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Alicia Morgans: Hi, I'm so excited to be here with Professor Oliver Sartor, who is the CE and Bernadine Laborde Professor for Cancer Research and the medical director of the Tulane Cancer Center. We're talking today about the RALU study, which was presented at ESMO, as well as several other meetings. And Professor Sartor is going to lend his insights on this update. Thank you so much, Oliver.

Oliver Sartor: Thank you, Alicia. It's always a pleasure to be here with you. And I'll be talking a little bit about the RALU study, and let me explain. So when we look at Lutetium, we have nicely data that everybody's seen for the VISION study, but there is very little data about sequencing. Now, if we look at the overall landscape and the really important prostate cancer trials. One of the things that you noticed is in the beginning, of course, there was no sequencing because we didn't have any things that were active. So some of the clinical trials like TAX 327, COU-AA-302, PREVAIL, it was really ADT then the development of castration resistant disease and then treatment. Well, as docetaxel was introduced in 2004, there began to be a whole series of studies that were conducted in the post docetaxel space. TROPIC, COU-AA-301, AFFIRM, really important studies, life prolonging studies.

And then ALSYMPCA came along. And ALSYMPCA was a little bit interesting because ALSYMPCA which is the radium phase three study really sort of bifurcated this space. And they gave it in the pre-chemo, post-chemo space, if you will. It was positive in both. And that was a pre-specified analysis. So it turned out that radium-223, when it became approved, was approved both in the pre-taxane or taxane naive, if you will, and post-taxane metastatic therapy C space. And then more recently we've had important trials like PROfound, CARD, and VISION. And each of these were in the post novel hormones. Some people calling it RP antigen receptor pathway inhibitors are novel hormones if you prefer that abiraterone, enzalutamide, apalutamide, or apalutamide and darolutamide. But nevertheless, important studies like CARD and VISION were done really in the third line space.

But when it comes to isotopes, there's been very little data about the sequencing of isotopes, and that's where RALU comes in. So here's the RALU study design. Hopefully, you see the screen. And these are individuals all with metastatic CRPC and all of whom got radium-223. And then these patients subsequently went on, and this was predominantly done in Germany and internationally. Subsequently, went on to get lutetium-177 PSMA. And this study is designed to be able to look at some primary endpoints around safety and efficacy for those who got radium first and then the lutetium-177 PSMA second. And here's the treatment population. And by the way, this was not all lutetium PSMA-617. Some of the patients were lutetium-177 PSMA-I&T, but nevertheless, we're going to group those together here. And these were patients who had been really quite heavily pretreated. If you look down on this screen, you see that four or more life prolonging therapies were actually received in the majority, and the taxanes were very prevalently used as well. So in these analyses, we kind of look a little bit at both kind of pre and post-taxane and other ways of doing it. But everyone had radium first and lutetium second.

Okay, so now that we understand what the population is, let's begin to look at some efficacy data. And on the left-hand side of the screen, you see PSA: change from baseline. This is after lutetium. And on the right-hand side, you see some Alcon phosphatase changes. Now, the Alcon phosphatase change we showed in the poster, we don't have a lot of comparison. So it's really the PSA that we're going to be looking at. And if we looked at all the patients, the decline of PSA of 50% or more is 42%. Now, there in the bottom left of the screen. If we look at the sequence of radium, then taxane, then lutetium, it was 46%. And if you went from taxane to radium to lutetium was 36%. Well, as a reminder, the PSA decline of 50% or more in the VISION trial was 46%. So the first thing you're seeing is these PSA decline numbers are all pretty much in the same ballpark.

Now, PSA declines are not the most important parameter. What's the most important is survival. And here you see in the upper left-hand screen, the survival for those individuals, all of whom at radium, that went on to get lutetium and it turned out to median survival was about 13.2 months, comparing really quite favorably to the sort 15 month range that you see in the VISION trial. And then in the bottom part, you look and see what about those individuals who had radium then are taxane then are lutetium are taxane, radium, and lutetium. And it was 12 to 14 months for each of these 12 months for the radium, taxane, lutetium, and 14 for the taxane, radium, lutetium. So the bottom one is this also is relatively compatible with the VISION trial.

