Lecture Presentation:

Neal Shore: Hello, and welcome to our program today. This is one of a series of modules, "Precision Medicine PSMA Targeted Therapies in Progressive Metastatic Prostate Cancer Educational Forum". We're really pleased today to have an outstanding faculty, Dr. Oliver Sartor, who is going to discuss the VISION trial, which I know we've all participated in and we're all super excited to eventually see the readout on it. Dr. Sartor is a Professor of Medical Oncology at Tulane, and we're really fortunate to have Alicia Morgans, medical oncologist, and Phil Koo, nuclear medicine radiologist, to weigh in along with myself, I'm Neal Shore, urologist, and have a really interactive question and answer period after the presentation. So thanks for listening. Oliver, please take it away.

Oliver Sartor: Thank you very much, Neal. I've got a talk here, and it's really about focusing more on PSMA very specifically, introducing the pivotal Phase III VISION trial, which we're hopeful, we don't know yet, but we're hopeful is going to be able to provide the data necessary for the new drug application and FDA approval.

So first of all, let's talk a little bit about PSMA. It's a transmembrane protein discovered some years ago. It is interesting that the cytoplasmic domain, which is really a very small domain, was actually the target for an antibody that was used for ProstaScint®. A lot of people forgot about ProstaScint®, but it bound to the internal cytoplasmic domain of PMSA.

It turns out that PSMA is highly prostate-specific, but not completely so. There are other areas that have small levels of expression, and when you go to the imaging, we can see that. But the bottom line is highly prostate-expressed, and that allows the targeting that is so critical for this particular approach.

I think a lot of you are familiar with PSMA PET, whether that's using the gallium-68 or the FAT. PSMA PET is clearly superior to conventional imaging, and here you can begin to see some of the uptake that is normally seen, such as in the salivary glands and the lacrimal glands. It's excreted via the kidney, and this is PSMA-11 right here that you're looking at, with a little bit of liver uptake and then down into the bladder.

So when you're imaging, you can see these elements, say in the right ilium here and the retroperitoneal nodes here and diffusely in the bone. This allows you to be able to see where that prostate cancer is, and what we're introducing now is sort of theranostics. We call it "see it, treat it." If you can see the disease, you can treat the disease if you bring in a therapeutic isotope.

Now, the key that has really been able to move this field forward is some very clever individuals out of Germany. Some at Johns Hopkins have been able to devise strategies to bind to the PSMA molecule and then have a chelate attached to this PSMA binder. Now, here are a couple of them. Here's PSMA-11. That's a molecule often used in imaging. There's PSMA-617, which is being used therapeutically. There's PSMA-I&T, which has been used both for imagery and treating, and you can put these molecules together with these chelates and bind them to lutetium-177, I-131, actinium-225, and even more.

Now, there are a large number of beta emitters that have been used in human studies. But the one I'm going to be focusing on is with lutetium-177. It's got about a 6.7-day half-life. It's a relatively low energy beta, and that actually is advantageous. You don't want a real high-energy, because then you end up radiating tissues that you don't want to radiate. It turns out that the average penetration in tissue is only about 0.3 millimeters. So if you put that lutetium into the tumor, it's not going to hit a lot of other tissues, which means your toxicity is going to be low.

Now, I'm going to go to the German studies and their initial studies particularly out of Heidelberg, and then as German aggregate studies became available, this was one that was published and I think it's a nice one for the Journal of Nuclear Medicine in 2017. Here, you see PSMA waterfall plots and here you're seeing after one cycle of drug, and here you're seeing after a second cycle of drug. You can see that many of the patients respond, but not all of the patients respond.

In these German retrospective studies, they really did not define the optimal dose schedule, but nevertheless, hugely important, because it showed the efficacy of these agents, particularly as measured by PSA declines and subsequently by other radiographic measures as well.

Now, one of the things that came out of the German studies is that there were important elements related to dosimetry, but it's more than dosimetry. Your response rate is going to depend on the prior therapies. It's going to depend on the PSMA uptake and heterogeneity. It's going to depend on whether or not there might be DNA repair defects present or not. When you talk to people, there's a lot of dosimetry talk, but dosimetry is only part of the story, and I think that's very important.

