Alicia Morgans: Hi, my name is Alicia Morgans and I am a GU Medical Oncologist at Dana-Farber Cancer Institute in Boston in the US. I am so excited to have here with me today, Dr. Karim Fizazi, who is a GU Medical Oncologist, as well as being a Professor of Oncology at the University of Paris and practicing at Gustave Roussy in Paris. Thank you so much for joining us today, Karim.
Karim Fizazi: Thank you very much for the invitation. Always a pleasure, Alicia.
Alicia Morgans: Wonderful. There are many things for us to talk about, but the first thing I’d like to talk to you about today is really diving into PEACE-1, a presentation on updated survival data that you gave at ESMO this year. Can you please tell us a little bit about the design of PEACE-1 and what you found?
Karim Fizazi: Sure. PEACE-1 is a phase 3 trial, which is enrolling patients with de novo metastatic prostate cancer, both low-volume, and high-volume, and it’s basically asking whether we should add multiple treatments on top of the standard of care. The Standard of care for these patients was mostly ADT plus docetaxel, and for the first patients enrolled in the trial years ago, ADT alone was the standard of care at this time.
We are asking two questions, one is whether abiraterone improves outcomes for these men when they are receiving their standard of care for M1 disease. The second question is about local radiation therapy directed to the prostate primary. Regarding the second question, as I’m speaking, we do not have data, and this is because we are focusing mostly on patients with low-volume disease who have a better outcome. So before we start analyzing the data for the radiation therapy questions, we have to have more reasons. So what is available now is the data for the abiraterone question.
Alicia Morgans: That sounds great. I think it’s great to focus on the systemic therapy question, which of course, we heard about a little bit at ASCO, really related to the progression-free survival outcome. What have you found in this updated analysis in that assessment of the addition of abiraterone to the standard of care?
Karim Fizazi: Right. Indeed, at ASCO we reported radiographic progression-free survival data, which clearly, I believe, favored the triplet systemic treatment arm with ADT, docetaxel, and abiraterone with 2.5 additional years without progression or death when these three agents are being used in combination, as compared to ADT plus docetaxel alone. So that is a big difference, from 2 years to 4.5 years in the median. This came together with benefits in all ways to assess progression-free survival, PSA, symptoms, et cetera, and the safety was, overall, as expected. So nothing bad.
What we just showed at ESMO here in Paris virtually, unfortunately, in September, was the updated analysis with, now, a sufficient number of overall survival events to look at the abiraterone question. I think that the news is very good, because, indeed, overall survival is improved with the triplet, with a 25% reduction in the risk of death when ADT, docetaxel, and abiraterone are combined, as compared to ADT plus docetaxel. The median was reached in the control arm. It was 4.4 years, plus or minus what we were expecting, and it is not [inaudible 00:03:53] event enriched in the abiraterone arm, which is showing us the benefit.
Also, very important was to dig into more details regarding the benefit, according to the disease and the volume of disease. For example what we found was that for patients with high-volume disease, there is a clear benefit, with a 28% reduction in the risk of death favoring the triplet treatment, and this is clearly significant. The median was reached at 3.5 years for the control arm and 5.1 years with the triplet treatment. So more than 18 months of additional life for these patients receiving the triplet.
Having said that, for the low-volume patients, the number of events is low, which is good, of course, meaning that most of these patients are alive, so it’s probably too early to say data, but I did make sure to see whether there is a benefit in overall survival for these men. And I just want to record with you that at EAU, we showed that for these men also, there is a benefit in RPFS.
Now, also very important, I think, is to look at treatment beyond progression. This is also where we saw good news. Indeed, 84% of patients in the control arm who develop castration-resistant disease, had access to at least one life-prolonging treatment, and 81% of these men received at least one next-generation hormonal agent, which truly shows us that the benefit that we see with a triplet is true, regardless of what you are using afterward. It really means that early is better than deferred treatment for these men, probably because it is easier to target cancer with a lower burden of disease and less complex biology, as compared to intervening when cancer has already progressed. And I think those are very important messages.
Alicia Morgans: I completely agree, and I think we’ve seen hints of that in several other studies and I think we’ve had that concept. But I think it’s so important to emphasize that as we are in clinical practice. It is not really acceptable in oncology at this point in time, perhaps, to wait until you have progression of the disease, and certainly clinical progression, we know, is associated with poor outcomes, and maintaining that patient status by having that triplet therapy right away. I think if that is an option for your patient, it really seems like the right thing to do both in terms of maintaining their function, but of course, this prolongation of survival is really, really interesting and so important.
I wonder from your perspective, though, Dr. Fizazi, would you do this for the low-volume patients? You did mention that they do seem to have a benefit in progression-free survival, just not quite mature yet in terms of overall survival. So how do you translate that into your clinical practice?
Karim Fizazi: Right. Obviously, this is a very important question practically. During the summer, since we have this data, I’ve been proposing triplet treatment for men with high-volume disease, where obviously, the benefit seems to be very robust, both in terms of rPFS and OS. For men with low-volume disease, I would be more on the fence at the moment. The rPFS benefit was there, but it was also less marked. I think the hazard ratio was 0.47, if I recall well, for high-volume, and maybe 0.58 something for low-volume patients. I would probably hesitate in men in-between, those with, let’s say, 3 bone metastases and extensive lymph node disease, that, I would probably speak with the patient. Now, if a patient is really oligometastatic, I would perhaps use only ADT plus abiraterone or one other AR drug.
Alicia Morgans: I think that’s rational. Just for the audience also to recall, these patients all had de novo metastatic disease. So that is also something that I think is important as we are trying to apply these clinical concepts. If we have a patient who had a prostatectomy some years ago or radiation and now has low-volume recurrent disease, these data may not actually apply. So really important for us to continue to dig into this concept, but so important for our patients that we do identify the patients who made benefit. And now that benefit has been demonstrated in terms of survival. If you had to sum up your findings from PEACE-1, and congratulations to you and your colleagues and to the patients in this process, what would those be, Dr. Fizazi?
Karim Fizazi: Well, I would say that, for the first time, we demonstrated that a triplet systemic treatment with ADT, docetaxel, and abiraterone improves, clearly, outcomes, in terms of both progression-free survival and probably a good time for patients without symptoms and other issues, even with psychological issues of having progression, but also overall survival is improved. This was achieved in a context where most men in the control arm were treated adequately with life-prolonging agents, including an AR agent, at least one, for most of them.
On top of that, the toxicity pattern that we saw in the trial was as expected, with no negative synergy between docetaxel and abiraterone with regards to the side effects. This is also very important. What we saw was only excess in hypertension, mild and rare transaminase increase, and that was mostly weak, and some hyperkalemia, as you would expect with abiraterone, but really nothing bad.
So I think, at least for men with high-volume disease, we have good reason to propose this as a new standard of care for these patients. Hopefully, we will have confirmation from other trials. The [inaudible 00:10:36] trial is testing the same hypothesis with darolutamide and should read out in the coming months, hopefully. And the same probably applies to ENZAMET with enzalutamide. But personally, though, I will already, and I have actually already, changed my practice based on this data, and I am proposing the triplet treatment to my patients with de novo high-volume disease who are fit for chemotherapy.
Alicia Morgans: Well, that is a great message and I thank you for your time today and for going through this with us.
Karim Fizazi: Thank you very much.