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Derya Tilki: I will start off—I have a question, Bertrand. Just to clarify, you showed the EAU high-risk classification, and then you said systemic therapy, but this was focused on the EMBARK criteria, right?

Bertrand Tombal: Yeah, at this point in time, unfortunately, it's not technically the same. So when people say, "Can we extrapolate EMBARK to all the high-risk patients?" I would say no. EMBARK has strict criteria. These are the criteria. No, the EMBARK patients aren't all high-risk, but there are probably high-risk patients who are not EMBARK patients. So we're going to need more time to clarify this. But the question here that was asked was in the EMBARK environment, so that's why I chose that. But high risk is broader than EMBARK.

Derya Tilki: Right. Yeah.

Barbara Alicja Jereczek-Fossa: Maybe I'll add something. It's interesting, because if you see the population of EMBARK—Bertrand, maybe you can comment on this—if 50% of patients already received surgery and radiation, so actually EMBARK, it was a second salvage. Can you comment on this? It was not what we discussed here.

Bertrand Tombal: No, that's why this is roughly 15% of patients. But it was a very common criticism, where, especially from the radiation oncology community, when they heard the EMBARK results for the first time, many people would say, "Oh, but it is not standard treatment because they have not all received salvage radiation therapy." But now that's really the question. The question is, assuming you get out of that window of opportunity—you have a PSA of 2, you have a Gleason 8, you have a PSA doubling time of, I don't know, six months—is there still a role for salvage radiation therapy? Which is totally different from the case that you, Derya, discussed.

Derya Tilki: Right. Dan?

Daniel Spratt: I don't think it's actually a criticism of EMBARK. Remember, the eligibility criteria of EMBARK is you would have to have what they termed a contraindication to salvage radiation. Okay. There are very few contraindications, but exactly to your point, the median PSA was around 5, the doubling time was around six. If I saw a guy post-surgery with a PSA of 5 and a doubling time of six months, whether I had a PET or not, he probably has metastatic disease. So that's why the NCCN guidelines has now made a whole section—Ted Schaeffer leads our guidelines and added a whole section—that most patients we're talking about, if they get the standard of care of early salvage radiation, this is totally different. But like I showed you, the guys who benefit from long-term hormone therapy massively, and probably the EMBARK regimens, are guys who have these PSAs in the solid single digits and rapid doubling times. And the UCLA showed, like, 90% are metastatic. So it's really not controversial to me at all.

Bertrand Tombal: This is a long-lasting discussion about adjuvant immediate salvage and, "I forgot to follow the patient and now he's coming to me."

Daniel Spratt: Yes.

Bertrand Tombal: So that's not salvage. That's a problem.

Thomas Zilli: We have some questions from the audience. Professor Sweeney?

Christopher Sweeney: Chris Sweeney, medical oncologist. Don't know who will want to take this one. Patients who have a PSA relapse—it's about outcome, but we are focusing on MFS and OS as the ones that we can really drill down and say there's a clinical benefit. Do you think we can use this data to show the clinical benefit from preventing a PSA relapse by documenting the clinical deterioration that they have from the hormonal therapy, the subsequent therapy that leads to the therapy for CRPC? Do you think we'll ever be able to use PSA-based endpoints as a clinically meaningful endpoint?

Bertrand Tombal: That's almost a health economist approach, to say is it a surrogate for everything that happened basically between PFS and MFS. Because it's still—we have an early, which is PSA, which is not good. And then it is a little bit like ESMO. They have this concept of PFS plus or MFS plus. Can you show that by delaying that biochemical progression, it is associated with patient-centered endpoints? But we still have to do that.

Christopher Sweeney: Can I get your answer, though, yes or no? Do you think we can do that?

Bertrand Tombal: Yes.

Christopher Sweeney: Thank you.

Thomas Zilli: Professor Briganti.

Alberto Briganti: Thank you very much. That was an excellent session. My question is about, again, the role of additional ADT in patients with recurrent disease, and again, it goes in the direction of understanding whether the impact of the ADT in higher PSA level is somewhat unrelated to the impact of salvage radiation therapy in a way. And the second question is we go as early as possible when we give indication for early salvage radiation therapy. Is it associated somewhat with some forms of overtreatment in some patients who actually might recur without any chance or risk of dying from prostate cancer?

Daniel Spratt: There's a nice study led by a number of urologists—I think Todd Morgan, Dan Lin, and a number were on—that tried to... It's the a priori probability of recurrence. They proposed for high-risk patients using the PSA threshold of 0.05. And so they looked at if you obviously had Gleason 6 disease and a positive margin, I think the PSA cut point was like 0.4. I think it's that pre-test probability that if you've got an 80–90% chance of recurrence and your PSA is going 0.03, 0.05, 0.08, they're recurring. So I think the concerns that I mentioned earlier about the RADICALS-RT, that there's a 3% difference in distant mets, a 2% difference in PCSM in a favorable population. So I think in these high-risk patients, if you're going to do early salvage, probably PSAs of 0.1—which was one of the definitions in RADICALS for failure—is what I would recommend.

