What is that, Scott?
Scott Tagawa: The PSMAddition trial, as the name implies, looked to add lutetium PSMA-617 to the backbone of ADT and ARPI for patients with metastatic, what we call, hormone-naive or hormone-sensitive prostate cancer. It's an interesting trial that started off, as you well know, within the US cooperative groups actually with radium-223. That trial came out. We wanted to ask the question, what else could we add to, at that time, the backbone of ADT and docetaxel?
And within weeks, there was an ALLIANCE submission, and then there was an NRG submission, and the Task Force said, "You guys should get together." We developed that concept. And as more data came out with ARPIs, at that time, abiraterone, we said, "This will be much more interesting if we did ADT-abiraterone with or without radium."
And then the radium-223 data came out, and that combination didn't look to be so safe, but we continued on. We were looking for a cooperative group trial. We said, "We should ask the question, does docetaxel add anything to ADT and an ARPI?" It was ADT-ARPI with or without docetaxel. A question that we still have not answered and a trial that just launched, actually, within the cooperative group.
I'm not unhappy that we changed what we did because I really enjoyed the trial, but it remains an unanswered question. But during that period of time, the two of us, Mike Morris, et cetera, talked with Endocyte, and we said, "This would be a good question to ask in this disease state.
What about testing there?" And that was the fourth version that essentially went all the way through Task Force, steering, basically up to a nearly activated trial, and Novartis took over Endocyte and then wanted to run a worldwide trial. We initially planned on the Foundation running the US version, and they were going to run the international version, but there were shifts of people. And anyway, it turned into a worldwide Novartis trial. Changed a little bit, not a ton. There was no PSMA PET embedded in our trial because PSMA PET wasn't around. It was really an OS primary trial with the last look at the final OS and rPFS.
And it was four cycles of lutetium PSMA-617 with an optional two, but the bar was much higher than VISION to get that additional two cycles. There were some tweaks that were a little bit different, but what we really wanted to demonstrate was, is there a benefit to adding lutetium PSMA-617 early? We think there is less likelihood of having PSMA-low disease, less likelihood of having some radiation-resistant clones and to get some of the synergy, at least that we'd seen maybe preclinically of upregulation of PSMA and radiosensitization using the AR backbone. There was scientific rationale as well as it made clinical sense.
Oliver Sartor: It's a nice big trial. 1,144 patients were accrued. How many of the patients got a PSMA PET scan? And how many patients were positive on the PET scan and eventually were allowed to enroll in the trial?
Scott Tagawa: To take one step back, the patients could be on standard-of-care hormonal therapy for up to 45 days before they signed consent. And nowadays, sometimes we're identifying metastatic disease with a PSMA PET. They might have had one as standard of care. They might have had a CT, MRI, or bone scan. They needed to have a CT or MRI and bone scan to qualify for metastatic disease and then have the Novartis-specific gallium-68 PSMA-11 tracer. Some of them might have had more than one PSMA PET.
But anyway, in that context where around two-thirds were on hormone therapy before signing, or actually three-fourths before signing consent, 87% had at least one lesion that was brighter than liver visually, and that's really all that was needed to qualify for the trial. Subtle thing: if they had liver metastases, at least one had to be brighter than the background of the liver. But overall, it happened to be around the same number as in VISION that were PSMA-positive with a slightly different criteria.
Oliver Sartor: 87%, 87% for VISION and PSMAddition.
I was really happy to see the intensification because the truth is, we had this feeling, or I had this feeling, that ADT and an ARPI was a great backbone, but I really didn't like the docetaxel addition. And a lot of people were intensifying with docetaxel. I just thought that quality of life is going to be compromised. Can we do better with lutetium? And I think we did. Of course, we don't have any comparative data, but the lutetium, to me, has a much better quality of life profile than the docetaxel, but that's just a personal opinion perhaps.
You began to execute the trial. You got these 1,144 patients up and going. They started ADT and an ARPI, and the ARPI became a choice. They had abiraterone, apalutamide, enzalutamide, darolutamide, whatever one they wanted. And then they got randomized to receive either the lutetium or not. It's ADT-ARPI versus intensification with ADT-ARPI and lutetium. That's really a nice design. I really like that.
What did they find?
Scott Tagawa: The primary endpoint is rPFS by the traditional definition using Prostate Cancer Working Group criteria and CT and bone scan. And there was an improvement, a 28% relative improvement in terms of the hazard ratio with a positive p-value of 0.002 at the first interim analysis for efficacy. There was a futility analysis that went through the DSMB, and they said continue, so it's an early look. The first interim analysis for rPFS was positive. And that happened to be timed with the first interim overall survival analysis. The rPFS is considered mature.
There'll be another look, but that's not going to be hypothesis testing. That's at the time of the second OS analysis, and there'll be a third OS analysis. Essentially mature in terms of rPFS by the study design. OS not yet mature but is trending positive—the hazard ratio is less than one with confidence intervals that overlap one. It's an interesting look.