One of the really nice things was that in the German studies and other studies that the toxicity related particularly to the hematologic factors was very, very low. Here you can see RBCs, hemoglobins, white counts, and platelets, and there's hardly any change. It was really quite a surprise to be able to give a radiopharmaceutical that has so little effect from the hematologic parameters. This is unlike, for instance, samarium-153.

Now there's a trial I'd like to go over briefly, because it's the first randomized Phase II trial with lutetium-177 PSMA-617, and here it's being compared to cabazitaxel in metastatic castration-resistant prostate cancer. All of the patients had progressed from docetaxel, and most of them, by the way, had progressed on either abiraterone or enzalutamide or both. This was presented at ASCO 2020 by Michael Hofman, who works at the Peter Mac Cancer Center in Melbourne, Australia. This was an Australian trial.

TheraP selected the patients using a combination of PSMA PET and then excluded patients that were FDG-PET positive and PSMA PET-negative. What do we mean by that? If we look down here, we begin to see PSMA PET positivity. No doubt that this patient has a tumor that binds PSMA. You can image that. With a gamma emitter, you can use something like gallium-68 PSMA-11 and turn out to see the tumor very, very nicely.

But now they used a second selection criteria in this TheraP trial, and they used an FDG PET. And here you can see that there's a large amount of uptake and a mediastinal mass on FDG that you don't really see on PSMA. This patient would have been excluded from the TheraP trial because they used a double selection process. Other trials have not done this double selection.

Here's the primary endpoint, a PSA decline of 30 to 50%. On the left, you can see an FDA-approved, known effective agent, cabazitaxel. Thirty-seven percent of the patients had a PSA decline of 50% or more, as compared to the lutetium PSMA, where 66% of the patients had a PSA decline of 50% or more. So here, on a very simple PSA decline endpoint, you end up with a 29% greater probability of response and really no doubt that there was better PSA response. Now, they also had a PSA progression-free survival that was favorable for the lutetium, but at the same time, that did not have radiographic parameters presented in this trial yet. So this is just PSA. Nevertheless, you begin to see these impressive results.

You also begin to look at safety, and this is also important. If you look on the lutetium side over here, you do end up with a little bit of neutropenia, a little bit of thrombocytopenia, but the most predominant side effect has been dry mouth, and that's because of the salivary uptake of these small molecules of PSMA, and you end up radiating the salivary glands. You also can get dry eyes, that's the lacrimal glands. So dry mouth and dry eyes are somewhat unique. A little bit of diarrhea, but that is not really apparent to me that it's related to the isotope. A little bit of dysgeusia. I think this neuropathy is probably unrelated, it's probably residual neuropathy. But you can see it compares very favorably when you look at grade 3-4 events, with only 11% thrombocytopenia, 4% neutropenia, and 5% on the fatigues. But these are very, very low. Anemia, 8%, but that's probably related to the underlying prostate cancer.

I wanted to introduce you to the pivotal trial called VISION that uses PSMA lutetium-177 and looks at a PSMA- PET selection criteria and the way the selection criteria was done is to run a PSMA imaging in advance and then to run cross-sectional imaging. If you had PSMA-negative masses that showed to be positive on cross-sectional imaging, something like a CAT scan or MRI, so if you have a mass on CAT scan or MRI that was PSMA-negative, that patient was basically excluded. It was not a double PET selection. It was not the European/Australian methodology. It was only using PSMA-PET and cross-sectional imaging.

The patient population were all metastatic CRPC, at least one novel prior hormone, that'd be abiraterone and enzalutamide, typically. At least one prior taxane, typically docetaxel, and again, this PSMA PET positivity selection criteria that I made a note about.

There were a couple of stratification factors, LDH, which is well known to be an adverse finding for patients with metastatic CRPC, liver mets, performance status, and whether or not there was a use of the novel hormone agents as the best standard of care. The trial randomization was two-to-one. Everyone received best standard of care, and this would be pretty much whatever you wanted to use except for chemotherapy.

Then in one arm, the lutetium-177 was given 7.4 gigabecquerels for six weeks for up to six doses. After those four, there had to be an assessment to ensure that the patient was benefiting before you would give cycles five and six. A total of 750 patients were implanted and it actually ended up being overrecruited with an alternative primary endpoint of either rPFS or OS, really a pivotal trial for FDA approval. If positive, this is going to lead to an NDA and I was fortunate enough to be co-PI on the study along with Bernd Krause, who's from Germany and a nuclear medicine physician.

