First Results of PEACE-1 A Phase 3 Trial with a 2x2 Factorial Design of Abiraterone Acetate plus Prednisone and/or Local Radiotherapy in Men with De Novo Metastatic Castration-Sensitive Prostate Cancer mCSPC - Karim Fizazi

June 8, 2021

In a presentation at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Karim Fizazi presented the first results of the PEACE-1 trial. PEACE-1 is a phase 3 trial with a 2x2 factorial design of abiraterone acetate plus prednisone and/or local radiotherapy in men with de novo metastatic castration-sensitive prostate cancer. Adding abiraterone to ADT + docetaxel significantly improves rPFS in men with de novo metastatic prostate cancer, with about 2.5 years of absolute benefit in medians, and no meaningful additional short-term toxicity.  PEACE-1 is designed to assess two co-primary endpoints: radiographic progression-free survival (rPFS) and OS with alpha splitting of type I error allocated with 0.1% and 4.9% to rPFS and OS, respectively. As of the current data cut-off, while the required number of rPFS events to achieve 80% power has been reached for the abiraterone comparison, it has not been reached for assessment of the role of radiotherapy. Dr. Fizazi also shared with Dr. Morgans that the addition of abiraterone acetate to the standard of care including ADT and docetaxel significantly improves rPFS in men with de novo mCSPC without meaningful differences in short-term toxicity. However, overall survival data are immature.  


Karim Fizazi, MD, Ph.D., is a medical oncologist at Gustave Roussy, and a full professor in Oncology at the University of Paris-Saclay in Villejuif, France.

Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

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Alicia Morgans: Hi, my name is Alicia Morgans, and I'm a GU Medical Oncologist and Associate Professor of Medicine at Northwestern University in Chicago in the U.S. I'm so excited to have here with me today a good friend and colleague, Dr. Karim Fizazi, who's a Professor of Oncology and a GU Medical Oncologist at Gustave Roussy in Paris, France. Thank you so much for being here with me today, Karim.

Karim Fizazi: Thank you very much, Alicia.

Alicia Morgans: Wonderful. So I wanted to talk with you about some of your presentations at ASCO 2021. One of the most awaited presentations that we were able to see was PEACE-1. Can you tell us a little bit about this prostate cancer study, please?

Karim Fizazi: Sure. So PEACE-1 is a two-by-two design, phase three trial, which is testing a combination of new treatments, on top of standard of care, generally speaking, for men with de novo metastatic prostate cancer. So basically, patients received standard of care and in the trial, most men actually received ADT, so androgen-deprivation therapy, plus docetaxel as their standard of care, and they were randomized in basically four arms. So standard of care alone, or standard of care plus abiraterone, standard of care plus radiation therapy directed to the primary cancer, or standard of care plus abiraterone and radiation therapy. So basically four arms. Almost 1,200 men were randomized in the trial and given there was no interaction between the effect of abiraterone and that of radiation, we were able by protocol, by an analytical statistical plan, to pool the two abiraterone arms for analysis so that we would have more power to look at the efficacy.

So the analysis we're reporting here at ASCO 2021 is about the role of abiraterone on top of ADT plus docetaxel. And this is really, I think, a key question, should we use a triplet systemic treatment or just a doublet? The first results that we are reporting indicate that indeed radiographic progression-free survival is very clearly improved with the triplet, so abiraterone on top of ADT plus docetaxel, as compared to ADT docetaxel as a standard of care. And actually, what we saw in terms of median, for example, was approximately two years for rPFS in the control arm with ADT plus docetaxel, and four years and a half when abiraterone is being added. So two years and a half of additional time without progression, and I'm talking about radiographic progression, obviously. So strong data and strong endpoint, I guess.

Alicia Morgans: It is a hugely strong endpoint, and really exciting to think that we might be able to use these treatments in combination to get that longer progression-free survival, at least. Can you clarify, just for the listeners who are familiar with the ENZAMET data, where we saw a triplet combination, and of course we're still waiting for survival data in ENZAMET, as well. We did see some prolongation of PFS. Were you giving the abiraterone concurrently with the docetaxel, or was this given after? Just so that everyone has that understanding. I think sometimes that can make a difference.

