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Jan 6, 2022

Dr. Karim Fizazi, medical oncologist at Gustave Roussy and professor in Oncology at the University of Paris-Saclay in France, tells guest host, Neeraj Agarwal, editor-in-chief of ASCO Daily News and director of the Genitourinary Cancers Programs at the University of Utah’s Huntsman Cancer Institute, about the practice-changing PEACE-1 trial, an ongoing phase 3 trial among men diagnosed with de novo metastatic castration-sensitive prostate cancer.



Dr. Neeraj Agarwal: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, the director of Genitourinary Oncology Program and professor of medicine at the University of Utah Huntsman Cancer Institute and editor-in-chief of the ASCO Daily News. Our topic today is the practice-changing PEACE-1 trial, an ongoing phase 3 trial among men with de novo metastatic castration-sensitive prostate cancer.


Joining me today to discuss the results of this trial is Dr. Karim Fizazi, who is a world-renowned medical oncologist practicing at Gustave Roussy and a full professor in Oncology at the University of Paris-Saclay in Villejuif, France. Dr. Fizazi has led multiple practice-changing trials in advanced prostate cancer and is also the founder of the Prostate Cancer Consortium in Europe known as PEACE Consortium. Our full disclosures are available in the show notes, and disclosures related to all episodes of the podcast can be found on our transcripts at the podcasts. Welcome, Karim. It is so great to have you on the podcast today, and thank you so much for taking time to be with us.


Dr. Karim Fizazi: Thank you very much, Neeraj. It's a pleasure and an honor.


Dr. Neeraj Agarwal: You recently presented the primary results of the phase 3 PEACE-1 trial in men with de novo metastatic castration-sensitive prostate cancer in the ESMO 2021 meeting. Could you please tell us more about the design of this study and why you did this study?


Dr. Karim Fizazi: Sure, yes, happy to do so. So, PEACE-1 is a large academic European phase 3 trial, which is enrolling patients with de novo metastatic prostate cancer. And it is basically asking 2 questions. Number 1, should we add abiraterone acetate on top of standard of care for these men? And in most of them, standard of care consisted in androgen prevention therapy plus chemotherapy with docetaxel. So, this is the number 1 question—in other words, 3 drugs instead of just 2.


And the second question is whether we should use radiation therapy directed to the primary cancer in these men who are treated with intensive systemic treatments? And we're doing that because we already know the answer regarding the radiation question, and it's a yes answer for men who received androgen deprivation therapy (ADT) alone, but we don't really know whether this applies when intensified treatment is being used.


So, it's a 2x2 design, and we were able to enroll almost 1,200 men in the trial. We completed the inclusion in the trial back in 2018, so the patients or at least those who are alive are on follow-up. And this year, 2021, we have analyzed the co-primary endpoints of radiographic progression-free survival and overall survival for the abiraterone equation. In probably 1 or 2 years from now, we will be able to do the same thing regarding the radiation therapy equations when we have sufficient number of events for these patients.


Dr. Neeraj Agarwal: Very interesting trial design and massive effort at the multinational level in Europe. So please tell us about the results of the study and how it will affect the current treatment paradigm of our patients with de novo metastatic castration-sensitive prostate cancer.


Dr. Karim Fizazi: Sure. So, as I said, right now, we have data regarding the abiraterone question. And again, the question is whether we should use ADT plus docetaxel with or without abiraterone acetate and prednisone. At ASCO [Annual Meeting] this year, we reported the radiographic progression-free survival data, which is a co-primary endpoint of the trial, and this is clearly positive (Abstract 5000). If patients received 3 agents—ADT, docetaxel, and abiraterone—they will enjoy 4.5 years without radiographic progression or death in the experimental arm versus only 2 years in the control arm. So, in other words, this mean 2 and a half year of additional life without problems, if you will, without a significant progression or death for this patient, which is big.


I think many people were already convinced with this data and thought this could be practice changing. I remember our discussion, you and me, Neeraj, at this time. But some others were not necessarily convinced and request the overall survival data before making their decision. Or if it's possible to collect the events, and of course, in the COVID-19 times, this has been challenging. But I think we made it, and we were able to show the data for overall survival at ESMO this year in September. And of course, this was planned—pre-planned and dependent on a pre-planned number of events, which was reached.

The news here is good again. And actually, patients receiving ADT plus docetaxel plus abiraterone clearly have an improvement significantly by overall survival as compared to those who received just 2 treatments. The reduction in the risk of death was approximately 25% for these patients receiving the triplet treatment, and it's even greater for men with what we call high-volume disease, so those with multiple bone metastases, at least 4, or visceral metastases, of course, men with a poor outcome.

For these men, the reduction in the risk of death achieved by the triplet treatment was 28% in reduction of risk of death and was translated in a marked difference in medians, 3.5 years in the control arm with ADT plus docetaxel, and this was actually what we were expecting for this population of men, as compared to 5.1 years for patients receiving the triplet treatment. So, in other words, it's more than 1 and a half additional year of life for these men receiving 3 treatments up front.


