Alicia Morgans: Hi, I'm thrilled to be at ESMO 2022 with Dr. Gwenaëlle Gravis who is joining us to speak about some updated PEACE-1 analyses. Thank you so much for being here.

Gwenaëlle Gravis: Thank you, Alicia. It's a great pleasure for me to be here.

I'm going to talk about the PEACE-1 study. It's a big European study, phase III, about metastatic castration-sensitive prostate cancer, upfront metastatic disease where randomized between start of care. Since 2013, the start of care was on androgen deprivation therapy and at the time of 2015 it was androgen deprivation therapy and docetaxel. And the question was, do we need to add abiraterone and prednisone and/or radiotherapy for prostate disease? And this history included more than 1000 patients and demonstrated that the addition of abiraterone produced [inaudible 00:01:05] with androgen deprivation therapy with or without docetaxel, improved overall survival and radiological progression-free survival. And the endpoint of the study presented today, was a planned study to the eight month per se for these patients.

So the median follow-up of the study is 4.4 years. And for the analysis, we need eight months PSA value, which was required and was available for 79% of patients. And we demonstrated that with a cut-off PSA of 0.2, the median radiological progression-free survival was higher for patients who had a PSA lower or equal to 0.2 at eight months with the standard of care with abiraterone and prednisone. And the median survival was also increased for the patients who reach PSA lower or equal to 0.2 at eight months. But we observed that for patients who had a standard of care with androgen deprivation therapy with or without docetaxel and abiraterone and prednisone, we had more patients who reach PSA lower or equal to 0.2 at eight months. And for the population who had, for standard of care, antigen deprivation therapy and docetaxel, it was the same.

The median overall survival was higher for patients who had PSA lower or equal to 0.2 at eight months. And 51% of patients with a combination of androgen deprivation therapy, docetaxel and abiraterone and prednisone reach a PSA lower or equal to 0.2 versus only 25% of patients with androgen deprivation therapy and docetaxel. And after we looked at PSA at four, at eight months and the median overall survival for patients with a PSA above four at eight months was very, very low, whatever the treatment, but less patients with the triplet association androgen deprivation therapy, docetaxel and abiraterone predinisone had a PSA above four at eight months.

Alicia Morgans: This seems like very clinically relevant information when counseling and guiding patients, and I especially wonder about patients who reached the PSA 0.2. Were the patients who did not receive abiraterone, who did achieve that 0.2, the 25% of patients, did they have similar progression to patients who received the triplet and also reached the 0.2?

Gwenaëlle Gravis: Only, it's a little percentage of patients, who reach. So it's difficult to compare. But the median survival for those patients, it's better than patients who had PSA higher 0.2 at eight months, but we didn't compare strictly. And the patients who had PSA 0.2 at eight months were only 79% of the world population. The subgroups, it's a little part of the patient. So we cannot really compare this.

Alicia Morgans: That makes sense. Such a small population, it's very difficult to compare but I think that especially because we can't compare and especially because of the good tolerability of abiraterone and the interest in making as many patients as possible hit the 0.2, we should, I think for patients who receive ADT and docetaxel, give them the abiraterone and give them that better opportunity to reach the 0.2.

Gwenaëlle Gravis: I think so. Actually, it's the overall survival, the median overall survival is significantly better and more patients reach this endpoint. So, I think it's better.

Alicia Morgans: Absolutely. Have you and the team ideas for what to do about those patients who only reach four or above? That is a high risk patient population. Very, very unfortunate.

Gwenaëlle Gravis: Yes. And whatever the treatment.

Alicia Morgans: Yes.

Gwenaëlle Gravis: And I think we have to look at those patients' clinical characteristics. Are they only high volume disease? Do they have specific [inaudible 00:05:59] ?

Alicia Morgans: Yes.

Gwenaëlle Gravis: So do they have PTEN loss or the aggressive variant?, TP 53, I think they are very interesting patients to look at and to give maybe more upfront or different, or maybe specific with the molecular alteration. For the patient who do not reach PSA less than 0.2 at eight months, we will develop a clinical trial and we have a P6 study that will be developed for those patients in the umbrella study with Karim and to randomize at eight months for those patients who didn't reach PSA less than or equal to 0.2 standard of care versus [inaudible 00:07:03].

Alicia Morgans: And that's so wonderful really to identify the patients at that eight month time point when their biology is demonstrated because they didn't reach the 0.2, demonstrated as poorer biology, poorer outcomes, and then identify them for randomization in another clinical trial. That's very, very smart and I think will help patients. To your point, those patients who really only hit four, this is a population that we need to understand so much better. The biology driving that disease is different and we need to understand if we can, even at the time of diagnosis, who those patients will be.

Gwenaëlle Gravis: I think that this information could be practice-changing tomorrow because I think for the patients who reach a PSA lower or equal to 0.2 at eight months, maybe we can do less radiology, less bone scan, less CT, and for the other we need to look at them closely. So I think those information are very practice-changing tomorrow.

Alicia Morgans: Absolutely. I look forward to you and the group maybe describing the ways that those patients progress. So if the PSA does not hit 0.2 or lower, how do those patients progress? Because we don't have standard guidance on how often to do our scans and perhaps this data set can help us understand, is PSA alone enough or do we need the regimented every six months' scan perhaps?

Gwenaëlle Gravis: Yes. That will help us. I think so. Of course.

Alicia Morgans: Agreed, and PEACE-1 continues to help us as a field. I'd love to hear from your perspective, the summary. What is your message, your main message from this analysis?

Gwenaëlle Gravis: The most important message is for those patients who reach PSA lower 0.2, maybe we have to think about de-escalate therapeutic and maybe for the other increase therapeutic to make surveillance more closely for them.

Alicia Morgans: Yes.

Gwenaëlle Gravis: Actually, we cannot change without progression, but with the unfavorable decrease of PSA to be close surveillance, radiology close surveillance, and last week I have a patient who had just unfavorable decrease in PSA and just one lesion, but he began the treatment, the castration one year before. So it was very short. And for some patients with few lesions, we try to do some stereotaxic radiotherapy and I say that not for this patient, I have to give more. If PSA increase, I have to give more and chemotherapy more. And we have to look at the DDR mutation and sooner.

Alicia Morgans: Yes.

Gwenaëlle Gravis: In France, it's difficult to do for all metastatic patient the research of DDR alteration, but maybe it's for those patients we have to do as quick as possible.

Alicia Morgans: That's a great insight from this, that these are the patients where we need to intensify not only in monitoring, but also in our understanding. As we allocate resources to do different tests, the genetic testing might be something that we want to prioritize in that population. And of course, closer monitoring, earlier next-line chemotherapy and other treatments as they're needed. But this is very, very important data and I sincerely appreciate you taking the time to walk through it with us, to explain the clinical implications and where we might go in terms of even future work within the PEACE-1 data set. Thank you so much for your time.

Gwenaëlle Gravis: Thank you, Alicia. Thank you very much.