Alicia Morgans: Hi, I'm so excited to be at APCCC 2022, where I am just delighted to talk to Professor Karim Fizazi, who is a GU medical oncologist at Gustave Roussy in Paris, France. Thank you so much for talking with me today.

Karim Fizazi: Thank you, Alicia. Thank you.

Alicia Morgans: Always a pleasure to talk to you, Dr. Fizazi, and today, I wanted to talk with you about a presentation you had at APCCC, where you really helped us think about the disconnect between conventional imaging and PSMA PET imaging when it comes to metastatic hormone-sensitive prostate cancer. And somehow, we can find ourselves confused about volume in that disconnect. Can you tell us a little bit about patients, specifically who have low-volume disease on conventional imaging, and then may have higher risk disease on PSMA PET imaging and how you work out that difference?

Karim Fizazi:Right. And this is very typical of APCCC. We are speaking about situations where, basically, we don't exactly know what to do, so this is why it's so interesting. And this was actually a debate for either you treat a low-volume man or you treat a high-volume man, and we're supposed to support the low-volume volume option. But, basically, I think we have to think that the doubt should benefit the patient for every decision we're making. And basically, you have to make a decision regarding whether you're going to use an AR-targeted agent, chemotherapy, triplet systemic treatment, local radiation to the primary, and maybe also metastatic-directed therapy. I think we should address all these questions one-by-one.

Let me start by the easiest, which is, I think, the next-generation AR-targeting those drugs abiraterone, enzalutamide, apalutamide, and now darolutamide actually work across the board. This is true if you have just one or two metastasis or a hundred. So, to me, that's a no-brainer. These drugs should be used on top of ADT in the situation of a man with a low-volume disease by conventional and high-volume by, say, PSMA pet. So that's the easy one, probably.

Now, regarding the radiation therapy directed to the primary, this is more touchy. But I think that all data that we have from randomized phase III trials were achieved on the ground of conventional imaging, so we should trust this data. And from STAMPEDE, we know that tradition therapy improves overall survival on top of PFS in these men with apparently oligometastatic disease by conventional imaging. So even if my patient has more metastasis on the PET PSMA, I would still recommend radiation therapy directed to the primary, understanding that maybe we overtreat some patients, but I want to make sure that we're not missing a novel survival opportunity for at least some of them, and also because modern radiation is usually well tolerated in my practice. Patients reacted very well. Also, I'm in a country where it's not very expensive, so this is not necessarily an issue for patients or for the society. So I really think we should recommend radiation in that situation.

Now, docetaxel. And for docetaxel, in a situation where there is debate regarding the use of the docetaxel, even with conventionally imaging in men with low-volume disease, CHAARTED not supporting it, STAMPEDE supporting it, probably because those were not the same patients with relapsed patients in CHAARTED, mostly, and de novo patients in STAMPEDE. But let's look at the data. And, indeed, there is some discrepancy between those trials. My easy proposition would be, in any case, don't use docetaxel alone if you use it.

Now, for the triplet, which is the next question, ADT, docetaxel, and an AR drug, the data are just coming to us right now for these patients with low-volume disease. And, indeed, in PEACE-1, what we found was that adding abiraterone on top of ADT-docetaxel clearly improves radiographic progression-free survival, actually, dramatically. For overall survival, it just didn't mature. Most of these men were alive when we did the analysis, so we just don't know. We need longer follow up in PEACE-1. ARASENS has not yet analyzed the data by volume, so hopefully we'll see the data in the coming month, and we'll see. And finally, ENZAMET will be realized hopefully this year, and we'll see also some more mature data regarding this question. So, let's see for the triplet questions.

And finally, for metastasis-directed therapy, we don't have evidence. So, please include your patient in a trial. I think this is the main message for these men. We need the data. We need to understand. We know that we can do it, but we don't really know whether we are helping our patients when we do it. So please randomize.

Alicia Morgans: Absolutely. I think that's one of the most important questions is really whether we should be using metastasis-directed therapy. And it's interesting in practice, at least in my practice, we've adopted that for some patients with one, two, not usually three, but even three, and it's usually a bone metastasis that we might do or pelvic node maybe. But I think it's clearly a question that hasn't yet been answered. Is there a trial in particular that you are excited about with metastasis-directed therapy integrated?

Karim Fizazi: Well, there are different trials ongoing, different phase III trials. We have a PEACE trial. PEACE-6-Oligo is enrolling patients and enrolling patients quite rapidly. I'm happy about that. We probably have randomized 200 patients yet. The beauty with that trial is that we are integrating next-generation imaging in the trial, so either PET choline or PET PSMA, so that for the future we can, base our decision on these next-generation imaging. I know that a Canadian trial is also ongoing and enrolling patients. I know that STAMPEDE has planned to start an arm with MDT. I don't think they have started yet and I don't think they will use next-generation imaging, which perhaps may be a limitation in the future.

But at the end of the day, the good thing is that we are enrolling patients in with trials. Maybe we'll need meta-analysis, et cetera, so it's important for all these groups to speak to each other. But, really, the most important is that we enroll all patients in. I'm like you, I'm a believer. I have to say, for a long time, I've been strongly asking my radiation therapist colleagues to sometimes irradiate patients with oligometastatic disease. I strongly believe that no cancer cells can resist radiation if radiation is properly delivered. So, it should work, but we need the data.

Alicia Morgans: Yes, agreed. And in that context, we should also not back down on our systemic therapy. We, I think, benefit from having that intensified systemic therapy and then adding the radiation, especially if we can do it on a trial, is sort of icing on the cake and in that setting. But agreed, to resist radiation, direct radiation, has got to be a very difficult challenge for a cancer cell and we hope that they are not good at doing that.

