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Alicia Morgans: Hi, I'm so excited today to talk with Dr. Oliver Sartor, who's joining me from the Mayo Clinic. Thank you so much for being here with me today.

Oliver Sartor: Glad to be here, Alicia.

Alicia Morgans: Wonderful. Oliver, we've had so many wonderful conversations about Radioligand Therapy, about what we're doing in the clinic, and we'll get there in a minute. But I'd love for you to tell me about some of the latest data, some of the advances that we have that have come rolling in, and some of the things we have to look forward to. Can you start, please, with PSMAfore?

Oliver Sartor: Sure. What I might like to do is talk about PSMAfore, SPLASH, and ECLIPSE.

Alicia Morgans: Perfect.

Oliver Sartor: Because all of these are in the context of metastatic CRPC trials. But the one that we have lots of data from is PSMAfore. This is PSMA-617 lutetium-177, dosed exactly as VISION was dosed, 7.4 gigabecquerels q6 weeks x 6. And this looked at 1 RP androgen receptor pathway inhibitor. Then moving on to the next, so a lot of people were struggling with what to do, "Do we give a taxane? Do we give a hormone? What alternatives might we have? First trying a PARP inhibitor for a certain type of patients?" Within PSMAfore, they excluded the patients who might have been eligible for a PARP inhibitor and they excluded the patients for whom chemotherapy was clearly the logical choice for BED disease, functional liver disease, or something like that.

These are patients who are candidates for a second hormone and then randomized to either receive a second hormone, which would be the ARPI alternative to what they were on before. If they were on enza, they went to abi; if they were on abi, they went to enza versus lutetium that's unlike VISION, which is standard of care plus or minus. This is lutetium versus the hormone. And what did they find? First of all, they found that the rPFS was better, unequivocally, 12.02 months versus 5.56 months. Hazard ratio 0.43 or something of that range, something really strikingly good. The overall response rate was about 50% of lutetium versus 17% in the RP change arm. Health-related quality of life was better. Skeletal-related events were better. PSA declines were better, 57% in the lutetium arm. And so, all of that's really good. Adverse events, by the way, were fantastic.

They were better with lutetium than they were with the alternative hormone, but there's a little bit of a caveat. There was a crossover allowed in the study, and that crossover went like this. First of all, you had to have progression on a scan, and that was a blinded independent central review, so-called BICR. If you had progression by the blinded independent central review, then the investigators would be told you have progression and you could cross over. Now of the individuals who had progression, 84% crossed over. Well, guess what? If you look at the intent-to-treat survival, there's no advantage because if you give PSMA lutetium after one hormone or after two hormones or after two hormones and a taxane, it's still active. The patients went on to get another active therapy 84% of the time. There was a crossover-adjusted overall survival that had a hazard ratio of 0.8, and that's good. But there was an intent-to-treat that came out at 1.16, that's bad.

Well, the actual data on survival is still relatively immature, with less than 30% of the patients having actually died. This was actually a second interim analysis that was presented at Madrid ESMO, but there's going to be more analysis to follow. There's a third interim and then there's a final. And I'll simply say that at this point, it's a bit premature to say, "When is it going to be in practice?" because we don't know. But I think with a little more follow-up, we'll get submissions to the FDA, and then we'll have an idea of how the regulators respond, and that may depend on the follow-up data, safety data, overall survival data, etc. But I will say rPFS home run. Overall response rate, excellent. PSA declines, great. Health-related quality of life, great. A lot of positive parameters from the trial. But is it ready for the clinics across the United States? The answer is no, it's not. It's not approved by the regulators.

Alicia Morgans: I do want to just congratulate you and the team before we go to the other two studies because an 84% crossover rate is phenomenal. And we talk a lot about patients not getting that next line of therapy when they're in clinical trials, and rates in the 20% and 30% are sometimes what we see. So, I commend the investigators for getting those patients to the treatment that ultimately proved to be quite effective, and I really think that's important to call out.