So one of the things that I want to emphasize, and one of the reasons that I believe my enthusiasm is so high, we're taking precision medicine into whole new realms. We're beginning to dissect all the potential genetic alterations that are present when we're treating these prostate cancer patients. And there's a lot of heterogeneity. I think everyone is aware we have new PARP inhibitors, two new PARP inhibitors who have been FDA approved for those with DNA repair defects. But the interesting thing about this targeted radiopharmaceutical is the radiation can kill the ball. And I think that provides a really unique opportunity to benefit our patients, not only with an effective therapy but also with no toxicity. I hope that gives you a nice overview. I know we're going to have little questions and answers, so let's go ahead and into the discussion right now.

Faculty Discussion:

Neal Shore: So thank you. That was a really wonderful, wonderful review. I know how dedicated you been to the arena of radiopharmaceutical development, which is exceptional, concise, and very enthusiastic and I think appropriately, so review. Yeah, we've got PSA declines, the VISION trial, and we see with TheraP and hopefully a positive readout of VISION that the targeted beta emitter lutetium-177 will go to all tumor sites.

And then the really fun and interesting aspect of having imaging be a biomarker as well. And I guess there's going to be some ongoing importance of additional studies to sort it out. Other imaging modalities in conjunction with PSMA-PET scans. And I think our Q&A will give some further thought to that, but the heterogeneity is quite significant. We talk about this all the time and thus the need for multidisciplinary teams. Let me ask you, Alicia, your thoughts on lutetium-177 and other things that you may want to weigh in on, trials that Oliver alluded to, which I think are really exciting as well.

Alicia Morgans: I think that lutetium is really exciting because it does seem to be a tolerable agent. It does seem to nicely lower the PSA, which is really not required necessarily as we've seen with multiple other agents but does help people feel better. The comment I would make and I'd love to hear Oliver's thoughts is really that I hear some people talk a little bit about this either-or phenomenon, if we use radium, then we can't use lutetium, if we use lutetium, then we won't be able to use radium. So at this point, I don't feel like that's been proven. We don't know that and actually some of the patients in the VISION trial had had prior radium, they just had to have it at least six months prior to enrollment. What are your thoughts on incorporating lutetium but we have to get rid of our other radiopharmaceutical in order to do that properly?

Oliver Sartor: You know Alicia you raise a good point and we actually submitted and had accepted a little abstract to Society of Nuclear Medicine. And in there, we looked at the potential to be able to give lutetium after radium. And we had a number of patients who've been radium pretreated, lutetium subsequent treated really found absolutely no safety issues. I'll tell you that there are a variety of clinical trials now that are proceeding using both the alphas and betas and combination. And I don't really see much in the way of safety issues developing here. I think we'll have to march down these paths in a systematic way to make sure that patient safety is a priority, but nevertheless, I don't see big issues arising for these combinations.

Neal Shore: Can I follow up on that for you also, Oliver? You mentioned the alpha and beta emitters and potentially the beta emitter lutetium could be the first approved agent pending the readout of VISION. And there are other conjugates radioligand pharmaceuticals that are also looking at alpha emitters and we've had the alpha emitter experience of radium. Can you comment on some of the differences and mechanism of action outcomes, the safety that you might potentially see? You did talk about it earlier in your presentation.

Oliver Sartor: Sure. And there are a couple of issues here. Let me just very briefly talk about some of the alphas. There are two in clinical trials right now the actinium-225 and also the thorium-227. And both of these were being used in combination with PSMA binding ligands. What I'll say is it's so far the toxicity to the salivary glands seems to be a little bit higher, but it turns out that [inaudible 17:03] suppression is really fairly minimal for this one as well. What I anticipate is that there's going to be a separate effort on the alphas. And by the way, they're not just small molecules like I showed you here, like the PSMA-617 or the PSMA-I&T, but also there are some larger molecules, like the J591 monoclonal antibody that Neil Banders worked on for years. And those are also moving forward with both alphas and betas. So anybody's small molecules, beta emitters, alpha emitters, I think we're going to see a really interesting set of experiments over the next couple of years, trying to sort all these things out.

