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Alicia Morgans: Hi, I'm so excited to be here with Dr. Oliver Sartor, who's the director of Radiopharmaceutical Trials at Mayo Clinic in Rochester, Minnesota. He also has appointments in medical oncology, urology, and radiology. Thank you so much for being here with me today.

Oliver Sartor: Great. Glad to be here.

Alicia Morgans: Wonderful. Especially given your new director position, and, of course, your decades of expertise in radiopharmaceuticals, I'd love to hear from you, Dr. Sartor, about where we are right now in this really rapidly changing radiopharmaceutical landscape for prostate cancer, and then we'll talk about where we're going.

Oliver Sartor: Well, first of all, I think it's changing amazingly fast. Everybody knows about the VISION trial, and that's the PSMA-617 lutetium. That's a late stage patient. Everybody had taxanes, everybody had multiple hormones, and the control group only had a median survival 1.3 months. I mean, these were really, really tough patients that come at the end of the line.

The first thing that's happening is that you're going to have a move forward and now you're going to have a pre-chemo trial that I think will be reporting out potentially even later this year. There's a, quote, top-line positive press release on the PSMAfore trial that suggests that it will be positive, and that is going to be the PSMA-617 lutetium pre-chemo metastatic CRPC. So that's important. There's another trial in that space that's completed accrual, but it's not PSMA-617, it's called PSMA-I&T, also with lutetium-177, very similar to the PSMAfore trial, also in the pre-chemo space. And so that one's from a different company, that's from POINT Biopharma.

Then there's an attempt to move into the very upfront metastatic hormone-sensitive space, and there's a trial called PSMAddition trial. That trial is accruing like gangbusters. It is a big trial, over 1,100 patients. And it's a simple question. It's just like everybody gets the best hormones, so they can do ADT Enzalutamide, ADT abiraterone, whatever, plus or minus the PSMA lutetium. In that case it's 617.

So, moving from the castrate-resistant to the castrate-sensitive. And then in a trial that's coming up, and it probably is going to open up this fall, new phase III, I'm excited about it, is you're going to take people with a PSMA PET-positive oligometastatic disease in the recurrent setting. These people would've already had radical prostatectomy, radiation of the prostate, PSA recurrence, get a PSMA PET scan, zap, zap. You see a couple little spots on the PSMA PET. Today, what many people are doing, including our center, is to SBRT those lesions. And I think that's quite common. There's a little bit of controversy, hormones, no hormones, but in this case, we're going to avoid the hormones. So it's going to be SBRT plus or minus PSMA lutetium. And so the systemic therapy is not going to be hormones, systemic therapy is going to be the lutetium.

This, I think, is a really big space. All of us are using a lot more PSMA PET today and all of us are finding these oligo mets in the recurrent setting, and so this could be a way to move the radio pharmaceuticals very early into the treatment paradigm. Those are some of the big trials. Of course there's a lot more, but that's just an initial view, if you will.

Alicia Morgans: Absolutely. And, of course, these are all registration trials that hopefully will allow us to have FDA approvals in, as you said, not just the very advanced mCRPC setting, but the pre-chemo setting, the hormone-sensitive setting, and maybe even in this oligo recurrent setting.

Now, one thing that I think would be really, really helpful for listeners, because this is your bread and butter every day, but can get confusing. We have to realize there are multiple compounds that are us using lutetium-177 as their radiopharmaceutical. They're a beta-emitting radiopharmaceutical, but they have different methods of targeting the PSMA protein on prostate cancer cells, so we've got PSMA-627, we have the PSMA-I&T point compound. Can you tell me a little bit about the difference here and what you expect may be different in terms of how these drugs ultimately work, even though they have the same radiopharmaceutical attached?

Oliver Sartor: Right. Let me back up just for a second. We're going to divide this into three different components. We have a receptor, presumably on the cell surface like PSMA, and that's where you're going to bind the ligand to, then you have the actual ligand itself, and that's going to be almost like a hormone binding to a receptor, and then you've got the isotope. So you can vary the target, vary the ligand, vary the isotope. Right now we're talking about just veering the ligand a little bit. And the two that are in registration trials, exactly as you said, the 617 and the I&T, they're fairly similar. Differences in the side chain. There's a little bit of difference in the way that they're going to be handled in the kidney, and it turns out the dosing is slightly lower on the PSMA-I&t and it's a Q8 week dosing instead of a Q6 week dosing. But I'm not sure that's going to make a lot of difference.