And then safety. We don't have a huge amount of safety data, but nevertheless, this is the grade three and four laboratory abnormalities. And what you're seeing is yes, you're going to get some thrombocytopenia, 13%, some anemia about 30% neutropenia and abnormalities in some liver functions on occasion. But again, these sort of numbers are relatively compatible with what was seen in the VISION trial.

So overall, I think the conclusions, and I think they're pretty legitimate, if you looked at the radium treated patients, subsequent lutetium-177 PSMA was clinically feasible and relatively well tolerated with acceptable mild suppression rates. And if you look at survival, I think that it turns out that the sequence of radium followed by lutetium gives fairly reasonable survival rates in comparison to those patients treated lutetium alone, such as in the VISION trial. So Alicia, that's what I wanted to cover is this sequence. And this is relatively unique data, and hopefully it will give some insight for those who are interested in sequencing radio pharmaceuticals.

Alicia Morgans: Well, thank you so much, Dr. Sartor. I think this is really, really helpful. One piece I wanted to dig into a little bit that's a little bit different than VISION, and please correct me if I'm wrong because you were of course one of the people who designed VISION, but I vaguely remember that when I was putting patients on trial, there had to be a window of about six months between radium exposure and enrollment and VISION in treatment with lutetium PSMA-617 which as you said, is only one of the lutetium compounds used in this particular RALU study. So in this particular analysis, it looked like that window was down to about 60 days. Is that true? And what can that help us understand from a clinical perspective in terms of safety that might be different than that six month requirement? Because six months is a long time when you have metastatic CRPC and usually requires an interim treatment for patients if we can't really put radium next to lutetium for a six month period. So can you expand a little bit on that or comment on that?

Oliver Sartor: I can, and thank you for raising the point. And one of the things, Alicia, that's important is that there's a real distinction between eligibility criteria and what actually happened. So in the RALU study, there needed to be about 60 days separating the two, and the VISION was of course much longer. The truth is, in the RALU study, most patients had received their radium many months beforehand, often several years. The patients who received radium in this study are the ones that lived a long time and typically receive radium relatively early. I'm a little bit hesitant to talk about something like back-to-back sequencing. So I am not advocating that somebody gets radium and immediately followed by lutetium. We really don't have data for that.

And by the way, you may or may not know, but they're actually combination trials that have been conceived that are now ongoing between radium and lutetium. And in addition to those with radium, there are other alpha emitters that are being combined such as actinium. So this field is rapidly moving right now. I think we all know the radio pharmaceuticals have a positive effect for patients, but I think we would all acknowledge there's so much more to learn and this area is going to be extremely active over the next couple of years. We're going to be able to answer your questions with data instead of wave our hands and say, "Well, in this case, in that case." So I look forward to the day when we have real data that we can use for combinations and closer sequencing.

Alicia Morgans: Well, thank you for that because I do think that distinction between, as you said, eligibility and what really happened is so important for the clinicians who are trying to enact this. And there is a lot to learn. And these eligibility criteria were sort of developed around our best understanding of safety. But this piece of this safety, I think we're still drilling down on some of the details there. But to the best of our knowledge, this seemed to be reasonable assuming count recovery after treatment with radium, I'm sure, or whatever treatment was prior, maybe that was a taxane in this particular study.

Oliver Sartor: Right. But that's important regardless of what you're doing, you always have to assess the patients for eligibility. And I'm pretty tolerant, by the way, on the anemia front because you can always transfuse. But for something like platelets, you have to be a little bit wary because some patients will have significant thrombocytopenia with lutetium. And managing the patients not only before the decision to give is made, but after in the middle of the sequencing perhaps, and giving three, four, or five cycles of lutetium, you have to evaluate those patients and properly monitor them.

