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Michael Morris: All right, I'm going to talk about moving into castration‑sensitive disease. There aren't that many studies in castration‑sensitive disease, so this is a design‑and‑thought discussion rather than a listing of what's going on in this space. And I'm not going to talk about oligometastatic disease, because we've already heard about oligometastatic disease. So it's really just going to be polymetastatic CSPC. Here are my disclosures.

So one thing that we need to think about in terms of moving radioligand therapy into castration‑sensitive disease is really the time frames at risk. With VISION, overall survival was around 15 months. With PSMAfore, it's just about two years. But when we're talking about moving into castration‑sensitive disease, we're really talking at least four to six years of overall survival.

We don't even have median survival on a lot of the trials looking at castration‑sensitive disease—that's the control arm. And so there's a lot more time for that ratio of toxicity to benefit to manifest, because now you're talking about long‑term potential, the emergence of long‑term potential toxicity in patients, living with impacts that really can negatively alter quality of life in earlier disease.

Let's talk about PSMAddition for a minute. So I think that this is probably the only registration‑level study in castration‑sensitive disease. It's fully accrued, and it's just waiting for events. Basically, the trial was ADT plus an ARPI of the physician's choice, plus or minus six doses of lutetium, 1‑to‑1 randomization. Again, with a crossover like PSMAfore at RPFS, the primary endpoint, therefore, is RPFS and not overall survival.

Here are some thoughts about this. So this is basically a cartoon looking at these two arms. So all six doses are going to get front‑loaded at the beginning of multiple years of ADT and an ARPI. And then they'll cross over at the emergence of new metastatic disease in the context of CRPC, and the primary endpoint is RPFS.

But let's think about the dosimetry of this for just a moment, because unlike CSPC, you're really impacted in terms of tumor volume by these patients being basically hormone‑naive. So they're going to have significant regression of disease. I've shown you a patient, for example, who over the course of just a couple of months on ADT and an ARPI is having such a reduction in the volume of their disease.

In essence, then, you're going to have a major reduction in tumor dosimetry just from the ADT and the ARSI. Ken presented, from VISION at EANM just last year, the dosimetry data from really advanced patients in VISION. He showed that in the first two doses of the sequence of six that PLUVICTO involved in the VISION space, almost the majority of the radiation dose—or the activity—was delivered to the cancers in those first two doses.

From that point on, you have diminishing gains in terms of tumor dosimetry, although the normal organs are receiving the same amount of radiation. So I think that the castration‑sensitive space is a good time to be thinking of adaptive dosing.

So let's go to ENZA‑p, which is Louise's study for first‑line metastatic CRPC. In that trial, she showed that you can hold therapy when patients are having a major response after the first two doses, and keep it going for those patients who aren't having a major response. In essence, you would keep your powder dry for a later date when you have a re‑accumulation of disease, and then you can re‑dose with PLUVICTO.

Something like this—this is just my cartoon; I'm not showing you any actual trial here—but you would give patients front‑loaded lutetium and then wait until they re‑accumulated some disease, so that again you would have optimal tumor dosimetry that probably would be at the point of emergence of castration resistance. Then you would dose and do the same thing over and over.

So in that construct, of course, you can't have RPFS as a primary endpoint, because it's actually part of the treatment plan. You want the patients to radiographically have increasing disease so you can optimize the tumor dosimetry. In that case, RPFS doesn't make any sense. A crossover doesn't make any sense. You just treat a randomized study with overall survival.

And remember that there will be a built‑in crossover, because now PSMAfore is approved—patients will just get Lu‑PSMA therapy at CRPC. It's built into the trial; it's built into the standard of care. You don't actually have to have it as part of the trial.

This is, in part, being worked into STAMPEDE 2, which is open and an international study. Half of that trial is for oligometastatic disease; half is for polymetastatic disease. In the polymetastatic cohort, those patients get dose‑intensified upfront lutetium. They get 7.4 gigabecquerels on day 1 and then day 8, and then they don't get retreated until later on—they get basically three doses every six weeks.

I think that dose intensification to take advantage of the early, favorable, and optimized tumor dosimetry is something that we should really think about in this space, so that we're really using radioligand therapy to its best effect in this long period of castration‑sensitive dwell time that the patient occupies before relapse.

I don't want to not mention Upfront PSMA, because it incorporates chemotherapy and lutetium in castration‑sensitive disease. This is six doses of docetaxel with or without a pre‑dose of two doses of lutetium. We saw these data presented at ESMO, and we saw that there was an improvement in progression‑free survival by scans and by PSA.

Although overall survival is really, really too early to assess in this treatment group—the lines aren't, at least yet, separating—let's not count our chickens. We remember from Mike's TheraP study that you don't always see a survival advantage when you see intermediate endpoints with divergence.

Now, everything I've just talked about is basically lutetium on top of standards. But I think we need to entertain, as we move to actinium or other radioligands—and it doesn't have to be PSMA as a target; it doesn't have to be a small molecule as a carrier—but as we think of other radioligands, we need to think about maybe supplanting standards of care.

It's not all about intensification. There's no one in this room who would raise their hand for castrating therapy. So if we could follow Mike Sathekge's model here with actinium, in which he didn't give patients ADT or an ARPI, but rather used actinium in lieu of ADT or an ARPI.

We see the really nice PSA declines, but very rarely would you see scans clear like this on just ADT and an ARPI. So you are seeing something here that's different, that I think holds the promise of making a new standard in the future that perhaps we could build upon, in which we are not using the same standards of care that we currently have.

So I just have 24 seconds still, so I can slow down a little here. I would just say these timelines are longer; concerns are longer in terms of the emergence of marrow toxicity, kidney toxicity, second malignancies.

But I do think that we need to be much more creative in terms of our design as we move into castration‑sensitive disease and start moving away from the traditional “let's export from late disease the same way we give therapy and dose it just in earlier disease.” I think that we really need to advance beyond those treatment paradigms. So with that, I thank you very much.