But these trials, and I want to emphasize exactly what you said, every trial that I mentioned is a registration trial. These are all phase IIIs with FDA-approvable endpoints. So we're not talking about little things that will not change practice. These are all potentially practice-changing trials.

Another thing, and this is just to kind of briefly open up the topic a little bit, there's different isotopes that are being looked at and there's a lot of excitement now we call the alpha emitters and there are two that are getting a pretty big push right now. One is the actinium-225 and the other one's called lead-212. There's other ones out there like astatine-211, but the big push is on to be actinium-225 and lead-212. So now you're changing from a beta to an alpha, and just explain what that is.

The beta is basically an electron and it's flying out. It goes really fast. It's near the speed of light. It's unbelievable. It's, like, boom. It damages the DNA, but it's mainly single-stranded breaks. If you go to the alpha particles, these are two protons to neutrons, so they're about 7,000 times bigger than the beta particle and they don't move quite as fast, but they have a tremendous energy and they don't go very far. So the betas, depending on the energy of the beta, they may go out a millimeter or 2 millimeters or 3 or 4 millimeters with the high energy betas, but the alphas are typically going to be going microns. And we're talking about 50 microns, maybe 100 microns. So very, very, very targeted radiation, big particle. And it turns out, very destructive and it causes double-strand breaks, which are particularly lethal. So, alpha, beta, both useful. A lot of people look at the alphas and say it might even be more useful.

Now, there are other targets. Other targets that are under investigation might be HK2. HK2 is sitting on the cell surface and there are companies that are looking actinium-based targeted HK2 monoclonals. And so the idea is we're going to try to hit the HK2 instead of the PSMA. There's also one called STEEP1 and there's discussion over other targets. You may have heard yesterday about prostate stem cell antigen. That's one. And then there are targets that I'm not supposed to disclose yet.

So the bottom line is, we're going to have kind of a mix and match. We're going to have different targets, different isotopes, different ligands, and what I'm hopeful is that we're going to put together a really nice portfolio. And the nice thing is if you get the right amount of radiation to the right spot, you're going to kill a cancer cell, I promise. And that's what's cool.

Alicia Morgans: Absolutely. Two more quick questions and I so appreciate you walking us through this because I think this is where we need to go in terms of our learning. You also mentioned a monoclonal antibody and we've been talking a lot about small molecules. So if you could talk about the difference there. And then if you could also talk about the difference alpha, beta, not necessarily from the distance and the energy, but patients treated with beta particles end up being somewhat radioactive for a few days, have limitations on their ability to engage with other people and all of that. Alpha particles are different. I'd love to hear both the antibody, small molecule and then alpha, beta in terms of the patient experience.

Oliver Sartor: Antibodies have long been used in medicine. We all know about them and they're cool because you can create specificity to go bind very specific targets. It turns out that PSMA also have antibodies. There's one called J591. I'm going to give a shout-out to Neil Bander and the Cornell Group, Scott Tagawa, they've been working with J591 a long time. They've used both the beta lutetium approach and now they're using the actinium approach. And so the antibodies combined to the PSMA as well. And actually, Scott Tagawa, I want to give Scott a little bit of a shout-out, used an alpha-beta combo using the monoclonal with the actinium and the small molecule PSMA-I&T with the lutetium, and was using combo therapy. This way you can avoid, potentially, some of the toxicity that you might have from high doses of alpha. But nevertheless, maybe getting some synergy. We can alleviate some of the toxicity.

But the bottom line is, the antibodies are being explored in a variety of settings. There are other companies that are looking at different ways to approach the PSMA to an antibody-based approach. I'm not going to list them all now, but antibodies are going to have a play. We just have to see how it works. You have to get the data.

