Karim Fizazi: My pleasure, Leslie, really. So this is about, as you rightly said, this is about the PEACE-2 phase-three trial, which is for patients with very high-risk localized disease. It's actually asking two questions. I'll come back to that in a second. Number one is about drug, and the other one is perhaps even at most interest to you, Leslie. It's a radiation question, should we radiate the pelvis or only the prostate in these men? But just to give you a bit of background, when we designed the trial, which was long time ago, basically more than 10 years ago now, very high-risk localized disease could be defined by various definition, obviously, but this could be designed by at least two risk factors among the classical T3-T4, high Gleason score eight to 10, PSA greater than 20. And already at that time, we understood that having only one of those risk factor did not any longer qualify yourself as a patient as really high-risk disease or very high-risk disease.
Radiation ADT really cures most of these patients. So we felt that the real subgroup of men with localized disease that we were not able to cure over time were really those patients with two or three of these high-risk factors. Of course, they had to had no detectable disseminated disease, nodal disease, no metastasis [inaudible 00:02:17] in by conventional imaging. And actually during the time course of a trial, some of these patients had also either choline PET or PSMA PET as the way they were assessed at baseline. Already at best time, the main standard of care was combining radiation therapy plus long-term ADT. In Europe, we used more three years. And I know, of course, this is debated. Some people use two years, some people use one and a half, but again, we believe that for these patients with very high-risk disease, three years of ADT was actually appropriated.
Already at this time, there was debated role of pelvic radiation therapy versus prostate only. We knew that docetaxel could improve relapse-free survival GETUG-12 and subsequently some other trial confirmed that data. Cabazitaxel at this time was emerging as an important drug for CRPC for castration-resistant disease with benefiting overall survival, and it was approved by many agencies worldwide at this time. And since then, we saw more recently, should I say, some discrepancy in outcomes for trials testing androgen receptor pathway inhibitors. In STAMPEDE five years ago, we saw positive OS data with abiraterone, but more recently in ENZARAD last year we saw more negative data with enzalutamide, and we may debate why so. This is the design of PEACE-2. As I said, patients with very high-risk localized disease, two or three risk factors. 761 patients agreed to be randomized to receive the either ADT three years plus radiation or the same plus radiation targeting the pelvis or cabazitaxel added to ADT radiation.
And in that case, we gave cabazitaxel during the first three months of ADT right before the radiation was prescribed or everything in arm D, ADT for years, cabazitaxel, four cycles and radiation prostate and pelvis. The primary endpoint was clinical progression-free survival. I'll come back to you in a second to the definition. Treatment, as I said, three years of ADT, the way you wanted agonist or antagonist. Radiation therapy, 74 to 78 grades using two grades fraction. This was before the eve of hypofractionation. IMRT was mandatory. Radiation was started three months after initiation of systemic treatment, and in case the patients was randomized for pelvic radiation, 46 to 50 grades were given. Regarding cabazitaxel, four cycles were given with GCSF support, and the dose was 20 to 25 milligram per square meter, depending on local practices. So this is a 2X2 phase-three design. The hypothesis was that either one or both of these treatments would improve clinical progression survival with events including death, metastasis, and proven local relapse, but not PSA relapses.
This is why we call it clinical progression-free survival. We needed approximately 250 events, and this is actually what we had last year when we did the analysis. Accrual time, 2013 to 2021 in four European countries and you see thee map. What is nice in the trial is that we have quite a long follow-up, seven year plus, which I think is reasonable for this population of patients. And we couldn't detect any interaction between the effect of cabazitaxel and that of pelvic radiation, which is always good because then you can pull together the two arms and get a greater power to detect a benefit if it exists.
This is just a short description of the population for the main parameters. Most patients had T3-T4 disease, approximately 90% of them. Median PSA was more than 20, and basically 80% of the patients had two risk factors, 20% had three risk factors, so clearly a very high-risk population by all historical definition. Median age, approximately 67 years. This is the primary endpoint of the trial. And as you can see, we don't see any benefit of adding cabazitaxel to radiation and ADT in terms of clinical progression-free survival. Really no benefit at all. And the same actually applies to secondary endpoints such as biochemical progression-free survival, which is capturing PSA relapses as an event, but also metastasis-free survival, we don't really see a benefit. The slide probably shows the good news from this trial, which is that patients don't die, which at the end of the day is what we want to see. This is really the worst population of patients with localized disease. Again, two or three risk factors and a normal CT scan and bone scan, but still, by approximately 10 years time, only 10% of the patients eventually die from their cancers.
