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Alicia Morgans: Hi, I'm so excited to be here with Professor Oliver Sartor. Thank you so much for talking with me today.

Oliver Sartor: Thanks, Alicia. Always a pleasure.

Alicia Morgans: It is a pleasure to talk to you and really a pleasure to dig into some of the challenges, controversies, and changes that are happening in the advanced prostate cancer landscape. You certainly know this landscape. You are an agent of change yourself as things are going. So tell me what is top on your mind when you think about advanced prostate cancer and all that has been happening in this space in the last year.

Oliver Sartor: Couple things. Number one is there's a huge amount of discussion about what many people would call the first-line metastatic CRPC space, and I hate to say it Alicia, I don't even see those patients anymore. All my patients are getting novel hormones, either upfront if they're metastatic or if they're non-metastatic CRPC, they're getting the novel hormones. By the time somebody gets to a metastatic CRPC state, they've all been treated with novel hormones, so this big sort of controversy about how do we treat the first-line metastatic CRPC, well that's just oh so 2018. It is not today, and the evolution is going to continue I think with the novel hormones going earlier in different settings.

One of the most important trials I think has come out in the last couple of years has been the STAMPEDE data with the extremely high risk patients being treated with radiation, ADT, and abiraterone, and abiraterone is showing a huge difference. That also is influential in terms of how patients are being treated today. So we're looking at evolution where the novel hormones go first and then the question is what comes second. We all know about the Pluvicto and the VISION trial. That's been discussed a great deal.

But now we have a new positive trial, and that's the PSMAfore trial. The PSMAfore trial is going to be that ADT post abi, ADT post enza, ADT post apalutamide/darolutamide, and when patients are failing with metastatic disease, the new PSMAfore trial reported positive in December, and that's in the pre-chemo space. So what do you have? Boom. All of a sudden you've got the PSMA-617 lutetium landing in the sweet spot for these patients when they fail.

Now, I didn't talk about triple therapy, and we could, but the triple therapy, when they progress, guess what's waiting for them? The PSMA lutetium from the VISION indication. So I'm seeing, I think, a large rise of the PSMA lutetium. By the way, I said PSMA-617 and I used the word Pluvicto. Maybe I shouldn't have.

There are other agents of change, and we have the POINT Biopharma trial completing accrual and likely also going to be positive, kind of a second line hormone as the option, and that's also in the pre-chemo space. And then you have the Curium trial, the ECLIPSE trial, and I can see in the not too far future, where isotopes will be the preferred option, but there may even be multiple isotopes of the lutetium variety. So that's the near term. Now, you want me to go long term or you want me to stick near term?

Alicia Morgans: No, well, I think ... So that's really, really helpful and interesting, and I think given the landscape shifts, especially in the metastatic hormone-sensitive setting, we really aren't seeing patients very frequently in our practices, and perhaps ... These patients do exist because we know from claims data that some patients still get ADT alone. Actually a lot of patients, half of them. But for the most part in our practices, these patients when they hit metastatic CRPC have already been exposed to a novel hormonal agent, so that makes complete sense and I appreciate you talking that through.

Before we move on to the long term, I wonder if you can just tell the listeners a little bit about what makes these other two lutetium-based radiopharmaceuticals different from the PSMA-617 lutetium-177 Pluvicto that we know we already have approved, at least in the late-stage setting per VISION.

Oliver Sartor: Sure. So the trials from POINT Biopharma and from Curium both use a different ligand called PSMA-I&T instead of PSMA-617. If you look at the structure for I&T, it's got a little aliphatic chain and then you have the chelator, and then you'll have the lutetium on the end, but the actual binding of I&T is extremely similar, essentially identical, with 617, which has a little bit of a different side chain but the same chelator. So same isotope, same binder, little bit different side chain, little bit different kinetics, but we know the PSMA-I&T works. It's actually proven, if you will, in a variety of the German retrospective studies to be active, and a lot of people are using it around the world.

So the Curium trial is not yet completed accrual. The POINT trial has completed accrual, PSMA-I&T very similar to 617, and then I think there'll be choices and they'll probably compete on different factors. So in the trial with POINT, they have a total of four doses and they give it every eight weeks instead of up to six doses every six weeks. The dosage is slightly different, but if you have a positive trial, I think you have a positive trial, so that's going to be a move forward point.

Alicia Morgans: Interesting. Well thank you for going through that. Let's jump a little bit then to the more distant future. So tell me what you see coming down the way, and I know that you're involved in a lot of this work and really do have such a lens looking forward.

