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Alicia Morgans: Hi. I'm so excited to be here today with Professor Oliver Sartor, who is joining me from the Mayo Clinic after a wonderful ESMO 2024 where he presented the SPLASH trial. Oliver, will you please take us through it?

Oliver Sartor: Thank you so much, Alicia. It's really a pleasure to be here. I love UroToday, and you have a fabulous audience, so thanks for having me. I'm going to be talking about the SPLASH trial, and this is about Lutetium-177-PNT2002 in patients who had progression of androgen-receptor pathway inhibitor disease with metastatic CRPC. We're going to call it the SPLASH trial. Now, let's look at some of the details.

First of all, as you can see here, PNT2002 is a molecule you may or may not be familiar with. It's Lutetium-177-PSMA-I&T. The I&T is going to be binding to the PSMA cell surface protein that you're quite familiar with, and it's going to give radiation in the form of beta particles to those cancer cells that express the PSMA, thereby causing damage to the DNA and cell death.

Now, when we put together this SPLASH trial, it's for patients with progressive metastatic CRPC with PSMA-avid PET scans. Everybody had to have had progression after at least one ARPI, with an ECOG performance status of 0 to 1. Taxanes for metastatic CRPC were not allowed. However, you could have had a taxane for castrate-sensitive prostate cancer. Patients were randomized 2:1 to either the Lutetium at a dose of 6.8 gigabecquerels every eight weeks for four cycles, or an alternate ARPI, either enzalutamide or abiraterone. The primary endpoint was rPFS. For those who had progression on the ARPI arm, they could cross over to the Lutetium arm. The endpoints: rPFS was primary but also OS, Objective Response Rate, time to skeletal events, PSA50, etc. I'm not going to go over everything in this little review, but I'll simply say that a lot of these secondary endpoints were positive.

Who was actually enrolled in the trial? Median age was 72 for each of the subgroups. A significant number of patients had an ECOG performance status of 0, with some having 1s as well. The median PSAs were pretty low here, 13.20 and 18.95 in the two groups. Hemoglobins were good and balanced. Alkaline phosphatase was balanced. LDH was balanced. Prior taxane was about 17.8% and 16.9%. Remember, all of this is in castrate-sensitive prostate cancer. Then, metastatic status at the time of starting ARPI was metastatic disease in about 89% in each arm.

Primary endpoint, rPFS, was positive, with a hazard ratio of 0.71. The medians were 9.5 months versus 6.0 months for the rPFS change, and the median follow-up was about a year in each of the arms. So you can see we still need a little more maturity in the rPFS, given that this was only followed up for about a year, but you can see that these curves are distinctly different, with a hazard ratio of 0.71.

So here we look at the rPFS in the forest plot. What we can see is the vast majority of the point estimates are actually in favor of the Lutetium. One I'd like to point out that is a little bit interesting: if you come down to the next to bottom, there's Baseline PSA, less than median or greater than median. Well, it turns out for those greater than median on the PSA, it clearly favored the Lutetium, whereas the less than median did not quite favor it. These, of course, are within confidence intervals, but nevertheless, the patients in the control arm treated with an ARPI with a low PSA did extremely well. That's maybe one of the lessons. A lot of people say that ARPIs may not be active, but for patients with a low PSA, they actually did quite well in the SPLASH trial.

Now, the Overall Response Rate favored the Lutetium arm. Here we have the Complete Response Rate at 9.3%. Partial Response is 28.9%. These are objective by RECIST criteria.

If we look at the PSA responses, we see that this is going to favor the Lutetium. 35.7% had a 50% or more decrease in the Lutetium arm versus 14.6% for the ARPI change. The biochemical progression-free survival, which is time to PSA progression, clearly favors the Lutetium arm, and we can see that the hazard ratio there is 0.58.

The Intent-to-Treat Analysis for Overall Survival is essentially the same between the two arms. The hazard ratio is 1.11, clearly within confidence intervals, but very importantly, 84.6% of the eligible patients in the ARPI arm crossed over to the Lutetium-177 arm. So 84.6% is a massive number of patients crossing over from the ARPI arm to the Lutetium arm, and that, I believe, will influence the overall survival. Now, there were a variety of ways to look at crossover. Adjusted analysis also looks positive. We won't go into that now. That was not a primary endpoint. Overall Survival Intent-to-Treat is shown here.

Now, the treatment-emergent adverse events were more favorable in the Lutetium arm as compared to the ARPI change arm. Here you can see the Grade 3 and greater adverse events: 30.1% versus 36.9%. The serious adverse events: 17.1% versus 23.1%. Discontinuation rates: 1.9% in the Lutetium arm versus 6.2% in the ARPI change arm, and reductions in the dose of Lutetium were only 1.1%. So, this is very, very well-tolerated therapy.

