is in the range of what you would expect with abiraterone. Hypertension is 22% versus 13%. And this is mostly manageable. Hypokalemia only 3% grade three, four versus zero. Cardiac toxicity, I think we saw six events versus five. Fatigue is at least numerically lower in the abiraterone prednisone arm. Dr. Karim Fizazi: So really nothing bad. And actually this is not even counting the different exposure to drugs because we stopped the assessment when patients progressed. So of course, patients in the abiraterone arm had a much higher likelihood for, if you will, to develop some toxicity just because we collected the data much stronger for these men. The difference is not there. So I think this is quite reassuring to me. It really means that we can use, and actually we use abiraterone with a median of approximately three years in the trial. So it means that even with three years of abiraterone this is quite safe in this combination. Brian: Well, Karim, these are great data. Certainly practice changing. And I think we’re going to be sort of building on these for years to come. So congrats on this. Tom [crosstalk 00:23:48] Tom: Yeah. Congratulations, If you can hear me, Karim. Can you hear me? No, still can’t hear me. Well, congratulations. Dr. Karim Fizazi: I hear part of what you’re saying, Tom. Sorry. Tom: Well, congratulations. Brian: He just said congratulations. This has been one of my favorite podcasts because Tom couldn’t speak. So he couldn’t interrupt me. So this has been amazing, but anyway, congratulations. Karim, we really appreciate your time. This is an amazing data. We look forward to discussing it further. Thanks again. Dr. Karim Fizazi: Thank you guys. Brian: All right. Take care. Dr. Karim Fizazi: Thanks. Bye. Brian: See you soon.

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