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Charles Ryan: Hello from San Francisco and ASCO GU 2022. I'm delighted to be joined by Professor and Chair Neil Fleshner of the Department of Urology at the University of Toronto. In addition to that role, he is the Founder and the Chief Medical Officer of POINT Biopharma, which is a PSMA-targeted radioligand therapy, and we are going to talk about the Phase III trial, the SPLASH trial, which is underway and accruing in many sites around the world. Neil, good to see you, and thanks for joining us.

Neil Fleshner: Likewise, thanks for having me.

Charles Ryan: There is a lot of excitement about this SPLASH trial. I was going to say it's making a big SPLASH, but I'm sure you've heard that already. But tell us about what agent you are studying, the mechanism of action, and what the opportunities might be able to offer for men with CRPC.

Neil Fleshner: Wonderful. SPLASH really is testing the efficacy of a PSMA-based radioligand, it's called PNT2002. It's been used extensively, actually, in Europe for many years under the rubric called I&T or PSMA I&T. There is a fairly large literature of experience using this ligand and we are really excited about it. So what we are doing is really, as a practicing uro-oncologist, I ask myself, "What are they, what are the needs of men as they are failing ARAT treatments?" Men who are failing all these next-generation androgen receptor axis inhibitors, feel well, they're ECOG 0/1, and really usually what is next for them is chemotherapy. And of course, many men, as we know, even centers of excellence, probably up to 50%, never even get chemotherapy. So I guess the question is, what would be the right agent for those men?

And we thought putting the radioligands in that space makes the most sense. We know now from randomized data from TheraP, that they actually have a better quality of life outcomes compared to chemotherapy. So the idea is to take men after they are failing the ARAT drugs, and then we are doing a 2:1 randomization of our compound, our PNT2002, and that's going to be compared to the ARAT switch, almost akin to the PROfound trial on the basis by which olaparib was approved. And the idea there is to follow men forward to radiographic progression.

We have also built in a crossover design. From a trial fidelity point of view and from an ethical point of view, we want men to stay on the trial. So we will hold the carrot of them receiving the therapy once they radiographically progress. And so we recognize that rPFS will be our primary endpoint, and we are really excited. This study is already open. We did have a 27 patient lead-in to the study, where the FDA asked us to do that around dosimetry and we will be presenting those data at the Society for Nuclear Medicine and Medical Imaging, actually next month in February 2022. So we're excited about that and now we've run into the randomization phase. It's open in Canada, US, and Europe, as well as the UK. And really excited. Accrual is going extremely well. We hope to have top-line results probably in the middle of next year, Q2/Q3 2023. So we are really excited.

Charles Ryan: Excellent. It's a really sound clinical trial design with rPFS being your primary endpoint, but then being able to offer crossover to patients, and that, I think, is always an aid for accrual. Tell us, are you risk stratifying based on PSMA expression in these tumors? And is that being done through PSMA PET? Are FDG-PETs also being incorporated into it?

Neil Fleshner: Right. Great question. Absolutely, our inclusion criteria do include PET scan criteria. We have SUV thresholds in order to become eligible. We have learned from our 27 patient run-ins that approximately 90% of patients who are in that state will fulfill trial entry criteria. So it's quite generous from that point of view. We are not doing FDG-PET. We did discuss it with our trial group, our steering committee, as well as others in the field, and we ended up not doing that, although we are very cognizant of the data demonstrating that if you are FDG-avid, you tend to not do so well with these therapies.

Charles Ryan: Right, right.

Neil Fleshner: But a lot of it has to just do with important decisions above my pay grade, ultimately.

Charles Ryan: Well, the reality is you have a biomarker in PSMA that's prevalent in 90% of the tumors in which it is searched for. And so we don't really have, in the world of prostate cancer, there aren't other selective inclusion biomarkers in which we see it at such high prevalence.

Neil Fleshner: I agree.

Charles Ryan: So it's almost like the FDG-PET is not necessary. It does drive up the cost, certainly, and certainly, it does in the US with regards to getting that pre-study.

Neil Fleshner: Right. We also love both gallium and F-18-based imaging as well. So now with PYLARIFY having been approved, that can be rolled right in, which obviously is a big plus for us as well because we had the foresight to have both of those PET-based agents as part of our inclusion criteria.

Charles Ryan: Great.

Neil Fleshner: It's really interesting. Maybe another interesting question is whether you need to do the scan at all.

Charles Ryan: Right.

Neil Fleshner: But that's going to be later. Certainly, I think payers and I think the FDA love this idea of coupling a marker, a biomarker, whether it's imaging or blood-based or whatever, with a therapeutic.

Charles Ryan: Right. One could envision a future where we have multiple other therapies available and we might wish to select out the 10-15% of patients who are not going to benefit from a radioligand targeting PSMA, and we would offer them alternative therapies.

Neil Fleshner: Exactly.

Charles Ryan: So I think the scans are here to stay. And of course, there are a lot of radiation oncologists who are doing focal radiation for oligometastatic disease, and sometimes that's an important consideration in this group of patients. So that gives me a couple of other just quick points about the study eligibility. Many patients who are on abiraterone or enzalutamide and are experiencing disease progression, are experiencing only a rising PSA, they are asymptomatic, they feel great, they can stay on the therapy. When those studies were done, we maintained patients on those therapies until they reached radiographic progression. So the question is before people enter the SPLASH study, can they come in with metastatic disease and PSA-only progression? Or are they required to be demonstrating radiographic progression on the previous agent?