In summary, the Lutetium in the form of PNT2002 reduced the risk of radiographic progression or death by 29% versus ARPI change. Hazard ratio of 0.71, p-value 0.0088. Let's say it continued to mature, but it's going to be a very high crossover rate, and that may obscure any changes in overall survival. I didn't really go into it here, but I'm going to tell you that multiple secondary endpoints favor the Lutetium-177-PNT2002. I showed you the Objective Response Rate and the PSA. I did not show the health-related quality of life, which also favors Lutetium. It has an excellent safety profile compared to the ARPI control.

I want to say thank you to UroToday for having me on. At this point, we'll go back to you, Alicia.

Alicia Morgans: Thank you so much, Oliver. A really, really wonderful presentation, just as you gave at ESMO 2024. Another exciting opportunity for us as a field to think about radiopharmaceutical opportunities in the first mCRPC setting before chemotherapy. A really difficult place, I think, to study these agents and to find things like overall survival, which you presented. One of the unique things about this particular agent was the schedule. I wonder if you can dig into the schedule a little bit because this is something that differentiates this agent as something for us to think about.

Oliver Sartor: Very well put, Alicia. We have a lot more familiarity with the use of Lutetium-177-PSMA-617. There, the dosing was 7.4 gigabecquerels given on a Q6W regimen for a total of up to six doses. Here, we're talking about 6.8 Q8 times four, so it's a lower dose of the radiopharmaceutical. Without going into all the details, that was actually a mandate by the FDA, so that part of the design was strictly at the request of the FDA. But what we have is a little lower dose and a little less frequent dose, Q8 as opposed to Q6.

Now, when we're looking at the rPFS, we clearly have a positive study. When we're looking at the OS, I think it's confounded by that very high rate of crossover to 84.6%. In the end, both the FDA and the individual clinicians will be making their decision. It could be advantageous to the Q6; it could be advantageous to the Q8. That'll potentially lie in the eyes of the beholder.

Alicia Morgans: Absolutely. To your point, this positive rPFS, which I think is so important, but these differences may lead to different decision-making in our own clinical practices. Now, just to confirm, too, because you're such an expert on all of these agents, these are both small molecules. So, can you tell me, just to dig in a little bit to the adverse events, as we're trying to think about this agent in the clinic, were there similar effects in terms of salivary gland toxicity? Should we think about that, maybe renal toxicity that we can see sometimes with the small molecules?

Oliver Sartor: We really didn't see much in the way of renal toxicity. That'd be true for the PSMA-Lutetium-177-617. What I'll say is that the salivary toxicity is going to be present, but it's probably a little bit less simply because of the dosing. Myelosuppression may be a little bit less simply because of the dosing. So, one could envision that there might be patients who might gravitate toward intensification, and maybe some others that may gravitate toward de-intensification. Again, I think what we'll need to do is to listen to our regulators, and we're going to be listening to our individual patients and their concerns as well. Like any therapy, if there are alternatives, I think there will be pros and cons of each.

Alicia Morgans: Absolutely. So as we wrap this up, I'm just wondering what are the next steps for this agent? Because clearly, this is the first study, but we may see more from this agent or from agents that are similar.

Oliver Sartor: I think as we move forward, and this is going to be true for the radiopharmaceutical space just in general, the question that has been progressively arising is whether or not there's been dose optimization. I think we're going to be hearing more about dose as we go forward with a variety of agents. We're going to be hearing more about alpha particles, and that'll be both with antibodies as well as with small molecules. We're going to be hearing more about new isotopes, things like lead-212, in addition to actinium. This field is going to continue to evolve. Combination therapies are important. This is a rapidly evolving field. What we're looking at today is a snapshot in time. Come back next year, and we'll probably have a little different story to tell.

Alicia Morgans: Well, I love to hear that. Final words. What do you take into the clinic when you think about Lutetium-177, the PNT2002 molecule?

Oliver Sartor: I think about tolerability, and it's unequivocally tolerable. I think about the opportunity to use an alternative agent for those that might need a little kinder or a little gentler therapy, potentially. I think that we're going to be having possibly two different molecules to consider, and I think that competition is a good thing. Competition makes us stronger. I see this field as being highly competitive, and you know who benefits? The patients benefit from competition. I'm looking forward to that.

Alicia Morgans: Absolutely. Options are always good for patients, certainly to meet all of their diverse needs, and I sincerely congratulate you. Thank you and your team, and of course, the patients for participating in this study, and to you for taking the time to share your expertise with us today. Thank you.

Oliver Sartor: Thank you, Alicia.