So I think this is very reassuring. Clinically speaking, it means that when we're now facing someone with localized disease, regardless of the risk factors, we can safely tell them, "Hey, calm down. I mean, this is not pancreatic cancer. With the current treatments, you'll be with us in 10 years." Which again, is something I would have dreamed saying 20 years ago when I started all those things. The curves of these patients were much worse as compared to what I'm showing here. Safety, no big thing and no drama. Obviously, ADT radiation is usually well-to-rated, as we probably all know. You see the single digit grade 3-4 toxicities. And for cabazitaxel, we mostly saw what we expected with mostly some neutropenia and neutropenic fevers, but not a lot, diarrhea, but that's mostly it. So nothing terrible here. Conclusion, cabazitaxel does not improve outcomes. This is the only phase-three trial in localized disease for cabazitaxel as far as I know.
We should probably not use it, but it was important, of course, to test the hypothesis. Data regarding pelvic radiation therapy will be shown hopefully soon. We decided that we should split the two informations because they obviously are potentially different. I know a large US phase-three trial read out last year, so let's see how it fits with this data. I think this will be interesting, and I'll be happy to hear your comment, of course, Leslie. But again, as I said, only one out of 10 men will eventually die from prostate cancer by 10 years time. Again, selecting the worst situations in this localized setting, which I think is very encouraging. But it means also that if we are on top of what I just showed, incorporate and integrate PSMA PET in the baseline assessments of these men, and those remove the few patients with detectable disseminated disease to the metastatic box, then it will become more and more difficult to conduct efficacy trials in what we used to call high-risk localized disease, because most of the game I think is already won in favor of patients.
Of course, I'd like to thank the patients and families, caregivers, clinical research staff, sponsors, versus an academic trial. It's always an enormous effort to conduct these trials and to have seven patients, 700 patients agreeing to participate and follow them for seven years plus. So really a big, big thank you to all those who made this trial reality. And with this, I think I can stop sharing my screen and discuss this data with you, Leslie, if you will.
Leslie Ballas: Thank you so much, Professor Fizazi. That was wonderful. I know that the trial was initially supposed to accrue 1,000 patients, and in the end, 700 plus patients were accrued. Is that because patients did not want to be randomized between the cabazitaxel? Was it lack of equipoise on the part of the investigators? What led to that decrease in accrual?
Karim Fizazi: Patients mostly said yes. As you saw, I mean, 700 plus patients said yes. It's more that we had difficulties opening more countries as we were initially planning. Initially, we were hoping to open the five big European countries and some smallers, but for various reasons, we could not make that. It was mostly France and Spain at the end of the day. Italy contributed less. Belgium helped, but we didn't have Germany, the UK for various reasons. And again, whatever the reasons are, and those are individual. So this was more a pragmatic decision to close the trial earlier. Also, because at the end of the day, what's most important in the trial is the number of events, not the number of patients. And we knew that with 700 patients and for quite long follow-up we had, we would reach anyway, the number of initially planned events, so we would not lose any power.
So this is why we decided to shut down the accrual also to save money. Again, this is an academic trial. So it's very important, of course, to be very careful with money waste if we want to do more trials. But again, I'm quite confident with the data. I don't think occurring 300 patients or so additional patients would have make any difference with regards to the data.
Leslie Ballas: I want to take a minute to discuss this definition of very high-risk. Obviously, this trial was conducted at a different time. We're nine, 10 years out from, over that actually when you started accruing, 2012. Currently, our NCCN guidelines have a very high-risk definition that is similar, but a little bit different. Very high-risk is T3, T4, Gleason eight to 10, and a PSA greater than or equal to 40, whereas yours was greater than or equal to 20. How do you think that that difference would affect the patients or the results really of the trial?