Alicia Morgans: Great. Yeah, and I appreciate that because safety first is always what we try to ensure even though patients may sometimes push us as clinicians, because I think these are really exciting therapies and patients sometimes find themselves feeling desperate, for lack of a better word, in terms of looking at their options. And so really ensuring that we are the best stewards of these treatments is so critical. So one thing that I just want to see if you can emphasize is that it looked like regardless of sequence, radium then taxane or taxane, then radium, there was not necessarily a difference whether it came to efficacy and PSA response or safety when it came to the end response to lutetium. That's what I saw on your graphs and those figures. Can you just clarify that?

Oliver Sartor: Yes, so you did see it correctly. And remember this, it's an analysis. It is not a prospective trial. So what we're looking at is necessarily potentially some cherry picking of patients. Lots of patients, as you pointed out, may have significant thrombocytopenias or performance status declines before the PSMA lutetium is even available. And clinical judgment is always the critical element. Safety first is a really good way to think about this. We never want to harm our patients. At the same time, one of the biggest threats our patients face is advancing disease. And sometimes as clinicians, we take risk to address disease that doesn't have any other alternatives. Both of these are often used when patients have few alternatives, but they're new trials. I don't mean to divert attention, but things like the PSMAfore trial, which recently completed accrual and was announced as a top one positive trial, we haven't seen the data yet. That's in the pre-chemotherapy space with PSMA lutetium. And I think the dynamics are going to change a bit when we move these therapies up a little bit closer to the front as opposed to the back, if you will, where often they're being used now.

Alicia Morgans: Well, thank you for that. And that leads to my next question because at least in my practice, and I think in yours too, we try to get in as many lines of therapy as possible. We really try to give patients access to every alternate mechanism of action and every type of therapy that we can possibly give them because it is the sequence of therapies over time that helps them to live longer and hopefully preserves their quality of life. Now, the study that you've presented, the RALU study, is really an analysis looking at the use of radium before lutetium, but as lutetium re-situate itself within our treatment landscape, you can imagine that people may think about using radium after lutetium. Do we have any data for that?

Oliver Sartor: Really very minimal data at this time. And the reason for that, Alicia, simply has been the VISION population is what is sort of predominant in the particularly US practices. We don't have the ability to bring it up sooner, and by the time you finish up with lutetium, you just may not have many options left. The patient probably would've been a candidate for radium beforehand, but afterwards we just don't have the data. So I'm not able to speak to that sequence of radium after lutetium. I just haven't seen data.

Alicia Morgans: Well, it sounds like a study that needs to be done or a database that needs to be compiled because certainly, I know we want to use every option and as these treatments just sort of recenter themselves and where they're going to be used in our lines, we will need to get that data. But thank you for that. Is there anything else that you'd like to share? Any key points that the listeners need to be aware of as they're thinking about, again, trying to get every line of therapy to their patients?

Oliver Sartor: Alicia, one of the things, and this is something we all know, I really do promote the clinical trials. They're going to answer the critical questions, and I think that when there are opportunities, we need to really think about clinical trial enrollment to give us the type of prospective data that can truly be practice changing. The interactions between the alphas and the betas between targeted therapy and bone targeted therapy, these are hugely important topics. I really believe that this sort of concept of alpha beta combo or alpha beta sequencing combinations as going to be an important element as we go forward. Let's get the trials, let's get them done prospectively so we can speak definitively about what they offer and what the risks are. I think that's the message I'd really like to leave the audience with.

Alicia Morgans: Well, thank you so much. I could not agree more, as is usually the case. I sincerely appreciate you really digging in to us understanding the sequencing of these radium followed by lutetium compounds. It's so important for our clinical practice, so important for our patients. Thank you again for your time and for your expertise.

Oliver Sartor: Thank you, Alicia. My pleasure.