Now, going from the patient experience for a second, the betas, and this gets a little bit complicated, because a lot of times the isotopes when they decay, they have other decay products than the one we focus on. So you can end up with gammas, which are basically like x-rays coming out and they can damage things. And so patients need to protect their loved ones from being too close when they're getting things like lutetium. As it turns out, the alpha particles, because they don't go anywhere, they go microns, they don't even go millimeters, and they typically don't have these high-energy photons that are coming off. There's a little different patient experience because you just walk out and you're done. You've probably ought to make sure you flush the toilet a couple of times when you pee because you have something coming out in the urine. But the truth is, it's a little bit different from the radiation safety perspective because the alpha particles just don't go very far. That's a brief summary.

Alicia Morgans: Great. Well, thank you for sharing that, because I do think that's an interesting distinction from the patient experience perspective. I know you've kind of laid out this landscape and where you see us going, but are there any trials, other than the ones that you've mentioned, that you're really excited to look forward to launch, to hear about, even considering phase II or smaller studies?

Oliver Sartor: There are a couple of things. One that caught my eye here is called the LuPARP, and this is coming down of the Australian group. Shahneen Sandhu will be presenting it as an oral today. If you're inhibiting the repair of DNA damage and using that in common with a DNA-damaging isotope lutetium, so maybe a PARP inhibitor and lutetium together might do better than either one alone. Shahneen has presented a phase I, and we don't have a lot of efficacy data. PSA declines and almost 50% of the patients had a PSA decline of 90% or more in that study, which sounds pretty good, but I want to look at durability and more. But the bottom line is, she wasn't using continuous PARP inhibitor, it was a truncated PARP inhibitor and she ended up day minus 6 to day plus 18, but on a 6-week schedule. So it's not like you get PARP inhibitors all the time. You use them around the time of giving lutetium. I like that.

There are other studies that have been looked at with immunotherapy with pembrolizumab, for instance. Again, Shahneen Sandhu has presented some of that, Rahul Aggarwal out of UCSF presented some of that. We need to see more. Scott Tagawa has now presented a little bit on that. So the interactions between IO and isotopes may be interesting, but it's really too early for me to say. I need to see more.

Other things that I'm excited about are other targets. I mentioned a couple with the HK2, maybe the STEEP1, maybe the PSCA. But it turns out, and I think this is really important, as we're treating advanced prostate cancer, we all acknowledge that there's considerable heterogeneity. I think things like neuroendocrine have gotten a lot of play, but there's more to the story. So we have our typical adeno, we have neuroendocrine, and then what's the rest of the story? I think that we're starting to define that a little bit more. There's some stem cell subgroups and then there's the Wnt-driven subgroups. This is coming out of a nice Cornell study that looked at a variety of chromatin remodeling and categorizes things.

But we have to stop thinking about prostate cancer as a singular entity and we have to begin thinking about it in terms of the heterogeneity that represents reality. And then now we have to figure out how to target these different components. By the way, it may take some combination because I'm now talking about heterogeneity like they're in distinct buckets, but they're not. There's, what we call, lineage plasticity where things are kind of moving back and forth. I think we're entering into a new world of targeted therapy. I particularly like the radiopharmaceuticals because I just think you can get that radiopharmaceutical to the right spot, you're going to kill the cell. But there's going to be different targets, different isotopes, monoclonals, small molecules, and maybe all the above. So, it's kind of an exciting time to be in the field.

Alicia Morgans: It is absolutely an exciting time to be in the field, and I think you've just laid out at least the next 6 years, if not longer. So thank you for that. Final thoughts, final words on your, I guess, excitement about this field and where we could go?

Oliver Sartor: Well, there are a lot of potential different ways to target a cancer cell. We could be talking about CAR Ts, we could talk about bispecifics, we could talk about antibody-drug conjugates, or maybe we could talk about the drug and radiopharmaceuticals. I think, in the end, there might be sort of an interplay between all these somewhat disparate techniques. But I have confidence in the radiopharmaceuticals in terms of their ability to deliver a lethal warhead to the cancer cell. It's not that the ADCs, not that the CAR Ts can't do it, it's just turned out they've been a little bit more problematic. So I see a pretty straight shot on goal, but I'm also aware that there are other shots on goal, and I think we have to keep all the above in mind.

Alicia Morgans: Wonderful. Well, I so appreciate you giving us an update on where we are and where we're going in radiopharmaceuticals. I always appreciate talking to you. Thank you for your time.

Oliver Sartor: Thank you, Alicia.