Barbara Alicja Jereczek-Fossa: If I can only add that if you postpone, obviously a patient will get more treatment. So the more you wait, the more treatment will be necessary. So I think that this must be also part of the conversation because either you get one treatment early—maybe in some patients it'll be overtreatment, we don't know—but if you wait, it means that you'll get really high burden of treatment, maybe for life.
Speaker 8: We are talking a lot about cancer characteristics, the potential the cancer has in the long term. But what I'm missing out here is the host having the disease, how to judge the life expectancy, make sure that the patient will live long enough in order to experience problems with this cancer. Biochemical recurrence usually is still a slowly progressing disease with favorable outcome. Many of these patients ten years later will still be alive, maybe with some disease but still living with good quality of life. How do we make sure that we identify the right patients that live long enough in order to merit and to receive an intensified treatment, whatever that might be?

Bertrand Tombal: That, I would say, is a bias of APCCC, because by recommendation, when we vote, we vote mostly on the cancer characteristics and not on the patient characteristics. I'll tell you that in my center, we start using the Omega model for deciding we need radiotherapy, we need hormone therapy, and we're very surprised that we have a lot of old comorbid patients that actually wouldn't benefit according to that model. So I agree with you. But we have other sessions when we're going to discuss that, and here we always speak about patients we believe will benefit from it or not.

Daniel Spratt: There are absolutely many indolent recurrences with high PSAs, and then that's why I think it's challenging to lump these together where you could have a PSA of 2 ten years after surgery. I probably, if it's a local recurrence, unless they're very young, would just continue to watch them.

Barbara Alicja Jereczek-Fossa: Yes, we still see many patients receiving ADT, just somehow during the recurrence, maybe given in the urology clinic and so on. So again, I have this question: Would the patient prefer one single treatment or lifelong added ADT? And today with radiotherapy, as you know, we have short treatments. We have hypofractionation, as was nicely discussed in the morning for the not-operated patients, but today we have also hypofractionation for post-op radiotherapy. So it is also becoming not yet high evidence for this scenario, but already moderate hypofractionation is there. What else with imaging? We'll have more and more patients with tiny macroscopic PET-positive, MRI-positive recurrence in bed, and then you give—maybe in the future we'll have evidence, now we have ongoing trials—we give five fractions ablative treatment instead of lifelong castration. So I think this is really an issue of balance between treatments.

Derya Tilki: We continue with the audience questions.

Speaker 9: In ASCO last year, there was an abstract that showed that after six months of ADT, patients take one and a half years to recover—18 to 24 months, five years to recover. So it is a pretty long time. The EMBARK trial showed that both arms, Enza plus or minus ADT, were positive for MFS. So my question is, for a man who has sexual function, should we give ADT and Enza, or should we give Enza alone based on the ASCO data and its prospective data from Dr. Freedland?

Bertrand Tombal: It's a fascinating discussion. I think it's a little bit outside. There will be a session on that, no?

Barbara Alicja Jereczek-Fossa: Yeah.

Bertrand Tombal: There will be a session in the afternoon on that. It's a complicated matter. I come from a country where the number one drug we use—at least me—is bicalutamide 150. And I still haven't figured, after 25 years, which patient is best for which drug. But we're going to discuss that this afternoon.

Derya Tilki: Tomorrow.

Bertrand Tombal: Just say sorry, chef. Sorry, chief.

Daniel Spratt: I would just say, I don't know if relugolix is available outside the U.S.

Bertrand Tombal: Yes, it is. And much cheaper if you want to buy it.

Daniel Spratt: But I will say, after a year of hormone therapy, within 90 days, pretty much most men recovered. So that's pretty much my standard.

Thomas Zilli: We have our next question from the audience.

Neeraj Agarwal: Yeah. Neeraj Agarwal, medical oncologist. For the biochemical recurrence, fantastic data emerging. I was struck by Bertrand's comment that we need a trial to determine who needs salvage radiation therapy in the context of the EMBARK trial. Until we have the results of the trial, what is the threshold for salvage radiation therapy—and PSA threshold, I'm talking about—in those patients who have biochemical recurrence with PSMA PET being negative? This is a question we see in medical oncology, like when to refer the patient for salvage radiation therapy. At what PSA threshold when PSMA PET is negative?

Bertrand Tombal: I'm going to give a totally biased view on this. I'm still a big fan of the EORTC 22911 trial by Van Poppel and Bolla, where actually on this adjuvant trial, every time we did analysis on this, it seems that what best predicts the benefit was the prostate cancer characteristics. Meaning if the patient had positive margin, large positive margin, or positive seminal vesicle, I would tend to recommend salvage radiotherapy. If the patient had a high Gleason score and a pT2—it happened—I would then. So it's an extremely difficult question, but to me the best trigger is still the specimen pathology because we have quite a lot of data, and consistently—I'm going to be provocative again—if the surgeon didn't do a great job, radiotherapy will finish it. So if the surgeon did a great job, unlikely—it's extreme—but it's a very simple way to do it. If the surgeon did a great job, not sure it's going to help.