Oliver Sartor: First of all, we can take some of the things that we know about and project them forward. So imagine for a brief moment that you've been looking at all these PARP inhibitor trials. There is one constant throughout, and that is the patients with BRCA mutations really benefit, and so bringing the PARPs into those populations in a variety of settings, whether it be upfront, maybe even in locally advanced, you can see that happening pretty quickly. So that's going to happen in some form, and when you're dealing with hazard ratios that are 0.27 or that magnitude, that's a win. So that sort of precision medicine is going to persist.

By the way, Johann made a very important point in his talk. You never want to miss one of these mismatched repair deficiencies, even though they're rare. Maybe they're only 3%, but when you give the agents, the PD-1 inhibitors to that group of patients, high MSI, TMB, mismatched repair, it's amazing what can happen, so you never want to miss them. So I continue to genetically test every single patient hoping to find those nuggets that'll be rewarded by good medicine.

Now, then you get to the other end, and I'll tell you, there's so much activity right now within what I'm going to call the alpha space, and there are three of these alpha emitters that are being looked at. Everybody knows about actinium-225; that's where the publicity's been, but watch out for lead-212 and watch out for astatine-211. There are some interesting and smart people who are focusing on all the isotopes, not just one. We have monoclonals and then we have small molecules, and it's hard to bet a winner right now because we have several things that are looking good.

We have Neil Bander's group that's been working with J591 actinium, and clearly it's an active agent. And by the way, at this particular meeting, there was a presentation from Scott Tagawa's group that looked at interactions potentially between the PSMA antibody bound to actinium and pembrolizumab, a PD-1 inhibitor, and so there could be some interesting things there. We'll have to wait and see.

Other combination trials we have to watch out for are with the DNA repair inhibitors, and yes, PARP inhibitors, but maybe even more. Maybe even things like ATR inhibitors or maybe even ATM inhibitors, so the whole DNA repair synergistic combination. We're going to have to think about the alphas in a multiplicity of ways. And again, hard to pick a winner right now, but there are lots of interesting avenues to explore. And by the way, do the alphas go after the betas, do they go with the betas, or do they go before the betas? And so that's an interesting thing.

And oh, one more thing, which I'm excited about. So the rise of molecular imaging has created a whole new space around the oligometastatic patient. It's a big space, and SBRT is becoming standard of care. It's no longer some sort of speculative, weird thing. You have the ORIOLE trial, the STOMP trial, things that have really helped to bring that into standard of care.

Well, it's a question about whether or not the PSMA lutetium may improve the time of progression for those patients, and so I think you're aware that we're working with SBRT plus or minus PSMA lutetium, that'll be PSMA-617. So that phase three is designed, already been through the FDA, and I think it could be a game changer. It'd be very nice to be able to avoid hormonal therapy for patients with oligometastatic disease, treating with hormones and systemic radiation, and give them a little breather. We're going to call it the PSMA Delay Castration Trial, so no hormones.

Anyway, I've been talking in circles, but that's okay. Thank you for the opportunity. The alphas are coming and they're going to stay. The betas are coming and they're here. And then there are all these innovative combinations that we have to think about, and I can just see all these trials developing, and it's going to be a very busy time for the next decade for people who like to study this disease.

Alicia Morgans: And certainly busy in the best of ways for the patients who need those treatments. And I just want to comment that I think one of the things I love about you in all of this work is, of course, your enthusiasm and your excitement and your ability to get these drugs through studies and get them to patients, but you're also so focused on ensuring the best quality of time for patients and delaying castration, avoiding things that we thought were absolutely necessary if we actually wanted to care for our patients. Changing that mindset is probably one of the biggest things we can do, and it doesn't necessarily even depend on fancy radioactive pharmaceuticals, although these radiopharmaceuticals will be in that trial, so that'll be a game changer as well.

Oliver Sartor: It's really interesting. And Alicia, you've kept the patient at the heart of your own research and as a priority for when you're in the clinic, and I know that because we've had many discussions. But if we think of what the patient needs, you can see that there are many opportunities for improvement. And yes, I understand treatment intensification, and I think it's very appropriate, but it's also time to talk about treatment deintensification.

I'll mention the NRG-GU009 trial. Paul Nguyen is the PI, I'm co-PI, and as it turns out, we're using Decipher to classify these high risk localized prostate cancer patients into higher and lower risk. The higher risk are going to be able to get intensification by the addition of apalutamide to an ADT radiation backbone. But the lower risk by Decipher patients are going to be deintensified. We're going to shorten up the hormonal exposure, hoping to impact their life in a positive way by treating with less hormones, not more. So intensification, deintensification, both important.

Alicia Morgans: Right sizing the treatment for the patient is the right way to go, so thank you so much. I could tell there's a lot of excitement on your part, certainly on mine, and there's a lot to look forward to in the field of advanced prostate cancer. Thank you so much for your time.

Oliver Sartor: Thank you, Alicia.