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Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist at Dana Farber Cancer Institute. I'm so excited to have here with me today, Professor Oliver Sartor, who is the Medical Director of the Tulane Cancer Center, as well as being the Laborde Family Professor of Cancer Research there in New Orleans, Louisiana. Thank you so much for being here with me today, Dr. Sartor.

Oliver Sartor: Great. Thanks, Alicia. Excited to be here.

Alicia Morgans: Wonderful. Well, I wanted to talk with you a little bit about a recent publication that you had looking at real-world data, looking at outcomes related to the use of radium versus a second novel hormonal agent, but also to talk more generally about this second, and even the third-line space for patients with advanced prostate cancer, because it's all rapidly evolving and is something that we all need to keep our eye on. Why don't we start with your recent publication? Can you tell us a little bit about it?

Oliver Sartor: Sure. Alicia, you probably are familiar with the Flatiron database, and the Flatiron database is US-based oncology practices and they feed the data in. It's really nice to see about sequencing, what we can understand about durations in therapy, including about survivals. It's obviously not clinical trial data, but it gives a real-world view, and I think that is very valuable.

So basically, these are individuals who occupy the post-first-line hormone space, so that's post-Abi/Enza with metastatic CRPC. And in particular, the two groups that we analyzed were those who were treated with radium or a secondary hormone. And it turns out that there were a number of patients in each group, it turns out, number one, there were no new safety signals or anything that would have given us some particular concern, it turns out that the immediate survival was pretty similar for both groups at about 11 months, and they then in each group, a number of patients went on to receive additional therapies. However one of the things I want to emphasize a little bit is the 11-month median survival time. This is real-world data and this is kind of post-Abi/Enza. I think a lot of people don't realize that these patients have a real sense of urgency and they have real needs. So a couple of things I think we learned from the patients, but that's just a quick, quick overview.

Alicia Morgans: Well, and I think that's really important and I appreciate your areas of emphasis here because what it sounds like to me is that these treatments remain safe, but there is a clear need for other mechanisms of action, other therapies that can come in and potentially be more powerful in this population than what is currently being delivered, or at least to add to what is currently being delivered to hopefully add time and quality of time to patients' lives. Is that your takeaway?

Oliver Sartor: It is. That's one of the important takeaways. First of all, I do like to see the real-world safety data, that really nothing came of note here for either of the arms. But I think you've emphasized a very important point. These patients, after they are failing, and it's typically abiraterone/enzalutamide, and then they're going on with metastatic CRPC, these patients have real needs. And currently, there are a variety of treatment choices, we have taxanes, but we also know that taxanes are not used in a substantial proportion of patients. In this study, we looked at sort of taxane use, and one of the things we did find is that age is one of the things that sort of inhibits taxane use, and not everybody gets a taxane. So these secondary hormones are important.  But then we need to think about novel therapies as well. We have a whole variety of clinical trials now ongoing in this space. All of these are important to consider. I think the landscape today is going to change, and I think these current clinical trials are going to be the way that the landscape changes. So those might be important to emphasize as well.

Alicia Morgans: Well, let's talk a little bit about those. Now, certainly, the VISION trial recently completed, and reported, you were heavily involved in that trial, of course, on the New England Journal of Medicine paper as well, so can you tell us a little bit about where you anticipate lutetium fitting in? And then we'll get into some of the other trials that are, of course, ongoing.

Oliver Sartor: Right. So first of all, let's talk briefly about VISION. I don't want to concentrate too much here. VISION was a third, fourth, or fifth-line therapy. Everybody had Abi/Enza, but in addition, everybody had docetaxel, and the truth is, 40% of patients had also a second taxane. So it wasn't uncommon for the VISION trial patients to be pretreated with Abi/Enza, docetaxel, and cabazitaxel.

Now here, we are moving it up earlier. And by the way, let me mention a clinical trial called PSMA-4. So the agent used in the VISION trial was called PSMA-617 lutetium-177. That agent is now coming into the second-line space, if you will, this post-Abi/Enza space, randomized against a novel hormone versus the PSMA-617 lutetium, but, very importantly, with the crossover. The primary endpoint is actually rPFS. Of course, we will be tracking OS as well. But the crossover ensures that everybody will have the opportunity to receive the PSMA lutetium, one thing that was not true in the VISION trial.

