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Barbara Alicja Jereczek-Fossa: And now we have time for questions. Are there any from the floor? If not, we have one from the—maybe we start with this one.

Jason Efstathiou: Yeah. So I think, Neal, this will come to you. It’s coming from our online participants. And then we’ll get to the mics. So tamoxifen increases thromboembolic events. In terms of risk-benefit, what do you think?

Neal Shore: So yeah, that is true. That is a risk factor for it. You can get some hot flush with it too. But it’s generally a well-tolerated drug. It’s generic, so it’s very accessible. It can be given once or twice daily. But yes, that is a factor. And then there’s going to always be the issue around drug-drug interactions with what other polypharmacy a patient may be on—

Jason Efstathiou: So your preference is prophylactic radiation, if possible.

Neal Shore: So for my clinic, yeah. I mean, I primarily will do prophylactic radiation at the start. I don’t wait. I have the discussion with the patient. My personal experience using tamoxifen is very limited. But I’m going to start using it more now because of the research I’ve done on this. I think it’s a very reasonable approach. And I think for someone—not for all patients, but for some—the combination with radiation is probably the best to mitigate symptoms.

Jason Efstathiou: Bernie, you had a quick comment?

Bertrand Tombal: Yeah. We stopped using tamoxifen with bicalutamide. And there are two aspects: it’s gynecomastia and mastodynia. Tamoxifen works well on mastodynia but not on gynecomastia when they get these huge breasts. Unfortunately, the only thing you can do is surgery. So that’s why I really believe that prophylactic radiotherapy is much better, because I don’t expect that if the guy has to wear size C bra, you’re going to give him a docetaxel, and he’s going to be like a young lady. It doesn’t work.

Trust me. You have to go to plastic surgery. So if you want to avoid gynecomastia, tamoxifen is not as good, I guess. And I don’t see why it would be different with monotherapy, because we’ve been using that for bicalutamide for more than 25 years now.

Jason Efstathiou: So I think we’re going to have, actually, specific dedication to gynecomastia tomorrow in the quality of life section. So maybe let’s move to the microphone over here.

AUDIENCE: Yeah. [INAUDIBLE] from Istanbul. My question goes to Dr. Paul Nguyen. You nicely demonstrated that combination—whole pelvis radiation plus ADT—is superior. So what would your response be to the proposition that the benefit actually comes from ADT alone, and if you omit whole pelvis radiation altogether, you may achieve the same result? Probably OLIGOPELVIS trial will answer that question, but that’s one proposition.

And the second tier is that can you use, actually, whole pelvis radiation as a filter to demonstrate that the disease is actually limited to the pelvis so that you can avoid additional androgen deprivation therapy? If you don’t have any response, you can further add.

Paul Nguyen: Yeah. Those are great questions. I mean, as to the first question—can you just do ADT alone or do you need the pelvis radiation—I mean, look, I think we just rely on retrospective data in this setting. And the best retrospective evidence would suggest that the pelvis radiation is going to benefit you. So I will continue to do that currently. As to the second question about whether you could treat just the pelvis alone without ADT and then see later, do you have to add the ADT?

Maybe. I mean, you can analogize to the salvage radiation setting immediately post-operatively, where some people do that. I think that for patients that are going to get a benefit, we know that there is a benefit of doing concurrent ADT with the radiation. We’ve seen that in the RTOG 9601. That’s where the survival benefit is. So for a patient where I’m trying to maximize survival, I would do them concurrently.

Jason Efstathiou: Maybe just a follow-up question for Paul, maybe Dan, anybody can comment. Let’s say you’ve done pelvic radiation. They have another recurrence now in nodes above your pelvic field, maybe in the para-aortic region. How often are you patching in now a para-aortic field matched to your pelvic field? Is that something you would recommend doing?

Paul Nguyen: Yeah. So that’s a tough scenario. And Jason, you raise a good scenario because that is the most common site of recurrence. If you treat the whole pelvis, patients then will sometimes recur right there in the para-aortic node, and that’s very frustrating. And it’s especially for the young patient that I worry about. So in that setting, if somebody is particularly young, I will sometimes go for it. I’ll patch on a little SBRT field, and I’ll even add a little bit of hormone therapy. We don’t have level 1 evidence for any of that. But if somebody is very young, I’ll do it. But it’s really case by case.

Jason Efstathiou: Yeah, I’ve been doing that with some reasonable success. I think it’s an emerging new clinical situation. Let’s go to the microphone over here.

Audience: Yep. Murilo from Sao Paulo. Fortunate or not, my question is also for Dr. Nguyen. So in the same case you had before, the only question you got for the radiation of the pelvis—you told us that you would radiate the whole pelvis. But I’d say the same patient did not receive prostate bed radiation before. So do you still radiate the prostate bed in case of your positive lymph node and a PSMA bed?

Paul Nguyen: That’s a great question. In that setting, I personally would, for most patients, radiate the prostate bed as well. I know that’s controversial. We don’t really have any kind of clear evidence on that. But if we just think about first principles, the majority of recurrences will happen in the prostate bed for those kinds of patients at the anastomosis or the posterior rectovesical space.

And so for me, if I’m trying to go for cure for younger patients, I would just treat everything. If they’re young enough and healthy enough that I would treat the whole pelvis and give them hormones and put them through all that, I’ll just treat the prostate bed as well, generally. But it’s tough when you have, let’s say, organ-confined disease and a negative margin and Gleason 7 in the prostate bed. So that’s a tough scenario.

Audience: Yeah.