Karim Fizazi: Yeah. The NCCN classification basically is based on the STAMPEDE definition, STAMPEDE trial. Frankly speaking, I'm not sure the definitions are very different. The main difference with STAMPEDE, the trial, the STAMP trial, is that the imaging is different because typically in STAMPEDE, at least at this time, they were using planar bone scan. So in other words, just one image with no direct and immediate correlation with a CT component. And because of this, first you missed a lot of metastatic disseminations, so there are false negatives, but also you have false positive, which actually may explain, for example, why STAMPEDE abiraterone for very high-risk is positive and very positive while ENZARAD is not. They were not done in the same countries. I mean, the drug at the end of the day, abiraterone and enzalutamide are very similar, or at least their efficacy is very similar. We all know it.
They may have different safety issues, but really the efficacy you would expect the same. And really out of a sudden, you have two trials with apparently similar populations, but different outcomes. One big OS benefit, STAMPEDE, one with zero OS benefit. And I really believe that this comes to the imaging techniques that were used. And in STAMPEDE, I strongly believe that many patients who were called very high-risk, localized, actually had metastasis, just because they had only a planar bone scan, nothing else, no CT, no correlation between CT and bone scan, no PSMA PET, no MRI, no nothing. So actually, their data probably reflects the benefit we know from AR pathway inhibitors in metastatic disease. Now, in ENZARAD, the imaging techniques were more modern, simply they more reflect what probably you, Leslie, and I are doing in our practice. And probably we are probably more able to identify patients with upfront metastatic deposits that STAMPEDE was not able to detect 10 years or 15 years ago.
Leslie Ballas: Yeah. I think that's a really important point and one that you brought up certainly during your presentation as well. As imaging has improved, the patient population is definitely very different and our separation of patients is quite different. I, of course, was hoping that we would get a sneak peek at arms A versus B, the difference in the radiation fields. As you mentioned, RTOG 0924 reported out earlier this year at ASTRO showing no difference in overall survival between whole pelvis and prostate only. And of course, there's a trial from Vedang Murthy, POP-RT, that looked at this question as well of prostate only versus whole pelvis. And that did incorporate a PSMA PET scan. So it will be very interesting to see how your data compares to 0924, which is sort of the most similar in its nature. Is that data forthcoming?
Karim Fizazi: I think so, but I guess I'm more [inaudible 00:18:40] with Congresses. I can tell you that the data are being submitted. Now, whether Congress says yes or no, all these things, you need to be humble, but let's say that hopefully the data will be presented, let's say before the summer.
Leslie Ballas: Wonderful. The other thing that I think is a really terrific take home that you highlighted was the 90% prostate cancer specific survival at nine years in these patients. That's higher than I would've expected, obviously, and higher than I think we're seeing today with more modern imaging, probably because we're separating patients. So do you think that that 90% prostate cancer-specific survival is for a more favorable or unfavorable high-risk patient population?
Karim Fizazi: Well, again, as I said, all these men had not just one, but actually two or three risk factors.
Leslie Ballas: Mostly two.
Karim Fizazi: Yeah, true. You're right. Mostly two for 80% of them. But truly, I'm like you, and actually our expectation was that more of these men would die. I don't think the causality of death is in curves. For the sake of time during the Congress, I did not present overall survival, but obviously we also have this data, and I can tell you informally that overall survival data are very good as well. They're really basically, I mean, typically these patients in approximately half of the case die from their disease and the other half will die from another cause. So you may imagine easily what the numbers are at approximately 10 years for OS, but really we were expecting more patients dying by this timeframe, given how we selected these men quite stringently. So it's good news really. I really believe it's good news. It probably reflects the progresses in radiation therapy.
Not saying that because your radiation therapy is because, but it's really because I strongly believe it. Most patients also truly receive three years of ADT. Most patients did not stop after six months or so, so it may also reflect the benefit from that and potentially also reflecting treatments that we are using more aggressively for relapse and probably earlier in the course of a disease, rare radiation, but also early use of systemic treatments for PSI relapses or for minimal oligometastatic relapses. Those are all the reasons I would see for interpretation. Don't know whether this is true or not, but whatever the reasons is, it's just great news for patients, really.
Leslie Ballas: I agree. Professor Fizazi, again, thank you for joining us and going over this abstract. It was really a treat to get to talk with you.
Karim Fizazi: Thank you very much for having me today. Anytime. Have a good one.