Karim Fizazi: Sure. So actually in our trial in PEACE-1, abiraterone was given concomitantly with docetaxel. And actually, this is another good surprise for, or good findings from the study, from this analysis. The safety was, I guess, very reassuring, even used, again, concomitantly with docetaxel, there was no excess of incidence of febrile neutropenia, 5% in both arms, so quite low incidence. And again, no more with abiraterone. Other hematological toxicity were also very well-balanced. Noteworthy, some side effects that are often seen with docetaxel, such as GI toxicity and fatigue, were actually observed less frequently with the triplet treatment, perhaps thank to the prednisone as compared to ADT plus docetaxel alone.

And regarding abiraterone, so what we expected to see, which is a slight increase in hypertension, 12% versus 8%, and same for kalemia and for transaminase increases. So nothing bad, actually. Having said that, those data regarding safety are restricted to the first six months. This is the data we have at the moment. We are hoping to get more data with longer-term analyses, perhaps after the summer, but I guess so far so good in terms of safety on top of what I reported for the efficacy.

Alicia Morgans: It is so far so good, I think because I do worry or I have thought about the concomitant use potentially causing LFT issues, but in your study that was not really a big issue. And then certainly augmenting the complications from docetaxel is also a concern, but we didn't really see that occur. So I think that's great news, and certainly, as we await the survival data and follow-up data over time, I think it's very nice to know that at least we're not significantly increasing the toxicity with this potentially quite efficacious combination, at least in terms of disease control. So that's great. So as you think about this, does it affect your treatment decisions at this point in time? I know you do a lot of clinical trials, so many of your patients are going on study, but in your standard of care practice, does this early PFS data affect your decision-making in this setting?

Karim Fizazi: Actually, I think it does, because in many cancers we would use PFS as the driver for decision-making. In prostate cancer, I guess we're more conservative, we want to see overall survival. And even if we don't want, the agencies usually want to see OS, and of course, there are exceptions. But having said that, in this particular case, we're talking about two and a half additional years of PFS. So starting again, some five years ago, you and I were using ADT as a standard of care and patients would progress after a year, just one year basically. Docetaxel improved that to about two years. And this is actually what we saw in the control arm of all the trials. And now we're talking about four and a half years with the triplet treatments.

And given that it comes together with an improvement in time to symptomatic control as well, which is pretty much the same delta, the same magnitude of a difference, not even talking about PSA control, which is also of course clearly augmented. I think this is enough, per se, to consider using the triplet treatment, at least for fit patients as a new standard of care, probably regardless of the overall survival data. Of course, except if we are detrimental in terms of OS, which I don't think we will, but even if at the end of the day OS is similar, I think having two years and a half of additional time without progression is probably sufficient to change practice. But I would love to see your opinion and colleagues' opinion on that, of course.

Alicia Morgans: I think in many ways it is, I think it's at least worth a conversation with the patient. And I think, conceptually, of course, it makes a lot of sense if you can live for that much longer and not have progression, that one would probably want to do that. The other piece that comes into my decision-making, which I think is not yet reported, but I imagine you've collected, is the patient-reported outcomes that might contribute to that decision. If people lived for longer without progression but felt terribly, then one might make a different decision. I have a feeling the patient-reported outcomes will be quite favorable for this. We've already seen them for patients treated with abiraterone, and of course for docetaxel. Is that something that you collected and might contribute, but I would imagine again at a later time point?

Karim Fizazi: Right, we actually did and you're very right. Our plan is to analyze the quality of life data later on. I don't know if this is going to be ready this year, but perhaps next year in the trial. And I totally agree with you, that's, if ever can show a difference in quality of life, favoring the triplet arm with abiraterone, I think this will be another good reason to change our standard of care.

Alicia Morgans: Fantastic. Well, thank you. This is extremely exciting data and it's something, as I said, we've been waiting for for some time, as we have to do with all of these large practice-changing studies, but this was highly awaited. So I really appreciate you taking the time to talk it through with me today.

Karim Fizazi: Thank you very much.