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Bertrand Tombal: Thank you. So the question here is a little bit different. We are speaking mostly about EMBARK patients, which are very late patients. And the question, as I understood, is that now that you have an EMBARK patient, is there still a role for local salvage treatment? These are my conflicts of interest.

As usual, I'm going to try to get a very provocative approach, at least for the sake of the discussion. So this is basically what we do. This is what we heard so far. When you have a PSA rise, you stratify patients into low risk, high risk. With the EMBARK patients, we are in the high-risk ballpark. If we follow the guidelines, we do a PET PSMA. And then, whether we have local, locoregional, distant metastasis, almost everywhere on the planet—I do insist, also in my center—we usually recommend radiotherapy and systemic treatment in one way or another.

If we look at the guidelines, indeed, it's been said already, they do recommend to offer early salvage intensity-modulated radiotherapy. There is a lot of work. They use the word "early." As has been discussed, it's very important. They word "strong." It's strange, because actually, "strong" meaning that we take our decision based on level one evidence, which, to be fair, we don't have. What we have is mostly retrospective trials that all point at something which I value as well, is the concept of window of opportunity. And if you remember the EMBARK patient, they had to have a PSA above one. So you would be already outside of that window of opportunity.

This is another Derya study. Very, very large group of patients like we usually have from Germany. Same message. There is a window of opportunity with the PSA. If you wait too long, these patients are not very good.

I know that the EAU guidelines, they like to say, "Okay, early SRT provides the possibility of cure"—okay, so we should define cure—"for patients with an increasing PSA." They say that you have a good BCR, and they say something very interesting, that biochemical progression is not widely accepted as a surrogate marker of prostate cancer recurrence, which it is not. This is a recent paper in which Dr. Spratt and many others clearly demonstrate that BCR is not. So if you want to play the devil's advocate, you should start by saying that, in general, no randomized controlled trial has demonstrated robustly that applying prostate bed radiotherapy, or even MDT or both, significantly delays MFS or OS.

On top of that, we know that the patients we are speaking of now, which are the very high-risk patients, the EMBARK patients, when you look at the same retrospective study, they usually don't do well. If you take prognostic markers such as high Gleason, high PSA, rapid PSA doubling time, usually these patients do poorly on salvage radiation therapy unless you use hormone, and this is the hormonal component that will increase the overall survival. There are many data pointing in that direction. I like that paper by Dr. Dal Pra where you look at Decipher and you see how much these high-risk patients are actually enriched in high-risk GC scores. So it points at a group of patients who are not likely to do very well on salvage radiation therapy alone.

When you look at the guidelines, they say you should do a PET PSMA. Honestly, we know now that the EMBARK population is most likely, at large, a metastatic population, micrometastatic population. And if you use this very nice paper by Louise Emmett, if they have distant metastasis on PET PSMA and you do irradiate only the prostate bed without hormone therapy, you should not expect a magnificent result.

So why would you still do it? One of the main reasons has been that, actually, you can delay androgen deprivation therapy. And I think, actually, it was absolutely acceptable. Why was it acceptable? Because we, and I say we, it's mostly the urological community, we failed to show consistently that it increased overall survival. The only thing it does is to give you a lot of side effects, even if you're using intermittent settings. So it was acceptable to delay it. The only trial is that TROG trial, where, honestly, that would make you pass FDA or EMA. So it was actually acceptable to delay systemic treatment because the benefit on OS was not good.

But that's the message of EMBARK. Enzalutamide, and probably the others, it very significantly impacts MFS and OS. So the game has changed. And by the way, enzalutamide was approved yesterday by EMA as a single agent or in combination with ADT. It's now going to be a reality. So should you start enzalutamide with or without ADT? Or should you still apply salvage radiation therapy? Many patients did not receive radiotherapy in the EMBARK trial, but we don't know exactly how many were actually judged to be already outside that window of opportunity. So I don't see that as a problem in the trial. And actually, when you look at the subanalysis in the supplementary of New England—usually the nice part in New England is the supplementary—you see that it doesn't change really anything whether they had received radiotherapy or not.

So I ask myself, as a conclusion, is it still acceptable to delay systemic treatment in an EMBARK patient after EMBARK? And if you agree, so that's the standard of care: short course of ARTA plus/minus ADT, and then you stop. But it has an impact on the radiotherapy as well, because I believe that, no, this is not the discussion anymore about salvage radiation therapy plus/minus short- or long-course ADT. The question, though, in EMBARK patients—please don't extrapolate to the other patients—I believe that in EMBARK patients, no, the question is, is it now a matter of short-course ADT plus/minus salvage RT? And to be honest, we don't have the answer for that. We may have to do trials. There will be trials. But at this point in time, I really believe that in an EMBARK patient, what you need to do is to start enzalutamide and another ARPI right away. Thank you very much for your attention.