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Alicia Morgans: Hi, I'm so excited to be here with Dr. Oliver Sartor of the Mayo Clinic. Thank you so much for joining me today.

Oliver Sartor: Thanks, Alicia.

Alicia Morgans: Wonderful. So Oliver, you had a recent presentation that was really exciting, talking about the PSMAfore trial. We were all really excited to hear the data, which we'll get into a little bit through this conversation. But I wanted to see today if you could really tell me about the trial design. How did you come up with this design with the team that really launched PSMAfore, and why is it so important to design it this way as we try to interpret the findings from this really important study?

Oliver Sartor: Sure. Step one is regulatory approval, and we got that with VISION. And just as a brief reminder, the VISION trial was post NARPI and post docetaxel, metastatic CRPC in patients with PSMA PET-positive disease. Okay. A lot of patients, Alicia, do not get docetaxel. In fact, if you look at the statistics, almost half of the patients will die with metastatic prostate cancer and never receive chemotherapy. So waiting until after chemotherapy to be able to give the PSMA lutetium is not the best strategy to reach the most men. And so given that we had a positive trial with VISION, the idea is to keep it moving, bring it up. And this trial, the PSMAfore trial, was designed for the taxane-naive patient with metastatic CRPC with PSMA PET-positive lesions. So the idea is really simple; we just want to move it up a little bit. Metastatic CRPC, yes, PSMA PET-positive, yes, but taxane-naive this time to try to enlarge the population of men who might be eligible to receive the drug. That's the basic thinking.

Alicia Morgans: And that's so important, because to your point, there are half of patients not receiving docetaxel and that could be a variety of reasons, including their fitness and ability to tolerate docetaxel, which is going to be different when we think about lutetium PSMA-617, which in quality of life data reported from things like TheraP, really actually quite well tolerated as compared to chemotherapeutic agents, would you say?

Oliver Sartor: Absolutely. And I was going to cite the TheraP study from Australia which did a comparison between cabazitaxel and the PSMA lutetium. And by the way, I actually think the cabazitaxel is probably a little easier to tolerate than docetaxel. It's just a little bit easier, a little more hematopoietic suppression, of course, but a little bit easier on the body. And there, cabazitaxel to the PSMA lutetium looked really, really good. And of course we had good experiences in the VISION trial with tolerability. Yes, a little bit of dry mouth, but rarely did we have to discontinue or dose-reduce for anything. And so that was part of the reasoning as well, to bring it up a little bit sooner, give people hopefully choices in the future. And it's not that we're trying to avoid chemotherapy, we're just trying to provide another option.

And by the way, just as a quick prelude, if you will, at ESMO there was a nice discussion by Chris Sweeney, who's one of our dear friends for many, many years, and he talked about the need for multiple therapies in CRPC, and I embrace that. I think we do need multiple therapies. So, long answer to your simple question, but health-related quality of life looks good. And we knew that it performed pretty well when we brought it up, and in fact it did. But that's another story.

Alicia Morgans: Absolutely. Well, one thing that I think is unique about lutetium PSMA-617 when it comes to radiopharmaceuticals is that there is the opportunity for dose reduction. Can you walk me through that a little bit? Because even medical oncologists don't always think about dose reduction when it comes to this class of agents.

Oliver Sartor: We had pre-specified in our protocol a variety of reasons why dose reductions might be appropriate, and it could be things for xerostomia, it could be things for fatigue or maybe mild suppression. But the truth is it was really interesting, the PSMAfore trial; there were more dose reductions in the hormonal arm than there were in the PSMA lutetium arm, which I think was just stunning. It was like 15% of the patients had dose reductions on a hormone, and it was about three or 4% in the lutetium arm. So yeah, you can dose reduce and there are reasons to do so, but guess what? It's not that common.

Alicia Morgans: Very interesting though, because in many situations I think we think about delaying a dose with a radiopharmaceutical. But in this case, this is an option for us.

Oliver Sartor: Yeah. One of the things that was unanswered, if you don't mind me going there, is we've been giving the lutetium on a regular basis, but if we talk to others who I respect, there's a lot of discussion about when do we stop? And can we stop early for those kind of super responders? And maybe do we need to intensify? And unfortunately, although PSMAfore is a really good trial, we didn't try to answer those types of questions. So I think there are additional studies that need to be formed about maybe intensification, maybe the addition of additional products, maybe it's an olaparib or whatever, for those who might be having a suboptimal response, or maybe the de-intensification for those who are responding really well. PSMAfore didn't address those, but they're good questions and no single protocol can answer all the questions that need to be answered.
So anyway, c'est la vie.

Alicia Morgans: Well, always more work to be done and more studies to launch, because to your point, really in order to trust the data and the findings from a study, we have to hone the question and then we have to design it to answer the question. And so this is more for you to do and more for us to discuss in the future, which is always going to be important.

So as you think about the findings, which I think were really impressive, and we think about particularly the rate of crossover, tell me a little bit about that, because this was the highest rate of crossover that I think we've seen in a registration trial, but it was on purpose. It was absolutely planned this way. You and the other investigators really put the trial together to ensure that patients would have access to this treatment. So please tell me about that.

Oliver Sartor: Yeah, thank you, Alicia. Really good point. So again, I'm going to view it a little bit in an historic context. That's so, so important, because a lot of people forget that we're shaped by our experiences in the recent past. The VISION trial did not have a crossover, and so many patients were disappointed that they were not able to receive lutetium. And yes, we hit the overall survival endpoint. We had a hazard ratio of 0.62 in the VISION trial. But as we brought it a little bit earlier, we knew that this would be an effective therapy. We knew that patients who were randomized in the control arm would probably feel like they were missing out on the opportunity to get lutetium, and we thought that crossover was the right thing to do, just from the perspective of treating patients, because we already had a demonstrated effective drug. We already have an FDA approval. We didn't want to hold it back.

