Charles Ryan: Hello from PCF 2019. I'm joined by Dr. Michael Morris and Dr. Oliver Sartor. We're going to talk about the VISION trial, which is with lutetium in advanced prostate cancer. Mike serves on the scientific oversight committee of the trial, and Oliver is one of the co-PIs of this clinical trial. Oliver, I'm going to start with you. Tell us quickly the design of the VISION trial, and what it hopes to achieve.

Oliver Sartor: Well, first of all, we have a large unmet need in what I'm going to call the third line space. You know, people get an abiraterone enzalutamide. Then they go on to a taxane. And then it's like, "What the hell do we do next?". And it's in that space that we've designed the VISION trial where people can get a standard of care, pretty much anything they would like to do, but not a chemotherapy. And then have plus or minus Lutetium-177 PSMA. And with the endpoints being both RPFS, radiographic progression-free survival, and overall survival. If it's a positive trial, it'll change practice. It's a pivotal trial with an FDA submission planned.

Charles Ryan: And for those unfamiliar with lutetium, briefly, this is infused therapy. It's given once a month and it's intravenous and how-

Oliver Sartor: Well, little modification of that. It's about every six weeks.

Charles Ryan: Sorry, every six weeks.

Oliver Sartor: Every six weeks in this trial, thanks to a guy named Michael Hofman who put together this particular regimen. And we're going to find out if four cycles is going to be the standard, and then up to six we believe there's clinical benefit. And we'll compare that plus or minus the standard of care and see where it goes.

Charles Ryan: Okay. So, Mike, let's imagine that this is a positive study. It gets approved. This is the study that would lead to the approval. Two questions for you. How would this be integrated into your daily practice with your patients? Which patients would you be thinking about for this therapy? And then put your research hat on and say where do you want to go next?

Michael Morris: So for the first question, refer back to what Oliver started with, which is we're in a space without really a good standard of care. After either abi or enza or both, and after then a taxane-based therapy, we really don't have very much in the way of life-prolonging therapy. You have radium that can be given there but really not much else in regards to an active life-prolonging treatment. So that very large patient population who really doesn't have a good treatment approach, that's going to be the patient population that's going to benefit from this. All these patients are post-taxane and so we're not talking about the full spectrum of CRPC, so it's actually not that hard to figure out where this trial would insinuate itself in terms of the ongoing regimen. But it's in a space where there are a lot of patients looking for a standard treatment that will let them live longer without too much in the way of side effects.

Where we go forward from there, of course, is a two-pronged question. The first is where in prostate cancer should it most optimally be placed? So that's a timing question that everyone has to sort of wrap their arms around. Should it be placed earlier in CRPC? Should it be in metastatic CSPC? And does it have a role in the non-metastatic patient population? Or even in the high-risk localized patient population? That sort of question of timing is one research question. And then there's the issue of optimizing the therapy by giving it with something else. Probably not, even in patients who have copiously PSMA producing cancer have some non-PSMA producing component, and there are other patients with truly heterogeneous disease for which monotherapy just won't target most of their disease, or some of their disease that will ultimately relapse.

So what can you combine this therapy with? Is that immunotherapy, DNA repair-targeted therapy, other AR-directed therapy? What can you use to both amplify the radiation effects of this treatment and target the non-PSMA producing component of the disease that may not be addressed by this therapy?

Charles Ryan: So before we get to all of that, which would be a great day if we can start doing those combinations, we have to sort of ask the question which is the optimal environment for a patient to receive it? What's the safety profile? Are there any sort of situations where we would not want to be giving this therapy? Oliver, where does this treatment sit in the spectrum of toxicity and safety of anticancer therapies that we use?

Oliver Sartor: You know, actually therapeutic index, which is what I would refer to that as, is exceptionally strong. We have a little bit of salivary gland toxicity, there is in the small molecules are targeting to the salivary gland, which you can see on the PSMA scan, by the way. But in terms of mild toxicity, virtually none. Maybe a little bit of fatigue, but I'm telling you it's really, really, really well-tolerated. And that's one of the advantages. So no serious toxicities that we've seen today.

Charles Ryan: Right.

Oliver Sartor: And of course the efficacy will live or die on the Phase III trial.

Charles Ryan: Right. We have a pretty good sense that it's relatively safe, but that's based on Phase II data. So we're waiting for the larger cohorts to be enrolled. But as you say, I think the early indication is it looks reasonably safe.

