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Alicia Morgans: Hi, my name is Alicia Morgans. I'm a GU Medical Oncologist and Associate Professor of Medicine at Northwestern University in Chicago. I'm so excited to have here with me today a good friend and colleague, Dr. Oliver Sartor, who is the Medical Director of the Tulane Cancer Center, as well as being a Professor of Medicine there. He is also the senior author on the VISION abstract presented recently at ASCO 2021, and also the Co-PI on the VISION trial, really involved from the beginning in terms of getting the design right and getting it going, and also, of course, seeing it through. Thank you so much for being here with me today, Dr. Sartor.

Oliver Sartor: Great. Thank you, Alicia. I really enjoy being able to do these with you. So, I'm going to enjoy it again today.

Alicia Morgans: Wonderful. So, can you just give us a little bit of background on the updated data? The really important new data that came out at ASCO 2021 on the VISION trial?

Oliver Sartor: Well, we had a press release a little bit earlier, but at ASCO, we really have the data being pressed out now. I think some of the bottom lines are that you've got an overall survival benefit hazard ratio of 0.62 with very, very strong p-values, a co-primary endpoint of RPFS, a hazard ratio there was 0.4 again, a p-value with lots of zeros and a one, and everything else is positive. The PSA response rate is confirmed, the PSA response rate was at 46%, objective radiographic response rate (PRCR) was about 50%. So these are really strikingly positive results and ones I think that will be practice-changing. I think regulators throughout the world will be able to adopt PSMA-617 lutetium-177 in a way that gives confidence that this will be a patient benefit going forward.

Alicia Morgans: Absolutely. Now remember everyone, this is a metastatic castration-resistant prostate cancer population. They had been pretty heavily pretreated, had received chemotherapy and AR-directed therapy in the past. They then were randomized to best next therapy, the best standard of care therapy or lutetium, PSMA-617 lutetium-177 with this best supportive care versus that best supportive therapy. Patients could not receive in the control arm chemotherapy or radium or immunotherapy. So that was a no-no. Those were no-nos. But otherwise, these best supportive therapies could have been AR- directed therapies, they could have been steroids, pain medicines, whatever it was that was deemed appropriate by the investigator. And as we heard from Dr. Sartor, this is an incredibly positive trial, really suggesting that lutetium prolonged survival in this heavily pretreated population.

Now, Dr. Sartor, as you, as we discussed, you have been involved with this agent for some time, certainly involved with VISION. One thing that is different in this trial from the TheraP trial, which folks may remember is a phase two trial that is from the group in Melbourne, Australia, looking at lutetium-177 as well. In this trial, patients had to have a PSMA positive scan, but they did not need extra scans other than that, in terms of having an FDG scan. And again, this is different from TheraP. Can you tell us a little bit about how this decision was made and how it influences, from your perspective the generalizability of the results from the VISION trial?

Oliver Sartor: Yeah, great question. You know, we had a lot of debate about patient selection and of course, we thought about the prior therapies pretty hard. And as you mentioned, they had to have received either abiraterone or enzalutamide and a taxane in order to be eligible for the trial. Many of the patients had actually received two taxanes, about 38% had received cabazitaxel as well. So it's a little bit different than therapy in the sense that many of these patients had already received chemo. So when we go to the PSMA selection and how it is distinguished from the Australian trial, we did not want to use an FDG PET. First of all, the use of a PSMA PET and an FDG PET, they would have had two pet scans. And there were reimbursement issues with FDG PET, particularly in the U S. So what we did was we had PSMA positive and that is relative to the liver and have PSMA positive metastatic disease.

Then we use also a PSMA negative selection. And if you had a PSMA negative lesion, of course, we can not see it on PSMA but on CAT scan, if there was a visceral lesion more than a centimeter in size and it was PSMA negative, then that patient would not be eligible. And if the lymph nodes were greater than 2.5 centimeters and PSMA negative, they were not eligible. So in essence, what we did is we created a selection criteria between conventional cross-sectional imaging, like CAT scan or MRI, and the PSMA-11 gallium-68 imaging, and we put the two together and we excluded patients that were PSMA negative. It turns out that if we had done FTG, many of these lesions that were negative of PSMA, but present on CAT scan would have in fact been FDG positive, but you didn't have to do the FTG in order to get here.

Here's kind of the good news. 87% of the scanned patients were actually eligible for the study. So the vast, vast, vast majority were eligible. This is a big tent type of protocol. You know, we've had some recent important advances with PARP inhibitors, recently important advances with things like pembrolizumab. Pembrolizumab is appropriate for MSI high and mismatch repair. Now that is going to come in at 3% or 4%, the HRR type of alterations that you have the FDA approval for olaparib, you know, it's a little bit hard to say the exact number because we get kind of different numbers, but certainly no more than 20%. Here, we have 87% of the patients that were PSMA scanned, actually are eligible for the trial. And I think that is important because a lot of patients will be eligible for this therapy going forward.

