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Oliver Sartor: Thank you, Silke and Aurelius. You've done another fabulous job. So glad to be here. Lugano is great. Thank you.

In which patients with synchronous, low-volume, metastatic hormone-sensitive prostate cancer do you recommend total therapy? Now, this is a little bit of a tough topic because we have a lot of points, and a lot of conjecture, and perhaps very little data. And by the way, I'm not going to talk about intensification or de-intensification, which could very well fit into this particular topic.

Now, I'm going to have some overlap, and that's OK. It's interesting how we can both look at the same data and look at it a little bit differently, and that might be the case. First of all, I think when we look at low volume, we're going to be talking about conventional imaging low volume at this point. But at the same time, there really is huge heterogeneity when we look at these low-volume patients by using PSMA PET. And this is a scan that would be a low-volume patient with a bone scan on the left and a PSMA PET on the right.

It turned out that Dr. Michael Hofman gave a really nice lecture on this 2022. And I'm not going to recapitulate his lecture, but I agree with his lecture. It is extraordinary how much variation there is in this group of patients. I'm going to say that we need to start thinking about all these data from the past, all of which are true. Nothing is negated, but we really begin to need to pivot toward the future.

Now, one of the things that I think is relevant, and not really on the agenda for my talk, is when we take these low-volume patients, we can really divide them into oligometastatic and polymetastatic by molecular imaging classifier. So the patient I just showed you in the previous slide really would have been polymetastatic. He would not have been a candidate for SBRT. Way too much disease.

But on the other hand, this is the way we're managing the patients today. We pretty much are going to get a PSMA PET on all of these patients, looking for those individuals that we might be able to call oligometastatic. Now, oligometastatic—five lesions or fewer. There seems to be a little bit of a consensus around that, although I think that consensus could change. I know that at Mayo Clinic, where now I practice, it doesn't really matter if you have five, or six, or seven. The question is, can you treat the oligometastatic disease with metastasis-directed therapy or not? And the old number of five is not necessarily the new number.

Now, total therapy. External beam, prostate and pelvic nodes, SBRT, metastasis-directed therapy, ADT, ARPIs, chemotherapy. Now, when we're looking at total therapy, we're going to talk about all the above, part of the above, one of the above. How do we view this idea of total therapy?

And the thing that—I almost have to say it—the other considerations. So this is an email I got yesterday, and I'm quoting. This is a quote. "I obviously did not like the side effects of hormonal therapy. So we decided to try intermittent. I want to explore Actinium-225."

And then from last week in the clinic, "Doc, I really can't afford all these medication. I'm retired, and things are tight." And so I do appreciate the way Silke and Aurelius have set up the discussion that the real world is complicated by a variety of factors that are not always apparent in the consensus conference.

Now, I'm going to quickly run through this, because I think this is what most people know, and I concentrated on just a few other issues. ADT radiation to the prostate versus ADT, STAMPEDE. OK, bingo. Got it. OK. But that's ADT. That's not what we use today. PEACE-1 is going to address this ADT/ARPI radiation. I'll come back to that.

ADT/docetaxel versus ADT. OK. We have a lot of data on that. CHAARTED, STAMPEDE, and the French studies. It's a mixed bag for the low-volume disease, but I'm going to call it some positives for the meta-analysis. I think that's a little bit fair, but it's not a slam dunk. It's very different than the recurrent low-volume disease. But nevertheless, we do have a little bit of a mixed bag here.

I'm not really going to talk about the ADT/ARPI versus ADT. It's just like ga-bing, ga-bing, ga-bing, ga-bing—they're all positive. I don't need to tell you that. You can read.

ADT/docetaxel/ARPI. In this case, we're looking at the ARASENS and PEACE-1 a little bit differently on the OS, but there's a little difference in the follow-up. I talked to Karim about it a little bit earlier.

I also want to remind people, triplet therapy has a huge flaw. We really do not know whether or not docetaxel will add to the ADT and ARPI. We know that the ARPI can add to the ADT and docetaxel. There is no trial that really shows us the added value of docetaxel in that setting. And then we're going to talk about metastasis-directed therapy. We don't have a phase III there either.

Quickly, on PEACE-1, you know the design. The low-volume subset, it's not positive. At the time it was reported, the number of events were really quite low. With longer term follow-up, this could potentially change. But look at this number of events, 29 and 31 on the OS events. I don't think you can make a lot of conclusion at this point other than lots of immaturity.

Now, going to the radiation of the prostate, I'm going to have a slightly different perspective. Remember, complex requirements for PEACE-1, because there was an evolution in the control arm going from ADT to ADT/docetaxel. And as it turns out, about half the people in the low-volume subset actually had docetaxel. And then you look at the randomization to the Abi, no-Abi.

The RPFS, when using radiation to the prostate, is actually pretty favorable. And you can actually have tons of CRPC being better, but it's not statistically significant. It's a trend on the RPFS. And then if we want to look at the low-volume subset for, in this case, overall survival, again, we see a trend, 0.77, but not statistical significance. And these are relatively immature data. So we need more.

If we look at the low-volume subset, I looked at it a little bit different than Rob did because if you look at the grade 3, you actually have to break down the grade 3 into different components. What really showed up is the prostate RT or TURP. The rest of the grade 3s that went into the composite endpoint were pretty much the same.

So what you're looking at when you radiate the prostate is preventing future radiation to the prostate, if it wasn't already given, or TURP. It's 27 versus 4. But if you look at the number needed to treat, it's not absolutely spectacular. So I'm not saying there's no terrible thing about giving radiation here, but let's be realistic about what the benefits actually are.

ARASENS. Everybody knows the design. The low-volume subset actually was reported by Maha Hussain at ASCO GU in terms of the darolutamide adding to the ADT/docetaxel. However, as stated, we don't really know whether or not the docetaxel adds anything at all.

Now, metastasis-directed therapy. I would love to talk a lot about it, but it's hard for me to talk a lot about it because, in this setting, we have so little data. Now, this is a nice randomized phase II trial. And this is presented by MD Anderson. I know Ana is here. Congratulations, Ana, for a nice trial here.

But if we actually look at whether or not these were de novo or recurrent, it turns out, most of the patients were recurrent. And we look at the imaging, it was actually CAT scan, bone scan, and fluciclovine PET. Now, we do see this benefit. You can look at the Kaplan-Meier curve for progression-free survival, but it's not really the setting that we're addressing right here.

So total therapy in low-volume, metastatic hormone-sensitive prostate cancer, not discussing intensification, which I think should be discussed. Nevertheless, there is no doubt that the ARPIs and ADT add value over the ADT alone. Docetaxel, to me, no clear value in this setting.

Radiation to the prostate improves local control. But remember, that's TURPs, radiation to the prostate, if you look at the PEACE-1. And it doesn't really show, at this point, an overall survival benefit. And RPFS is a little bit dicey, but we need more data.

Metastasis-directed therapy with SBRT seems a good idea. And by the way, I do it. But on the other hand, if we're talking about evidence base, we have to be honest with ourselves about how much evidence there is, and there's not much.

So one of the things that may be important is radiation treatment to the prostate. All the lesions in oligomet patients may be important in the future—and I'll say a little bit provocatively—when we're not using ADT or maybe we're using intermittent therapy. Thank you very much for the opportunity to be here today.