Alicia Morgans: Hi, I am so excited to be at SOGUG 2022 with Dr. Karim Fizazi who's visiting us from Paris. Thank you so much for talking with me today.

Karim Fizazi: Thank you, Alicia. Always a pleasure.

Alicia Morgans: It's always a pleasure to talk with you and I know that they invited you here, to SOGUG, to really kind of dig into the practical implications of the data around treatment of men with metastatic castration-sensitive prostate cancer. Can you tell us a little bit about how you think through all of these studies and try to make sense of how we treat an individual patient who's sitting in front of us?

Karim Fizazi: Sure. Well, the first thing is that, again, it's fantastic to see that within just less than a decade, we've made so important progress for these men with metastatic castration-sensitive disease, with docetaxel, with second-generation ER targeting, with triplet treatment now, but also with radiation therapy directed to the prostate.

The question for many colleagues is how best to use all this data from numerous trials in their practices. Actually, I'd like to help them, to really separate at least four different scenarios based on volume, and people have been speaking about metastatic volume again and again in the last years, but honestly, I'm not sure that volume is the most important thing for decision-making. But I'd like also to emphasize that the timing of the metastasis is also important. De novo metastatic disease is biologically different as compared to a man who had local treatment for localized disease and who relapsed after, say, 5 or 10 years. Just to support what I'm saying, there are now data indicating that men with de novo disease, in general with ADT, just don't do well with ADT alone. The likelihood for survival for men with high-burden or high-volume de novo was less than 3 years with ADT alone. For those with low volume, it was more 4 or 5 years. So it's not that good.

On the other hand, for men with a relapse and mostly low-volume disease, because this is typically the scenario with C4 patients relapsing, the life expectancy is much longer, even with ADT alone, approximately 8 years, showing us that it's really different biology. Finally, the last scenario, which is that of relapse and high volume actually doesn't really exist. I'm saying it doesn't exist, but it does exist sometimes. It's super rare. That's those situations where a patient basically was treated locally and then it completely disappeared in nature and is coming back after years with pain everywhere, for example. That's super rare in my practice. I guess you share the same.

The second scenario I see is really one we should not see, that a patient who had, say, a Gleason 8 cancer and who was operated on and the urologist did not do an imaging checkup before prostatectomy. All of a sudden, the PSA post-op is 15 while it was 16 just before the operation, imaging is done, there are metastases everywhere. So again, this is supposed to be a relapse because the prostatectomy has been done already, but it's obviously not. That's a de novo. Again, these four scenarios are really different.

For patients with relapse oligometastatic disease, I think we should simply be cautious. Because the evidence is minimal supporting treatment intensification, these patients who are rare in the trials, either 0% to 20% max, so those are small subgroups, it seems that intensification with second-generation AR drug works and can help these men. But again, we need to be cautious. Having said, this is more my practice. The key question for those men is, really, can we help them with metastasis-directed therapy? And, as you know, there are ongoing trials.

Now, for patients with de novo, I think we should not pay too much attention to the volume question. The volume definition can help for decision-making regarding the use of radiation therapy directed to the prostate, as we probably all know. Overall survival is improved for patients with low-volume, not necessarily for patients with high-volume. Now, regarding whether radiation can help control symptoms across the board for these men, we just don't know. This was not rightly studied in the past trials. We're waiting for more data hopefully in 1 or 2 years from now.

Now, regarding the use of systemic treatment for these men with de novo disease, actually, if you look at docetaxel, it works. If you look at AR-targeting agents, they work also, and they work across the board for one, two, metastases, for five, or 100, whatever. And actually, the triplet seems to be working in them even better. So I think for these men with de novo, we should go more and more to the triple treatment, especially, of course, if they're fit, young, willing to receive chemotherapy, obviously if they have numerous metastases. But we're waiting for the ARASENS data and the PEACE-1 data to tease out better whether also de novo low-volume men can benefit from triplet treatment. So you see, and sorry if I was too long, but there are numerous situations and we should pay attention to that, not even speaking about comorbidities, cardiovascular disease, all these things.

Alicia Morgans: I appreciate you breaking them down into patient subtypes. One patient subtype that we almost never talk about was your final patient subtype. I think it's important to acknowledge that there are differences in disease relapse after prostatectomy. And you and I have both seen the unfortunate patient who, even some of them have had a relative workup for metastatic disease, but perhaps it was too far in the distant past and this is just an aggressive cancer, that within a few months, has already blossomed. I saw one actually just a few months ago, and rising PSA post-op, it never really mattered, and by the time we get what we thought was going to be a PSMA PET to find a single met or two, the patient had blossomed all the way up the lymph node chains. I mean, it was impressive. These things happen. They are unfortunate. Those are different patients than the patients who relapse after 5 years.

Karim Fizazi: Absolutely. I fully agree. And for patients relapsing, say, after 5 years in your example, again, their outcome is pretty good. This is also why many colleagues when they think about low-volume/oligometastasis think mostly about these men, forgetting that patients with de novo and oligometastatic disease are different and their outcome is not that good. So we should really separate those two entities at least, and hopefully in the coming years, we will also have biomarkers to help us better for decision-making instead of only these clinical parameters, which are imperfect, obviously.

Alicia Morgans: Absolutely. Just to dig in a little bit more, you mentioned quality of life. You also mentioned that in the context of radiation to the prostate and how that has not actually really been studied, whether that can help reduce some of that local burden. Are you studying that at all in the PEACE-1 trial?

Karim Fizazi: We are. We are really making the effort to collect even the urinary events or the pelvic events in general, bleeding, stents, etc, not only during the course of experimental treatment, but also beyond progression, which is, of course, the most important part in the patient's life regarding the risk of these events. So we are really trying to do our best to collect all events and hopefully, maybe next year we should be able to analyze that and to see whether radiation therapy can prevent those events to occur. With all respects and friendship to my STAMPEDE colleague, but this was not studied in STAMPEDE, where actually the CRS stopped at progression regarding the collection of those events. So we don't really know that from the STAMPEDE experience.

Alicia Morgans: Yeah, and it's okay, we can only ask so many questions at a time in a given trial, but I'm so glad that you and the team are looking at that, because I think we do that clinically, but we often have discussions and we don't have data to really quote when we're thinking about things. So, kudos and thank you for answering that question. If you had to give some final thoughts on metastatic castration-sensitive prostate cancer, what would your message be to listeners?

Karim Fizazi: Well, thanks to clinical research. In less than a decade, if I take, for example, the situation of men with de novo and high-volume disease, we've switched from survival expectancy of less than 3 years with ADT alone to more than 5 years now with triplet systemic therapy. And again, this was achieved in less than a decade, which I think is fantastic. So we should carry on and keep on fighting.

I think that the next step is probably, especially for this man to better tease out who is a good responder and who may not be more intensified, at least right now, versus who is not a good responder, who might benefit from other treatments such as PSMA targeting, for example. Also, I'd love to see more data about PARP inhibitors for this population, which is typically enriched in BRCA2 patients. I suspect that PARP inhibitors can help these men, but I want more data. So again, we did well in the last decade, let's say. Let's do that again in the next one.

Alicia Morgans: Well, absolutely. We have to keep up the good work, and I sincerely appreciate you talking us through these studies. It can be a lot to put together, especially, as I said, when you are looking at one individual patient in your clinic, but the way that you've broken down these patient subtypes and given us an idea of what to look for in the future is really, really helpful. As always, thank you for your time and for your expertise.

Karim Fizazi: Thank you very much.