Michael Morris: So I'm going to take your question that you just asked of where does this therapy sit very literally. That is, where will it be administered, right? Oliver and I are medical oncologists, but this is the kind of therapy that is going to require a multidisciplinary approach to the disease, where there will need to be cooperation between medical oncologists, radiation oncologists, and nuclear medicine physicians. How it will be given and where it will be given physically will depend from site to site, institution to institution. But I think that it does represent one of those treatments where we're seeing an ever-increasing amount of collaboration between the disciplines in terms of treatment of prostate cancer patients. This is really the ultimate vision, if you will, of multidisciplinary care for the patient where the patient is really being tended to, treated by, and then the after-treatment care administered by a group of experts in prostate cancer that will be supporting the patient.

Charles Ryan: So if a clinician is watching this and they're thinking, "Well this is great, but I don't have a PSMA PET scan at my institution. How am I going to deliver this therapy?", what's your answer to that? Are we all going to need to have PSMA PET scans?

Oliver Sartor: I actually think it's a great question. You know, we actually have done some initial analysis on the VISION trial with regard to how many of the patients actually are excluded because of the PSMA PET. And in the day-to-day, it's about 10%, maybe even a little less. So-

Charles Ryan: Why are they excluded?

Oliver Sartor: They're excluded because there is lack of PSMA uptake-

Charles Ryan: So they have a form of prostate cancer that does not elaborate PSMA. 

Oliver Sartor: They have a form of prostate cancer that is not imaged by the PSMA ligand that we're currently using. Now it could be, if this is a remarkably positive trial, and you're only excluding 8% of patients, it could even be a regulatory decision to dispense with the scan.

Charles Ryan: Right.

Oliver Sartor: Now, if there is a clear dependency on the scan, then it becomes a whole other issue. So I'll simply say that there's a lot of evolution. Now, I'll mention one other thing you may or may not be aware of, and I'm talking about the audience, not Chuck Ryan. But, there's been a submission to the FDA for PSMA scans and that has come from UCLA and UCSF in a combined academic submission. And if that goes through, or there's a Progenics application that is also being worked on, then I think the availability of the PSMA scan will change. So there's a lot that can change between now and then.

Charles Ryan: Okay. But even so would dosing, Mike, depend on the PSMA scanning? Are we going to think differently about how to deliver a lutetium-based therapy based on the PSMA PET scan? Let's assume it's positive. Does the clinician, the oncologist have to integrate that data into his decision for the patient?

Michael Morris: So really in that question you're embedding two different principles. The first is, is PSMA going to be used as a predictive biomarker for whether you get this therapy or not? And I think that, just to amplify what Oliver was saying, that's probably a short-term question because my guess is after these two products that Oliver was just talking about... I'm an optimist and I think that one of them or if not both will be approved, and I think that pretty much standard imaging will not be used very much. The second question though that you're asking is should the dosing be specific to what we call the dosimetry that's established on that initial scan? Where you could anticipate a toxicity to response benefit that would favor treatment of some patients or not others, and specific doses for an individual patient.

Scientifically that's a very appealing way to go because then each dose accommodates the distribution of the drug to disease versus normal organs. But in reality that is actually quite a bit of work to do. So you're torn between what might be the most individualized versus the most practical way to go. And there have been other therapies in the hematologic world which did individual patient dosimetry, and it is quite a bit of work in that respect, as opposed to scan and treat. And so you're torn between practicality and scientific optimization.

Oliver Sartor: Yeah. But one thing I do want to emphasize is in the VISION trial, it's a fixed dose. So even though the dosimetry is a consideration, and appreciate Mike's remark, in the VISION trial it's a fixed dose times four cycles with two more depending on the clinician's judgment of benefit.

Charles Ryan: Right. But what's interesting, and we're all medical oncologists, is to think that if this is in our clinics and we're using it, we probably aren't going to be the ones thinking about the dose like we think about the dose of docetaxel, right? This'll be something we do in conjunction with our nuclear medicine colleagues who this is what they do essentially, right? Is figure out these issues in terms of dose and therapy delivery.

Oliver Sartor: You know, I've had a similar issue with radium to some extent. And there there's been a discussion about optimal dosing. And it just turns out that the fixed dose is what happens about 98% of the time.

Charles Ryan: Correct. Right, right, right. So, very good. Well, we're all anticipating the results of this trial and it's great that it got launched and accrued so quickly. And I think that reflects the enthusiasm around this new modality of treatment, and really a new way to deliver radiation and radioisotopes that's very targeted and sounds very acceptable in terms of its safety profile. So thank you very much for your expertise and joining me today to talk about the VISION trial.

Michael Morris: Thanks for having us, Chuck.

Oliver Sartor: Thanks, Chuck.