Daniel Spratt: I'm not sure. I think you can be an amazing surgeon and cancer can be left. But I think that, again, if I were to just try to pretend I'm a nuclear medicine doc—and you guys, please stand up for those that are—at a PSA of 5 after surgery with a low doubling time, you're talking very, very rarely will you not see anything on a PSMA PET scan. I think in our institution, if it's local only, which is uncommon, we'll discuss using EMBARK with local salvage radiation therapy. But if they've got distant metastatic disease, that's a whole other trial that's kind of STAMPEDE-esque, HORRAD-esque. Like, do you treat the primary with metastatic disease after surgery? I don't know.

Neeraj Agarwal: So no PSA threshold from your perspective?

Daniel Spratt: Of the patients enrolled on EMBARK, you had to have a PSA over 1 post-surgery. So you're already very—

Neeraj Agarwal: Upper limit of the PSA?

Daniel Spratt: No, no, no. What I'm saying is, the lower limit is 1, and so you already are very, very late. So I don't think I could say you could have a PSA of 10 with a local-only recurrence and we would discuss could there be a benefit potentially. But yeah, the probability I'd use radiation goes exponentially down because those patients are going to have metastatic disease.

Bertrand Tombal: That's the big difficulty because, I must say, probably most large centers in Europe, we rarely have this discussion of an EMBARK patient who has not received salvage radiation therapy before. Usually we see EMBARK as a second line. So that's why it's difficult and we really go case by case. I value extending the duration of intermittent androgen deprivation therapy. So I think, in this regard, there's a lot to do with radiotherapy to gain on the total duration of the drug. So I would probably recommend it to patients who have not—like Dan said, PSA of 5—and anyway, they would be metastatic on PSMA.

Derya Tilki: We have time for one more question from the online audience too—or Anna.

Thomas Zilli: Okay, we have just a question.

Derya Tilki: We have time for your question.

Anna: Thanks. I just wanted to go back to the relugolix issue real quick because can you extrapolate if the duration of testosterone suppression is actually shorter? Is it going to be equivalent? I know a lot of the radiation therapists are using relugolix, but I wonder about that.

Derya Tilki: Actually, that was the audience question.

Bertrand Tombal: We published on that in European Urology. Unfortunately, we don't see major differences in the quality of life domain around sexuality and other. However, a caveat is that consistently a company has been using QLQ-C30 and PR25; they're not fine enough to see the difference. The granularity of this questionnaire is not good enough to sense if the patient is actually doing better in real life.

Daniel Spratt: She means tumor control.

Bertrand Tombal: Tumor control.

Anna: Well, I was going on the relugolix, mostly, actually, Dan's comment earlier.

Daniel Spratt: Yeah. I'll say in HERO, which we just put on JAMA Onc, there's no difference between Lupron and relugolix in time to mCRPC. We have a different study that's about to be submitted from MARCAP and the trials that collected testosterone. There are guys after Lupron that do bounce back in a couple of months. It's just not on average. There's no difference in oncologic outcomes based on T recovery, whether it's two years, six months, two months, and so it'll be submitted shortly.

Anna: But then that would argue for shorter hormone courses.

Daniel Spratt: No, I think it's that we're assuming that it's... Remember it's the difference in castrate T versus sub-normal T. So we only focus on the therapeutic duration of castration, but that duration of two years of recovery, most of that is above 50. Most of it's 50, 80, 100.

Anna: I mean we can take it offline, but I think that that should probably be compared.

Bertrand Tombal: It's extremely difficult to do that trial, we discussed, because the problem is, on one hand, you have a drug with an extremely predictable testosterone recovery profile. And on the other, especially when you use injection, it varies from one patient to another. So how are you going to match these patients? It's extremely difficult.

Of note, speaking with Michel Bolla, he always said that when you go for short term, you should use monthly injection. This was the first trial. I know people use sometimes. Because the bottom line is that six months with a single depot of six months is not six months with six monthly injections. This is absolutely not the same kinetic of recovery. Take a drug like Eligard, for instance, with a six-month depot, because it is overloaded, you're going to be physiologically castrated for one, two years. Whereas with six months of degarelix, Laurence Klotz has shown that you have a time to recovery of four months. So the difficulty is that not everybody's recovering at the same pace. So doing the trial, we discussed doing it, but it's going to be extremely difficult to really capture that information in the injection group.

Daniel Spratt: More data is always better.

Bertrand Tombal: Yeah.

Thomas Zilli: Thank you so much again for this great session. It's time to close it.