So the crossover was baked in from the very beginning. Now we knew that when we did that, that we were going to be compromising endpoints that would occur after the rPFS. And just backing up just for a second, it was radiographic progression-free survival, prostate cancer working group three along with resist criteria. Kind of traditional stuff. And in the control arm, in order to crossover, you had to meet the rPFS with a blinded central review. Okay? So one investigator was blinded to central review on the rPFS. And then, it was an interesting thing, some of the investigators actually didn't want to stop the hormone. They didn't think that there was a consequential rPFS event, and maybe they did a little SBRT or whatever in order to keep the patient on their current therapy. But if you discontinue the ARPI and met the rPFS by Becker, then you could crossover. Of those who did meet those two criteria, 84% crossed over. I'd never seen a crossover rate that high.

Now, there was a second thing that was very interesting, and I won't say this was an ulterior motive, but we wanted to make sure that the people in the control arm stayed on until they actually hit the endpoint. Because in VISION, we have a lot of problems with dropout. In this case, the dropout was amazingly low. Hardly anybody dropped out, but I think that's because they wanted to get the PSMA lutetium after the rPFS. And the penalty we paid is that we've probably diluted the overall survival endpoint.

Now, in a crossover adjusted overall survival analysis, which was pre-specified and written as a secondary endpoint in the protocol, that has a ratio of 0.8, with big confidence intervals. And by the way, the number of survival events, death events, if you will, is 29% of the total patients enrolled. So still pretty earlier. When we looked at the intent to treat, it turned out that the hazard ratio was 1.16, going the wrong way. But if you look at the actual number of deaths, that's 69 versus 65. It's a really small number, and the confidence intervals were still big.

So we crossed over the patients with an extraordinarily high percentage. I think that is a good thing. And what we effectively did is to give the PSMA lutetium early or a little bit later, with maybe a second hormone sandwiched in between. But even though the crossover adjusted OS is trending in the right way, the early analysis, and I want to emphasize early, on the intent to treat trended the wrong way. But it was only four events, and I think probably it's going to just straighten itself out with a little bit of time. But the confidence intervals are still going to be big because so many people crossed over.

That's a long answer to your short question, but I have to explain not only the historic context, the crossover, how crossover occurred, and then the consequences of the crossover. So anyway, there it is.

Alicia Morgans: No, that was a perfect answer, because I think this is complicated, and to give a short answer to a complicated question would also be the wrong thing to do. So thank you for walking us through that. When I think about this data, which certainly is practice-changing, and we'll have to wait for the regulatory decision-making to understand when we can actually start to implement these findings in our clinical practices, if we are able to do that, I think about the number of patients that are going to be coming through our clinics and the opportunities for more patients, but also some of the struggles sometimes that we have as we're trying to ramp up and get things to patients. I do think that there are more centers that are hopefully going to be coming online to provide this care, but as you anticipate these patients coming in and wanting treatment, what are your thoughts in terms of how we as a community can come together to really support this influx of the patient population?

Oliver Sartor: Yeah, really good question. And I'm actually going to start where you did not go, and that's with the supply chain, because a lot of people are aware, the supply chain was very, very problematic in the beginning, in the post VISION FDA regulatory approval stage. Now, it turns out that Novartis has spent an enormous effort in order to strengthen that supply chain and start at the beginning. Now, that's not the question you asked, but it is a very important issue as we go forward.

I think personally, as the demand rises, that people will see the patients either leaving their clinics to go get the PSMA lutetium elsewhere, or coming to their clinics when they offer it. And I think there's going to be ... I'm just going to say a capitalistic response, for the people who have patients leaving their clinics to go elsewhere for treatment, they're going to say, "Let's get that open here," and they're going to create the opportunity, because good therapies will find a home. And I believe that this relatively non-toxic therapy, even though it does have some regulatory barriers like nuclear medicine and radiation oncology and radiation safety, even though there are a few barriers to really be able to get it up and going, I think those barriers will melt away when the patient demand is fully evident. That's the bottom line.

Alicia Morgans: Well, that's certainly hopeful, and I think that's what I see in our area, that there are plans, at least for clinics that are outside of larger cities, to try to get this going because they want to take care of the people who need this treatment. And it is quite a burden to have to drive three, four or five hours to a clinic to get this, especially when you're through with it and you're radioactive, and now you need to get home, which only of course lasts for a few days, but is something to consider.

Oliver Sartor: Absolutely. But once you're actually set up to do it, it's really easy.

Alicia Morgans: Yes.

Oliver Sartor: A lot of people don't realize how smooth it is once you get set up. And yes, you've got to have your licenses, you've got to have the people who are qualified to do the injections, but once you're set up, it's very smooth and easy.

Alicia Morgans: Well, and that's encouraging too, and I think something that people need to hear. So as you think about this, as you think about going from trial design, which was years ago, all the way through these positive results and the way that we're going to move forward in the future, what would your message be?

Oliver Sartor: I think one of the really nice things, Alicia, is that we have a new class of active compounds. I believe that men are going to be benefiting from this, not only in this particular space, in the taxane-naive metastatic CRPC. I think there are reasonable trials that are going to be moving it forward even more. And if we can do this, the truth is patients are the beneficiaries, and that's what I work for. I work to make patients better, and this is a tool. And it turns out that if we do it properly and do our trial designs right, I just feel like patients are going to be the beneficiaries. And that gives me a very satisfied feeling.

Alicia Morgans: Well, it certainly makes the rest of us happy too. So thank you so much for the work that you've done, and of course, thank you to all the patients who participated in this trial and all the others that are still in process. We appreciate your time today.

Oliver Sartor: Well, thank you, Alicia. Glad to be here.