Oliver Sartor: Thank you, Alicia. I think it is an important call-out. And you're absolutely right, so many times in clinical trials, patients go on and do not get effective therapies. And I think 84% is pretty phenomenal. And by the way, we're going to hear that same number again from SPLASH, 84%.

Alicia Morgans: Well, tell me about it. Tell me about SPLASH.

Oliver Sartor: Okay. Now, SPLASH is a little different. SPLASH is PSMA-I&T lutetium-177, not PSMA-617 lutetium-177. The I&T is a bit distinct in the molecule, but the isotope is the same. However, it turned out that when they went to the FDA, there were restrictions on the dosing because of some fears over the renal dosimetry. And instead of dosing at 7.4 gigabecquerels, it was dosed at 6.8. Instead of giving it every six weeks, it was given every eight weeks. Instead of giving it six times, it was given four times. The dosing was reduced. The clinical trial design was similar, but not the same. The patients in the SPLASH trial could actually receive a prior taxane if it was given more than one year ago for hormone-sensitive disease, but not for castrate-resistant. And it turns out that, of course, there are some differences in the geography.

The bottom line is that there was less positivity to the rPFS outcome. Instead of running it at the 0.43 range, like we saw in PSMAfore, it came in at 0.71. Now interestingly, the control group was pretty similar to PSMAfore. It was 5.56 for the RP change in PSMAfore. Here it was 6.0, so 6.0 months for the RP change. The control arm was the same. But when it came time to look at the rPFS in the experimental group, it's about 9.5, and that gives a hazard ratio of 0.71. Safety, fantastic. Crossover, unbelievable, 84%. That's not a mistake, 84%, twice. And so, 84% crossover and the hazard ratio of the intent-to-treat OS was 1.11 instead of 1.16. There's an incredible similarity in the crossover rates and the overall survival, but it too is relatively immature in terms of the survival input. There's going to be a necessity for more follow-up. But anyway, that's SPLASH and PSMAfore comparison.

Alicia Morgans: Wonderful. Well, thank you. Can you tell me about ECLIPSE?

Oliver Sartor: Yes. ECLIPSE is another PSMA I&T lutetium, but weirdly the dosing is different than the other PSMA I&T lutetium. And here you're going to go with 7.4 q6 x 6. Different day, different people got out of different sides of the bed. Okay, same FDA, different dosing regimen. Control arm, the same. Completed accrual, November 12th. We don't know what it's going to show yet. And we'll just have to wait and see.

Alicia Morgans: I think this is so exciting and really there's a lot for us to look forward to seeing. Of course, as you've just explained. But right now, we do have Radioligand Therapy available in our practices. We're all quite familiar with lutetium PSMA-617. This drug is available at this point in time, post-AR pathway inhibitor, post-docetaxel. When it came out, we had lots going on. We had a lot of fears. We were afraid that we wouldn't get our PET scans. We were concerned that there wouldn't be sufficient centers to deliver the drug. At a certain point in time, we didn't actually have enough drug to go around because of manufacturing. But I feel things have really changed, and I'd love to hear your thoughts on that. How is your practice delivering lutetium PSMA-617 now and what's different than when we initially thought about access and had all of the concerns that I just mentioned?

Oliver Sartor: Yeah, thank you, Alicia. By the way, I agree completely, really a lot of change. The first problem was the PET scan and having the PET scan of patients with advanced disease was not sorted through the insurance companies that we were familiar with. It was still some supply chains on the PET isotope. And before you know it, you had to order the PET and then you'd have a two-week delay and then a three-week delay, and then God knows when you would get it. Basically, PET was a problem. I might also mention that in the trial VISION, you looked at Gallium 68 PSMA-11. But a lot of people were getting the PYLARIFY, which is the 18F-DCFPyL. And then there was a discussion, "Oh, well they got this scan instead of that scan." NCC guidelines came down and said, "Okay, they're pretty much morally equivalent." And then the insurance companies came in line.