Thomas Zilli: I perfectly agree with you. So even in the STORM, I saw we keep open the decision for the people to include or not the prostate bed just based on the high-risk factors. We have just a single publication with retrospective data suggesting that when we omitted the treatment of the prostate bed, we have an increased risk to have some local relapses on the side of the prostate bed. So I think this will be an open question that we will explore on PEACE-V.

Barbara Alicja Jereczek-Fossa: One more question.

Chris Sweeney: Chris Sweeney from Australia. Neal and Bertrand, I’m going to do a calculation, a calculus here. ADT and enzalutamide—it looked better than enzalutamide alone in multiple endpoints, including the restart. And there’s a hit on quality of life on libido, with the testosterone driving the libido. Enzalutamide alone—less cancer control, it looked like earlier restart, and we’re saving them libido to cause gynecomastia and all the struggles around that. Can we make an argument that a big blast with ADT and enza to stop all this other body self-image type stuff and the quality of life decline from that?

Neal Shore: So I think that the problem is that we don’t have data that if you stop the ADT and you get a testosterone rebound effect, you could ultimately have the worsening, that 40% to 30% breast-related issues. And so the study wasn’t inclined to do that, nor was the study powered to be a comparison of combination versus monotherapy.

The study was first powered—the primary endpoint was combination versus LH-RH and placebo, which was the endpoint of the study. Secondary endpoints were the enza monotherapy and then overall survival, which we’ll be reporting on sometime next year.

Chris Sweeney: But just looking back at the totality of the data—granted, we make compromises on our primary analysis—but just stepping back and looking at the total picture, I think we can make an argument for ADT–enza to save a lot of downstream effects over enza alone.

Neal Shore: Well, I think I would probably push back a little bit on that, given the amount of toxicity that you see with testosterone suppression.

Chris Sweeney: We’re radiating breasts. We’re giving tamoxifen. We’re possibly causing a whole—

Neal Shore: Other radiation—the radiation, if given upfront, can be given as a single dose, maybe over two or three days. There’s a cost to it. I get that there’s a cost to giving ADT. That’s a separate issue as well. And then there are the associated T-suppression side effects, from bone demineralization to hot flush, etc., and all the sexual dysfunction side effects.

So I think it’s all part of the shared decision-making. I really do think that you have to just—it’s not going to be a one-size-fits-all. The other question that hasn’t been answered, but you may be thinking about too, is if I start on enza mono and I start to see progression, can I then add ADT, which is an important area that has to be answered.

Bertrand Tombal: And one of the problems is, I believe nobody believed that the enza monotherapy would be better than the ADT. So I think that the first consequence of this is that we should no longer speak about escalating treatment in terms of starting somebody on ADT but adding enza. But in this patient, the question, though, is what is the benefit of adding ADT?

Unfortunately, most of the tools that were used in this trial and others don’t allow, once again, to pick up all the differences between monotherapy. Just the quality of life questionnaire is not good enough. So if we believe the question of adding ADT or not is important, we should do—we don’t need huge randomized trials—but we should at least try to invest a little bit, trying to really understand what is the gain for the patient that would not have ADT, because clearly speaking, like with patient organization, very little about libido.

Because we, urologists especially, we see sexual activity just through erection. But there is much more than that. We need to dig in on that so that we can advise patients, starting from the point you mentioned, and even say—it was for bicalutamide 150. We always tell the patient, look, the data we have point to an inferior oncological benefit with bicalutamide 150. Still, when you explain the toxicity, the side effect profile, the perception of the patient, many would go for bicalutamide.

So to me, EMBARK is just about a new—we can say that what we call the backbone treatment for years is not anymore. The backbone is the [INAUDIBLE]. And now we’re going to have to understand much better what are the pros and cons of adding or not adding ADT. But at this point in time, I don’t think that even torturing EMBARK to the end will give us all the information.

Chris Sweeney: I’m feeling a patient preference study coming up.

Bertrand Tombal: Yeah.

Jason Efstathiou: I think, Chris Sweeney, you’re foreshadowing a really hot side effect management session tomorrow.

So let’s go to this mic. Yeah.

Audience: Would you consider time off systemic therapy as a benefit, or do you eugonadal progression-free survival is a benefit of the combination, which I think—time off treatment?

Bertrand Tombal: I would say it is more from the AR pathway inhibitor than from the combo. Because for the combo, it’s not a true time off therapy. It’s still a time with suppressed testosterone.

Audience: But is it? I don’t think—in the EMBARK, I think that’s not necessarily the case. So the time off treatment with a recovered testosterone, I think, was longer in the combination because with the single-agent enza, you had to get back on treatment fairly quickly, if I’m not mistaken.

Neal Shore: So you’re right. The testosterone recovery was about 11 months in the enza mono, 16 months in the LHRH alone, and 20 months in the combo. So that would speak to—there are quality of life analyses that we’re doing on that. And I take your point. I think it’s important. It’s a very big debate on this notion of here we started with intensification, then deintensification, and then use certain PSA recovery metrics. But having that T recovery, I think, is going to be something that we need to really further evaluate. And we are.

Daniel Spratt: One of the points that Dr. Sweeney’s raised, that I think we need to just be mindful of, is if we give everyone tamoxifen—and I see Nima Sharifi here, so he can correct every error I say—is that if you’re blocking the androgen receptor, you’re giving tamoxifen, it has to all result in cortisol and progesterone, which both have been shown in studies to promote cancer progression.

So I don’t know, Nima, if you would agree with that statement or not. But I do think because that’s not part of EMBARK, there could be potentially downsides, that you may not see that benefit if everyone got tamoxifen on that study.