I think what is very unique also in this trial is that men in the control arm were treated very aggressively when they progressed. And actually, more than 80% of them received at least one next-generation hormonal agents, and basically, 85% of them received at least 1 drug associated with proven life prolongation. Again, this is in marked contrast to what we saw in previous pharma industry-sponsored trial conducted in the past, where patients in the control arm were not necessarily very aggressively treated. This is clearly showing us that—


Dr. Neeraj Agarwal: Yeah. This is very interesting. I was really impressed by the fact that patients in control arm and as well as experimental arm—so basically patient on ADT plus docetaxel versus ADT plus docetaxel plus abiraterone—more than 80% patients were receiving subsequent life prolonging therapies, which is in marked contrast to other trials we have seen in the recent past. And despite that, you were able to show a remarkable, clinically meaningful improvement in overall survival with the triplet therapy. I think that is the most important message I got from the updated presentation in ESMO 2021. Would you agree?


Dr. Karim Fizazi: Absolutely. I think it's truly a demonstration that early intensification is better than use—a subsequent use of these agents when the cancer is already more heterogeneous, more aggressive, and harder to treat. We should intensify treatment up front. I think this is very important, especially those with predicted poor outcome.


Dr. Neeraj Agarwal: So, Karim, these data are obviously very impressive, in my view, practice changing. Many of my community oncology colleagues have asked me about the potential side effects of this combination versus chemotherapy with docetaxel or abiraterone therapy alone in addition to ADT. Any tips for our colleagues and friends out there in the community on how to manage side effects or what should we be looking for as a community? What should we be telling the patients and any tips on managing the side effects?


Dr. Karim Fizazi: Absolutely. I think this is a key question, and also, this was great news from the trial. We couldn't find basically synergistic toxicity between docetaxel and abiraterone in the trial. So, in other words, what we saw was the expected toxicity from docetaxel, and we expected toxicity from abiraterone, but nothing additional or nothing worse, if you will. For example, the neutropenic fever incidence was exactly the same in the two arms. The GI toxicity from docetaxel was not increased, and actually, it was even a bit less, numerically speaking at least.


And regarding the abiraterone toxicity, what we saw mainly was an excess in hypertension, usually of lower grade, and an excess in transaminase increase, which was actually rare, approximately 6% if I recall well, which is really in line with what you would expect with the general use of this agent. And of course, this is something you can monitor, and you should monitor. We know how to handle toxicity with abiraterone, and the same also applies to the hypertension management with this agent.


Dr. Neeraj Agarwal: Got it. So, say a patient is hesitant, and of course, this was not addressed by the clinical trial. But given compelling survival benefit, if I'm talking to a patient in the clinic tomorrow morning and the patient is hesitant to start all 3 drugs at the same time, do you think it would be reasonable to start chemotherapy with docetaxel, finish 4 to 6 cycles, and then start abiraterone? With the caveat that this was not addressed by the trial, but I'm just asking a very practical question.


Dr. Karim Fizazi: Again, this is a difficult question you're asking. And I'm saying that because, as you rightly said, in PEACE-1 we combined abiraterone with docetaxel. So, in other words, abiraterone was given concomitantly with docetaxel and then was continued when docetaxel was stopped. So, we don't really know whether giving abiraterone as a maintenance strategy, if you will, in your example, post docetaxel would be associated with the same benefit. It's probably reasonable to think it does, but it's not a given. So, my preference would be actually to combine up front, if possible, of course.


Dr. Neeraj Agarwal: Absolutely. And as I said, this was not tested or addressed by the trial. So final message is, as far as combination therapy is concerned, there is no synergy—there is synergy with the efficacy, but we are not seeing synergy, if you will, from the side effect perspective. And if we are deciding to start triplet therapy, we should be starting all drugs at the same time. At least docetaxel and abiraterone should be started together and not sequenced. Any final message for our friends and colleagues in the community by you, Karim?


Dr. Karim Fizazi: Well, maybe just 1 or 2 final messages. The 1 is a hurrah message because I'm happy, of course, with the data. And just to put this into perspective, back in 2015, before we had all of the recent trials in M1 castration-sensitive disease, men with high-volume disease had approximately 3 years of life expectancy. And now just 5 or 6 years afterwards, thanks to all clinical research we conducted during this time frame, in PEACE-1, these patients can live more than 5 years, which I think is remarkable.


I think the second and last message is that we should soon have more data for these men regarding the triplet combination with ADT, docetaxel, and a next-generation hormonal agent. Specifically, the ARASENS trial (NCT02799602), which is testing darolutamide randomly in this setting, is to release its data probably very soon. And the same applies to the enzalutamide trial with ENZAMET, which should be updated specifically for these men receiving the triplet treatment. So, we should see even more data than what I was fortunate enough to report this year with PEACE-1.


Dr. Neeraj Agarwal: Thank you. So, thank you, Karim, again, for sharing these exciting data from the PEACE-1 trial. Congratulations for conducting this massive trial and coming out with such great news for our patients. I wish you all the best.


Dr. Karim Fizazi: Thank you very much, Neeraj. It was a pleasure. Thank you so much.


Dr. Neeraj Agarwal: And thank you to our listeners for your time today. If you enjoyed this podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Thank you very much.



Dr. Neeraj Agarwal:

Consulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Exelixis, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Foundation Medicine, Gilead Sciences

Research Funding (inst.): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, ORIC Pharmaceuticals, crispr therapeutics, and Arvinas


Dr. Karim Fizazi:

Honoraria (inst.): Janssen, Sanofi, Astellas Pharma, Bayer

Consulting or Advisory Role (inst.): Janssen Oncology, Astellas Pharma, Sanofi, AstraZeneca, ESSA, Amgen, Bristol-Myers Squibb, Clovis Oncology

Consulting or Advisory Role: Curevac, Orion Pharma GmbH, Bayer

Travel, Accommodations, Expenses: Janssen, MSD


Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guests’ statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.