Neal Shore: Yeah. And so thank you for that. And I think that's what's so exciting for all of us, not only for treating patients in the future but for clinical trials research. Phil Koo, you've had an opportunity to listen to this really outstanding presentation and feedback from both Oliver and Nick. What are some of the things that are exciting to you moving forward, assuming an approval of lutetium-177.

Phillip Koo: Thank you. So, you know, this idea of precision medicine I think is what really excites me and being able to use an imaging tool to really maximize the precision of what we're doing and offer patients options. I think that's what's really gets me excited about all these developments. I guess the one question I have for you Oliver is, you clearly see differences in PSA response in a lot of different patients. And those German studies clearly show that there's something going on with those non-responders versus the responders and the trials that have come forward thus far, they have very different inclusion criteria, PSMA, some have PSMA, some have PSMA plus FDG. I know the Alliance trial that's being planned, I think does not have PSMA imaging as part of the initial inclusions. So in my mind, I think this binary approach, the positive-negative PSMA might be too simplistic as well, but I wanted to hear your thoughts on how this is going to all evolve moving forward.

Oliver Sartor: Yeah, that's so great. Great question. Let me begin to isolate some of the factors that I think are important. Number one is the degree of PSMA uptake and there is heterogeneity. Absolutely no doubt. There are some patients who have more uptake in some sites that have more uptake than others. So PSMA heterogeneity and degree of uptake, absolutely a variable that makes a difference. Number two, the location of the disease. It turns out that to date, most of the lymph node metastases seem to be particularly responsive, perhaps more so than some of the bone or liver metastases. So the location of the disease matters. Number three, dose matters and Scott Tagawa and others have been pushing the dose and clearly that as you move into the higher doses, you're able to deliver more to the tumors. So dose matters, uptake matters, heterogeneity matters, location of disease matters.

In addition, there's tumor biology, things that are important here included the DNA repair defects. There are some DNA repair defects and I'll just say, BRCA is one where you end up with extreme sensitivity to DNA damaging agents. We've known this through platinum, the PARP inhibitors take advantage of this synthetically validate damaging the DNA and a tumor that is deficient in DNA repair is a strategy.

In addition, there are elements related to prior history of treatment. So has a patient been treated with carboplatin previously, only hormones previously? There's a lot of heterogeneity in these unregulated studies that have been reported from Germany. And we don't get a lot of [inaudible 00:21:08] in the prior treatments. So adding together a lot of these variables I just discussed are all important. And I think we have to dissect each one and take a little time to understand what really is going to predict response.

Neal Shore: Yeah. Thank you, Oliver. And thank you really for your leadership with the VISION trial and thank you to our colleagues in Australia and around the world who've really been pushing it. I know our colleagues in Germany were just having great results and they had access, but we can't get full regulatory approval in the US and many other countries until we do these studies.

So really this is a great achievement and we certainly look forward to the readout on VISON. I think it'll really open up an entire new class of agents for us to not only have available for patients to improve their outcomes but as you point out for the most part it's quite well-tolerated. We have to overcome implementation barriers without any doubt about that. But I think we can do that. And especially in a multidisciplinary way and has Phil Koo said, it's not a one size fits all model. There's going to be a lot of different ways that we can come about it. We have a few more minutes. Let me ask for some final comments. So, Alicia?

Alicia Morgans: Thanks, Neal. I think that my final comment would be that I'm just really excited to have another tool available to us as we try to take care of these patients with advanced disease and I do look forward to further investigation to see if we can continue to move it forward. And I think it's an exciting time for patients and hope that it continues to be.

Phillip Koo: Great. And I'm going to be brief because I want to hear more from Oliver. So I agree with everything that Alicia has said and I'll turn my time over to Oliver.

Oliver Sartor: Gosh, I've pretty much covered the areas that I wanted to cover, but I will say that I'm excited about this therapy because not only is it efficacious, but the toxicity is so reasonable and we've been able to treat people here at Tulane on trial and have seen some really outstanding responses and the ability for patients to sort of feel that benefit... It really is exhilarating because as clinicians, what we really want to do is help improve the lives of our patients. I'm very hopeful that this tool is going to allow that to occur even more often than we have in the past. So really a privilege to be able to work with teams that have been put together to study these molecules and surely hope that we have some positive results to record.

Neal Shore: Wonderful. Thank you. Great panel, Great discussion. Thanks for all your efforts. Really appreciate it, thank you.