The PET scan problem is solved. The next problem, as you well know, was manufacturing. Lots of manufacturing problems. They had shutdowns in the plant in New Jersey. We were trying to supply globally out of Italy. And then they had clinical trials. Even the clinical trials, I didn't mention them, but PSMAfore had some delays in therapy because they just couldn't ship. It was a serious problem. And you get your PET scan, you put your order in, they said, "Four weeks to drug, six weeks to drug. We don't know when the drug's going to be there. Maybe just don't tell people about it because we don't have the drug." And it was really problematic. Guess what? Those problems were solved.

The PET problem is essentially solved. I just don't get it. I'm sure that somebody gets denied, but I get my PET scans pretty promptly now, and I get my lutetium pretty promptly. I put in the order and I get it done. The insurance company is familiar with it. Yes, it is in the post-taxane, post-ARPI space. You need to have your enzo, apalutamide, darolutamide, whatever, and a taxane, and then you're eligible so long as you have the PSMA PET uptake that is appropriate under the VISION scan guidelines. But I'm saying we've made a lot of progress and patients are getting access to the therapy now.

Alicia Morgans: And it's so important because patients feel well. They seem to do well on the therapy. And one of the things that I still see as an issue, but one that I think is actually relatively quickly resolving, is that there is still some difference in where the drug is offered and the way that we're trying to ramp up and make sure that all patients have access. Now, you and I work at centers that have been involved in these clinical trials, in urban centers, essentially where we can get the drug, but there are a lot of patients that live in communities that are much more distant from those types of centers. And what I have seen too is that there's a real need and interest to ramp up additional centers across the country and probably around the world to ensure more equitable access. What is your thought around that?

Oliver Sartor: I agree completely. Clinical trials are typically done in fairly large centers like yours and mine, but it turns out that most patients are not treated at the major centers. What's happening is that a larger number of centers in smaller municipalities are being approached and are interested in Pluvicto, getting trained to get Pluvicto, getting the radiation safety standards in place, etc., but the number of sites capable of administering Pluvicto is dramatically expanding, and that's due to hard work on the part of the sponsor, Novartis. And I would say good work on the part of Novartis as a sponsor. They're working hard to ensure that access is less of an issue. I think they're succeeding. I think they're doing a good job.

Alicia Morgans: Wonderful. If you had to put all this together, where we're going in the future with these studies that we're still waiting to hear more information on, and certainly where we are right now, what would your message be on these radiopharmaceuticals, and what should we take home as we're continuing to find hope and excitement in them?

Oliver Sartor: I'll take a short-term view, a medium-term view, and a long-term view. The short term is we're sitting really nicely in terms of the VISION space, that post-advanced hormone and taxane. I think we're solving a lot of the access problems. We're getting to the patients who need the therapy, and I think the adoption rate is going really well. That's short term.

You get to the medium term. We've got these three important trials that are all in the pretext, same as metastatic CRPC space. I think it's a little too early to come up with a final opinion. The regulators will make the determination and the regulators will determine the access to the drugs because without insurance coverage, it's just not going to happen. And I think there's a lot of work on the part of the sponsors to ensure that the best possible presentation and data are available for the FDA to review. I'm very respectful of the FDA. They have patients' interests at heart. And they want to see safety. They want to see some overall survival trends. They have to wait a little bit before we get there.

Now, the longer-term vision. I think we're very bright. This competition we see in the field is creating the possibility for patients to benefit from that competition. And people are thinking creatively about going earlier, going in combination, doing different isotopes. We have lead on the rise now. We have actinium on the rise. We have copper on the rise. And so, the field is expanding and the long-term view, I think, is incredibly optimistic. We can have better therapy for our patients. The companies are fighting to show that their therapy is better. And that competition, great for healthcare, great for the patients.

Alicia Morgans: I could not agree more. When we all compete to do better for patients, everybody seems to win. And I so appreciate your time, your expertise, and like you said, it's just wonderful that the future is so bright. Thank you so much for your time.

Oliver Sartor: Right. Thank you, Alicia.