Neil Fleshner: Yeah. They do not need to have radiographic progression. So they just have to have what's called, clinical progression, which could be either radiographic or clinical based on PSA or, in theory, symptoms. We deliberately did it that way. And I think the rationale was that the ARAT switch itself is generally considered a fairly minimally effective treatment. And I think from an ethical point of view, our investigators, and I think ourselves, felt the earlier we get to those patients, then we have more buffer to allow that those not randomized to the radioligand could now have the opportunity to progress without really declining in their functional status.

Charles Ryan: And you hinted at symptoms, and I'm assuming that the majority of patients enrolled are not going to be overtly symptomatic.

Neil Fleshner: Correct. You cannot be on opiates at baseline to come in. And again, it's just for this reason, as I enunciated earlier. We are trying to take the well patient failing those drugs, and ask ourselves, what is next instead of chemo, instead of maybe waiting, as you just mentioned, probably. The threshold to jump from a treatment A to B to C is not only on efficacy, but it's also on the toxicity of the next agent.

Charles Ryan: Correct.

Neil Fleshner: So given how well tolerated these agents are, it seemed like a nice niche to put it to men who are fairly asymptomatic, but are starting to get into trouble.

Charles Ryan: Right, right. That's well stated, and I think it's just a really important niche within the disease that we should be drilling down on for patients who are listening and thinking about, "How could these therapies be available for me? Or, "Am I eligible for this trial?" It's important to know that there is a pretty significant gray zone between PSA rising on enzalutamide and overtly symptomatic disease where you absolutely need chemotherapy or something like that. And that is a space where there is a lot of opportunity for a therapy that could obviously, hopefully, delay the pain, delay the progression of the disease, and ultimately we hope to improve survival and outcomes.

Neil Fleshner: Wonderful.

Charles Ryan: Is there a set minimum number of metastases that a patient is required to have?

Neil Fleshner: They don't. The only patients essentially not eligible would be super scan-type patients because it's hard, obviously, to measure rPFS in those patients. But they don't have to, they just have to have... and those patients can enter from three different scenarios. They can either be HSPC having failed combination ARAT plus LHRH, they could come from M0 CRPC having now progressed to M-positive CRPC that way, or they can come from the traditional CRPC, meaning started at LHRH, failed that, then went to ARAT, failed that, and then they are there now.

Charles Ryan: I think that the traditional CRPC group is shrinking.

Neil Fleshner: It is shrinking big time.

Charles Ryan: The question is, does that really matter in this context of a new therapy? I'm sure it may not.

Neil Fleshner: From a biological point of view, you wouldn't think it would be too much.

Charles Ryan: So a couple of other final questions on this. The inevitable question that you're going to face is, how is this different from the other PSMA-targeted radioligand therapies that may become available? What do we hope to see in the future in terms of a menu or a selection of these different therapies? Can they be used interchangeably? Can they be used in sequence? Where are you at with that question? Now, I realize it's early.

Neil Fleshner: Yeah, it is early, but we're really excited about the field. The field, obviously, is in its infancy. And I think whether you look at the PSMA-617 molecule that AAA Novartis has, or our molecule, I think those agents are going to have a limited capacity, where it's going to be focused on end-stage disease. And the reason for that is both agents can have renal toxicity issues. But renal toxicity associated with radiotherapy tends to happen 5, 7, 10 years later because it's the sort of inflammatory [inaudible] that the irradiation induces. Of course, you're not going to see that in the patients we are studying now. So we like it in this space because, as we talked about, the lack of symptoms and the safety profile, basically, of those agents.

But I think when we think about where the whole field is going in prostate cancer, we're only at its start. And actually, our company also is testing the next-generation PSMA ligand now, which we think could perhaps go earlier in the disease and we are really excited about it. It has much less off-target activity, and we think that bringing that to some of those patients you just mentioned, the oligometastatic patients or the rising PSA post-surgery, all this is really exciting. My vision as a surgeon is to try and emulate the thyroid cancer model, where a man or woman has their thyroid, and then everything's mopped up with a radiotherapeutic strategy. I think as the isotopes improve and as the ligands improve, that is what our future is going to look like. And I think it's extremely exciting.

We're also looking at actinium-based PSMA both earlier, but also later. And I think where I think our vision would be to have lutetium sitting, perhaps, where we like it in that post-ARAT space, and then perhaps thinking about actinium-based PSA later. Right now, again, with the current ligands, there is significant salivary toxicity with that treatment and of course, there is a global supply chain issue around actinium, which we, at POINT, and other companies are trying to solve as well.

Charles Ryan: Well, it's great to catch up. It's great to hear about this trial, which is really exciting. I do applaud you for getting into that important space in the disease after, as you call them, ARAT failure, and it's really exciting to be part of and observe, and helping to bring along all these different types of therapies. I love your idea of the thyroid cancer model because that is something we should be thinking about and imagine what the world would be like if that's how we treat prostate cancer in the future.

Neil Fleshner: Amazing.

Charles Ryan: It's going to be interesting to watch these data come out. Do you want to give us a hint as to the timelines of when we're going to be seeing some results?

Neil Fleshner: Yeah. Again, I think top-line, hopefully, Q2/Q3 next year of 2023. So we're excited about that. Obviously, we need accrual, barring another COVID catastrophe or some geopolitical problem that could have an effect on supply chains. Most people don't realize that the raw material for lutetium actually comes from Russia.

Charles Ryan: Oh, I didn't know that. Okay. All right. Well, we can't do anything about that today.

Neil Fleshner: No, for sure.

Charles Ryan: But, great to catch up.

Neil Fleshner: Good. Likewise.

Charles Ryan: Thank you so much for joining us.

Neil Fleshner: Thank you for having me. Great. Thanks.