Let's dig in just a tiny bit more to the triplet therapy, because there may be exceptions to that high-volume, low-volume, de novo versus recurrent situation where often we're thinking about these being, of course, chemo-fit patients, but generally, a lot of the talk is around high-volume patients and de novo metastatic patients. What are your thoughts on these low-volume patients? Who are the people where you might say, I'd like to intensify or offer that to you anyway?

Karim Fizazi: Sure. Well, first, you're very right. Prognostically, low-volume, high-volume makes a difference, but also de novo versus relapses. And I think this is very important. If you want simple data, there is just one outlier group, which is that of an oligometastatic relapse from localized disease upfront. And those men do quite well. Overall survival, even probably before the outset of all the new treatments was about 8 years, which is not bad for a metastatic disease, I believe. Now, the other groups, low-volume, de novo, and all the high-volumes don't do super well. 4 years plus, or minus. Probably a little better now with, again, all these new treatments that we have, but still.

So, I'm actually with you. I think that for the triplet treatment, if I'm facing a man with de novo and low-volume disease, I think we should challenge whether we should stick with just a doublet. And of course we need more data, but again, as I said, in PEACE-1, rPFS is dramatically improved in these man. And if they're fit and young and if the number of mets is not that easy to count or if it's a big one and you don't really know whether it's a fusion of two or three or more, whether that's a good patient for a triplet is something we should ask for ourself.

I typically have a conversation with a patient and we're making the decision together. Actually, some patients are really keen to go for more intensification. They're miserable because of a diagnosis of prostate cancer, and on top of that, the diagnosis of metastasis. So they're happy to fight against their cancer. And if you're telling them the pros and cons of chemotherapy on top of ADT and AR-targeting, some of them are really keen to go for the chemo and for the triplet. On the other hand, some other patients, the elderly, more frail, et cetera, are not really keen to go for chemo and I totally understand and accept that. So I think, of course we need guidance, general guidance, to help us, but when we are facing a patient, it has to be a one-by-one decision.

Alicia Morgans: That is certainly for sure, and I think it's interesting to consider how molecular testing may ultimately help inform this decision. And one other piece to that that you mentioned, not necessarily molecular testing, but those men who want to fight, they also often want to fight now, because if they don't fight now that chemo's coming in the future. It's not if/or, it's if or when. So it's very, very important, I think, to offer that.

Karim Fizazi: Itotally agree with you. And, actually, this is a discussion we had with Fred Saad, who was telling me, "I don't understand why people are sometimes reluctant to use docetaxel for castration-sensitive disease as a triplet therapy while they know that they will use it for mCRPC in the same man." Well, actually, not the same man, the same person, but the man is not anymore the same because he has CRPC already. This cancer is more resistant, docetaxel will provide less of a benefit, and, of course, the tolerance is likely to be more difficult.

Alicia Morgans: Yes.

Karim Fizazi: So if you think that chemotherapy can help with man, you should probably advise them to receive it upfront together with ADT and an AR drug.

Alicia Morgans: Unless we have, ultimately, molecular information that suggest otherwise.

Karim Fizazi: I agree.

Alicia Morgans: Is that something that you're going to be doing in PEACE-1?

Karim Fizazi: Yes. We have a quite strong biomarker plan. We are currently collecting tissue. It's almost done, so hopefully we're going to start the analysis. We're speaking with STAMPEDE, CHAARTED persons so that we can align what we're we're doing and try to have more power to get better information. So this is really work in progress, but I'm quite confident that we will be able to stop the conversation about only high-volume, low-volume, but eventually go to this biomarker versus that one and try to make better decisions, basically.

Alicia Morgans: I think that will be great. It takes a lot of the art out of what we do. Those decisions that, as you said, when you're looking at one lesion, that could be the confluence of three. So it takes that guesswork out of our hands and gives us a little more clarity, which is phenomenal. So, as you think about this topic, and you see these patients all the time in your clinic, I'm sure, what would your message be to clinicians who are trying to sort through this situation of low-volume metastatic disease on conventional imaging and maybe higher borderline high-volume disease on PSMA PET?

Karim Fizazi: Well, I would say that, number one, the imaging is perhaps not the most important thing, to be honest. If you think about it, prostate cancer is probably almost the only cancer where we are giving so much power to the imaging for decision making and metastatic disease. To me, there's no real reason to believe that a cancer is different if a patient has two metastasis versus five or six, so this is totally imperfect. And we also know that there are false-positive, false-negative, so we should be super careful about that. I think this is important.

But maybe more generally, I would like to remind all the colleagues that in just less than a decade, we've made tremendous progresses for these men. If I take, for example, men with de novo high-volume disease, their likelihood for survival with ADT alone, just back in 2015 was less than 3 years. And this was super consistent in all phase III trials we've been conducting with ADT alone. Less than 36 months. Now, the docetaxel has improved that. Abiraterone and all these AR drugs also. And then with a triplet, these patients live over than 5 years. So in less than decade, actually half a decade, we moved from less than 3 years to more than 5 years. So I really think that's quite dramatic and important to remember. And this is for the worst situations, the high-volume de novo. So you can imagine for patients with a lower burden of disease, et cetera, and easier to treat biology, that's probably even more. But we need longer follow up to demonstrate it.

And it might be that, in the future, we can carry on with those progresses, whether you should integrate PSMA targeting, PSMA lutetium, BRCA targeting, et cetera, et cetera for the treatment of these men is something very relevant, and there are ongoing and planned trials to address these questions. So, stay tuned.

Alicia Morgans: I think stay tuned is a perfect message. This is absolutely a target influx, and as the landscape continues to evolve, I so appreciate you lending your advice and guidance and expertise on the topic. So, thank you so much for your time today.

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