At that point, of the patients that had progressed on the control arm of ADT-ARPI, about 60% of those had crossed over to lutetium PSMA-617 on the study. A handful got some lutetium PSMA-617 outside of the study in addition to that. That will certainly likely, number one, increase in numbers and percentages, and number two, probably impact the overall survival. I think the timing of that is a little bit different than PSMAfore. It's more than a year in general versus significantly less than a year on PSMAfore. How much of an impact it's going to have, we don't know. We need more follow-up, and we'll see what happens.
Oliver Sartor: What's the median follow-up now?
Scott Tagawa: It's a little less than two years in terms of the overall study.
Oliver Sartor: And in terms of the percentage of patients in the control arm who've gone on to have an rPFS event, what percentage are we talking about?
Scott Tagawa: Of just the total number of patients?
Oliver Sartor: Just total number. Are we talking about 50% of the patients enrolled?
Scott Tagawa: No, it was 25% or something like that—
Oliver Sartor: About 25%?
Scott Tagawa: Yeah.
Oliver Sartor: It's still a pretty early look. And the OS is trending positively. Now, what about toxicity? A lot of people are concerned about, hey, you give an isotope, don't know what's going to happen in long-term follow-up. Have you seen concerning signs where you might think that toxicity could be a problem for those on the study?
Scott Tagawa: Broad answer, I would say this is what I would expect to see in terms of toxicity. And even though this study represents the longest follow-up at this point of intensive adverse event follow-up from any phase III study, it's still short. Two years is still short relative to the expected survival of this patient population.
There was, as expected, some fatigue that was more in the lutetium arm. And then the other toxicities that were more common are probably related to areas of PSMA expression that can be accessed by the small molecules. Salivary glands in terms of dry mouth. Lacrimal glands in terms of dry eyes. GI toxicity in terms of the small bowel. The other area of PSMA expression that we know about is the kidney. It's also excreted there. Luckily, at this early time point, there's not a huge signal. There can be some more renal events, but that's one of the areas that we'll need to watch closely.
There were more cytopenias. None of the individual cytopenias were grade 3 or higher in more than 5%. Anemia was 5%. That's not so surprising that we have more cytopenias. Also not surprising to me that they're not so high in terms of high grade, but we do need to continue to watch.
The data cutoff for this analysis was January 2025. There were zero cases of MDS or leukemia in either arm.
Oliver Sartor: That's good.
Scott Tagawa: But it's only two years. We'll have to see.
Oliver Sartor: If I were to think about the results, I'd say rPFS is positive, 0.72, OS trending positive with 0.84, confidence intervals overlapping one, but of course we have the crossover.
Safety signals—nothing that's going to be raising a big red or yellow flag. Still relatively immature, but this seems like a very good start. It's a big, important patient population, and the median survivals now are out to four years and beyond. Relatively early maturity for the trial. Seems like a good start.
Scott Tagawa: I agree.
Oliver Sartor: All right, Scott, any other final comments or suggestions on the PSMAddition trial?
Scott Tagawa: In the overall context, we now have essentially four options in terms of positive phase III trials, counting docetaxel, even though we don't know for sure how much docetaxel adds. We'll have PARP inhibitors. We'll have first niraparib; talazoparib will presumably look similar in that biomarker-selected, HRD-selected patient population. In the PTEN-selected population, an AKT inhibitor. And then this is also a molecularly selected patient population. It just happens to be the broadest in terms of PSMA expression. Hopefully, we'll have choices because that's what I'd like to have for my patients. There are different options that we'll have for each individual subset. Hopefully, we'll have all those.
It'll be hard, in a way, for an average doctor who doesn't specialize in prostate cancer to navigate. I suspect we'll use the biomarkers as well as the anticipated toxicity profiles of the drugs, and of course the patient's wishes as well.
I think that within each of these, and now I'll shift more to lutetium PSMA-617, I think we'll learn how to use it better. I think we're doing that already for the hormone-resistant population where it's not an automatic six cycles. Some are stopping early because of lack of efficacy. It's not that everyone responds. Certainly there are people that respond very well and are probably getting a little bit more than they need, at least at that time. Pausing, I think, is a practice that many of us will do. We don't have the level I data yet... We'll hopefully see in the relatively near future continuous versus intermittent dosing. That'll be based on PSA. But the nice thing with this theranostic platform is we can see the target. We can't see 100% of the target. There's still micrometastatic disease, but the gross lesions we're going to be able to see with SPECT and a little bit better with PET.
Oliver Sartor: Scott, you're very reasonable. I like to listen to you. Your logic is very clean, and I think we're going to make more progress, and we'll be sorting it out. We'll probably have some patients that may get a little more intensification, some may get a little bit less, and some who are better suited to get a PARP inhibitor, and maybe somebody else is better suited to get an AKT inhibitor. Let's just let the data sort of flow a little bit better. But exciting times. We're starting to make progress again.
Scott Tagawa: Absolutely.