Alicia Morgans: Well, and I think that's so important because it certainly will improve the rapidity with which patients are interested in enrolling in the trial, but also answer some of the questions that came out regarding control arm opportunities for patients on VISION. What else should we anticipate is being developed in this space?

Oliver Sartor: Well, I may tell you a little bit about a trial that a lot of people are not particularly aware of. It's called the SPLASH trial, where there is another way of delivering PSMA in targeted lutetium-177, and that is where the molecule called PSMA-I&T, and this would be developed by a little company in Canada called POINT Biopharma. And they have a similarly designed trial that is sort of in this second-line space, if you will post Abi/Enza, randomized to a secondary hormone, and then the PSMA-I&T lutetium-177, and again, with the potential crossover. So that trial is just about to begin accruing. There was a little bit of a lead-in phase prior to the randomized phase 3, and that trial is about to begin. So that's a second PSMA-targeting agent.

Then we have trials that have attracted some interest, and these are the enzalutamide plus or minus pembrolizumab trial. We know Julie Graff and colleagues have potentially demonstrated some synergy between enzalutamide and pembrolizumab. And that trial is also going to be going forth in a phase 3. And then we have another one with the cabozantinib and atezolizumab combination, and that combination is being looked at, Neeraj Agarwal is taking a look at that particular combination in a phase 3. And then we have VERU-111. VERU-111 is an oral taxane, basically a microtubule inhibitor, and that's moving forward. So whatever we have today is probably going to be different tomorrow, and I think that's exciting because we all know that we need more and more effective therapies for these patients.

Alicia Morgans: Absolutely, and I think it's also important to emphasize that, of course, we need to ensure that these agents are safe, that they are tolerable for our patients who may be older adults and have other comorbid illnesses. So it's wonderful to see us taking these approaches that I think will also maximize the quality of life during treatment, as well as improved quality of life from improved disease control, and phase 3 studies typically do include some assessment of patient-reported outcomes and quality of life as well. Do you anticipate that these agents, that these studies, will generally show safety profiles that are consistent with what we need for patients in this population?

Oliver Sartor: I think so. I mean, there is a little bit of concern, I think, for each of the agents. PSMA lutetium-177, I think we have a pretty good picture from the VISION trial. As we bring it in earlier, there are going to be fewer symptomatic patients. So the only thing you can do to an asymptomatic patient is either prolong their symptom-free period, or to cause some sort of side effects. So there could be a little bit more of an impact, so we will watch that. That will be true for the SPLASH trial and the PSMA-4 trial, both.

I worry a little bit about the cabozantinib and atezolizumab. I think we've all used cabozantinib, typically in the renal space, and we know that it does have some capacity for TKI-type side effects, appetite suppression, and more, so I'm going to be watching that one closely. The VERU-111, the truth is I don't know much about it, and so we will have a lot to learn.

And then with regard to the pembro and enzalutamide, I think we all know enzalutamide. I don't think we are going to have any unknown adverse events for the pembro. But you know as well as I do, that every now and then you can have real pembro-induced side effects, everything from pulmonary disease to rare endocarditis and rare problems with the liver, et cetera, et cetera. I just saw a patient yesterday, by the way, it's something I had never seen on pembro before, he had fasciitis in his hands and his hands were very, very tight, and swollen. I dosed him with prednisone, and overnight it got better, but it had to be due to the IO.

Anyway, well there is a lot that we are going to learn about health-related quality of life, there's a lot that we are going to learn about adverse events, and a lot to learn about efficacy. So as usual, prostate cancer is changing rapidly.

Alicia Morgans: Well, I sincerely appreciate you going through all of this, and of course appreciate the work that you and your team did to really investigate those real-world data that tell us a little bit more about how the drugs work in a population that may look like those populations that we really see in clinic. Maybe a little older, maybe with a few more comorbidities, it's an all-comers kind of approach, and so always very, very important data for us to consider and to review. So thank you for your expertise and your time today.

Oliver Sartor: Thank you, Alicia. Always glad to chat.