Alicia Morgans: I think that's critically important and also begs the question. Is it possible that more than 87% of these patients might have actually still had benefit from treatment with lutetium? Just because they had a little bit of an imbalance perhaps, and had some lesions that may not have been PSMA progressing, doesn't mean necessarily... I don't think that they couldn't necessarily benefit, obviously makes sense for this trial, but in the larger scheme of things, given that these patients were so heavily pretreated and that so few of the patients actually were kind of disqualified from entering the trial. What are your thoughts in terms of whether patients in the long-term will need to be screened with a PSMA scan? Of course, recognizing that PSMA scans are actually still not operationalized in a way that makes them available for most patients currently in the U.S.?

Oliver Sartor: Yeah. Great question. And you know, I might channel my good friend, Scott Tagawa here. And Scott has argued that you don't really need to use the PSMA selection. You know, I think as you go forward, this will be bound by regulatory procedures. And I think there will be a PSMA PET required for selection, just that was part of the inclusion criteria within the VISION trial. Now, something, you know and I just want to emphasize, so on about May 27th, we did have the PYL, which is the PSMA PET scan from Lantheus, actually get FDA approval [inaudible 00:07:51] broadly, Prior to that, December 1st of 2020, we had the FDA approval at UCF and UCLA.

So we do have the FDA approval for PSMA PET now, but the reimbursement is not yet operationalized. It is going to be a barrier, but at the same time, the FDA is of course not giving any opinion because of all the applications that are yet to be filed. So by the time the applications are filed to the FDA, I think we will have an operationalized PSMA PET. At least that is sort of my thinking. I anticipate the FDA will require the PET, but I cannot guarantee it. And to your point is, I don't know how necessary it is. I think you could take pretty much all comers and potentially have benefits.

Alicia Morgans: Well, we will definitely leave that decision to the FDA. And, to your point, I think we are all very excited about the PYL PSMA compound that has been recently approved and we are hoping that this is going to be available for patients on a broad scale in the relatively near future which is definitely important. Now, as we think about this VISION data, I know you are very focused also, not only on the disease directed or disease control efficacy but also the tolerability and the patient experience as they are getting this treatment.  In the VISION trial, was this treatment relatively well tolerated? What did the AE profile look like? How did patients seem to tolerate treatment on study?

Oliver Sartor: Yeah, they did. They really did extremely well. You know, there are some imbalances in the AEs relative to the control group. However, the patients were followed for a much longer period of time. When you look at the RPFS, and the period of study in the experimental group, those receiving the PSMA lutetium as compared to the control group, so it's not necessarily a surprise to me that the AE's were a little bit higher. What type of AE's?  Most of them as usual were not really related to the drug itself. What does the drug cause? You can definitely get some dry mouth, you can get some dry eyes. I think there is a little bit of hematologic toxicity, a little bit of anemia, but in truth, not very much. So a little bit of bone marrow suppression, not much. And remember these are heavily, heavily pretreated patients. And one of the things that you encounter, I know you know this from all the experience you have in your own patient population, having some degree of mild suppression after chemotherapy and with advanced disease is common anyway.

So as these patients live longer, it's sort of inevitable, the results that some of them are going to have marrow problems. There was an imbalance or more marrow problems within the PSMA lutetium group, but not really to a significant degree, and patients tolerated the therapy quite well overall.

Alicia Morgans: Wonderful. Well, just so that we kind of round everything out from your perspective, what is the bottom line on the VISION trial? Putting it in the context of the design, certainly the patients who were included, and your findings, what would your message be?

Oliver Sartor: Well, I believe that this is a strikingly positive trial. I believe that this agent now has a real proof of principle, and I think we can look forward to additional trials with patients who are less heavily pretreated. We have the PSMA four trial, which is going to be in the metastatic CRPC space without prior chemotherapy. And that trial has actually accrued its first patient now. We also have the PSMAddition trial and PSMAddition is for the patients all the way up front, the castrate sensitive metastatic patients. And we are going to be testing the PSMA lutetium-177 upfront in combination with ADT and a novel hormone. So we not only have the proof of principle here and now with the VISION results, but I think we can anticipate that there could be additional positive trials moving forward. I think that is really important for us to be able to be hopeful for.

Alicia Morgans: I think it is important for us and certainly for our patients and their loved ones. So just to remind everyone, and I'm sure you're already aware, but this was a trial of metastatic CRPC patients who were randomized to receive treatment with PSMA-617 Lutetium-177 versus best supportive care. All of these patients had previous exposure to an AR-targeted agent and docetaxel chemotherapy. Many of them had multiple chemotherapies and the best supportive care could be an AR targeted agent or steroid or other supportive medicine versus again, lutetium. And we saw very clearly an overall survival benefit with a tolerable toxicity profile. So really groundbreaking, game-changing. And thank you to Dr. Sartor for his work in preparing this protocol from the beginning, and certainly for talking with us about the results today. Thank you so much for your time and your efforts, Dr. Sartor.

Oliver Sartor: Great, Thank you, Alicia. Always a pleasure to be able to discuss these new and exciting results with you.

Alicia Morgans:  Thanks.