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Oliver Sartor: Hi, I'm Dr. Oliver Sartor. Really a pleasure for me to have Dr. Michael Morris, Chief of the Prostate Cancer Section of Memorial Sloan-Kettering, incredibly well known. Honored to have you here, Michael, on UroToday.

Michael Morris: Pleasure to be here, Oliver. Thanks.

Oliver Sartor: We're going to be talking about a provocative topic because I find it provocative. We're going to be talking about actinium. We're going to be talking about PSMA, and we're going to be talking about an antibody. And this little company called Convergent that you've been involved with.

And these are some studies that initially grew out of Cornell but are now being industrialized, if you will. And I want to ask you, first of all, we're very familiar with these small molecules but not much with the antibodies. Tell me a little bit about the antibody to PSMA. And is there an advantage or disadvantage to having an antibody-based therapy?

Michael Morris: The irony is, is probably most people are familiar with the small molecules. But the antibody actually preceded the small molecule by many, many, many years. J591 was an antibody that was really the basis of the initial PSMA identification studies, PSMA-based imaging. And it was later that the small molecules came into development and, really, from an imaging and therapeutic standpoint, replaced the antibody.

And at that time, that was because small molecules have a shorter half-life. So you could image more quickly after injection, and you had less retention in the blood pool with a small molecule because the elimination half-life is relatively short. So in many respects, the emergence now of antibodies back into the consciousness of drug developers and radioligand therapy is back to the future because we're taking a technology or a molecule that used to be the standard then was replaced.

And now we see advantages to antibody-based therapy that we might not have in the small molecules, namely in salivary gland toxicity. The small molecules do tend to localize with their payload in the salivary glands and the lacrimal glands. And especially with the alpha-emitting radio conjugates, this can lead to really significant xerostomia, whereas you don't have that degree of uptake, at least on imaging, with the antibody.

And there's the hope then that, with alpha-based radioligand therapy that's antibody-based, you might be able to spare the salivary glands and spare the patients the xerostomia that follows from that. There may also be an advantage to the antibodies in regards to tumor retention relative to the small molecules. We'll see.

Oliver Sartor: Let me ask a question. I've looked at some of the imaging from the antibody. The liver looks really hot. Now, you might have the advantage of not much renal excretion, but is that a danger with the antibody, to have all that hotness in the liver?

Michael Morris: I'd point out two things. First, the liver tolerance to radiation is relatively high relative to the kidneys. So if anything, that hepatic excretion pathway may be advantageous because there are significant concerns that perhaps, with some of the higher energy radioligands, you'll see more nephrotoxicity.

Second, you alluded at the start of this discussion to some studies that were investigator-initiated initially with the actinium J591, and this was really excellent work by Scott Tsugawa and his colleagues. And there was really no hepatotoxicity that was seen.

So I think that the dosimetry may be higher, but whether that actually translates into clinically concerning events, there's not evidence to date that there is any form of transaminitis or hepatitis. There's also been some discussion—and this goes back, again, a long time ago—that perhaps that is really nonspecific binding in the liver, not PSMA related. Really, the only thing in the liver that is expressing PSMA is Kupffer cells.

So I guess the question would be, what is binding in the liver? Where is it binding? And to date, there's been no suggestion or signal that there is related hepatotoxicity that's associated with it.

Oliver Sartor: Thank you for the clarification because I've looked at some of those images, and my first impression is, oh my gosh, what about the liver? Now, this is going to be with actinium. Now, you and I probably know a little bit about actinium, but not everybody else does. I wonder if you could explain how actinium might be different than lutetium, which is kind of the Pluvicto isotope, and what advantages and disadvantages might be present with actinium?

Michael Morris: Sure. Well, I think that the best comparison that I've heard in terms of analogies is that lutetium, as a beta emitter, in boxing terms, has a longer reach but a softer punch. Or conversely, alphas have a stronger punch but a lesser reach. So there's a lot more energy that's released with the alpha emitters, for which actinium right now is the most discussed. But there are certainly other isotopes that are being discussed since the supply of actinium has been somewhat spotty.

But the real advantage of actinium relative to lutetium is it releases a lot more energy in a very, very short pathway. So you really can kill cells that are a couple of cells deep but not too much more than that. That's not to say there aren't advantages to having the beta emitter for lutetium. Beta emitters can kill on a bystander level, even if it's not bound to PSMA.

The drug isn't bound to a PSMA-expressing cell, for example; it could kill neighboring cells. But by the same token, it's killing normal tissue or damaging normal tissue as well. Actinium has the potential to spare much of the normal tissue that surrounds the tumor cells or the tumor mass but does have more of a lethal effect with just a hit or two on double-stranded DNA and so can be much more lethal to the cancer, whereas normal tissue is much more spared.

Oliver Sartor: Succinctly, Mike, explain exactly what an alpha particle is versus a beta, just to help our audience understand the contrast.

Michael Morris: Sure. Alpha particles are much larger than beta particles. So they carry a lot of energy, but they move very, very short distances. So it's a subcellular subatomic component of energy that is released.

Oliver Sartor: Got it. Developmental pathways, PSMA is a very competitive field. And the PSMA-617 is in the lead because we have an approval in the VISION space and perhaps an approval coming in the PSMA-4 space, which is the post-ADT ARPI but pre-taxane for metastatic CRPC. How do you see the development of this actinium-based antibody? And what is the strategy to get it from point A to over the finish line, which means FDA approval?

Michael Morris: So in prostate cancer, like with most solid tumors, our newest therapies are generally tested first in our least responsive patients. And then if you have a drug that is active in those sickest patients with the most advanced disease, you generally see more gains as you move therapy earlier.

At some point, though, you have diminishing gains with the betas because, as you get to a lesser and lesser and lesser disease burden, you're actually delivering less amounts of energy because the molecule does need to bind to individual cells. That is what we call the dosimetry, the delivered dose to the—or the absorbed dose to the tumor. Alphas, as you move earlier and earlier into lesser and lesser disease burdens, because they release more energy over a shorter pathway, can kill individual cells. So we think that alphas have the capacity, as you move into micrometastatic disease, to potentially eradicate disease on a cellular level.

So perhaps, as we follow that common pathway of ever earlier treatment—and you mentioned VISION and the PSMA-4 space and the PSMA addition space, which is also metastatic disease but castration sensitive—that as we get even earlier than that, perhaps to just the biochemically relapsed space or the perioperative or peri-radiation therapy for primary therapy space, that's when we may need to make the switch to alphas to get enough energy in those really minimal disease burdens in order to achieve what we really want to achieve, which is cure for that minimal disease burden. Earliest disease patient—that's where I think that the alphas have much greater potential than radioligand therapy has to date.

Oliver Sartor: Now, thinking about those curative therapies relatively early-stage disease is a little bit of a conundrum because now we're talking about big trials or long trials. And then we also have a little bit of concern about the toxicities of radiopharmaceuticals in longer-term follow-up. And it's hard to cover all those issues at once, but do you think there are regulatory strategies for these early disease patients that are feasible within a timeline that's affordable for the companies?

Michael Morris: Well, I think you raised two really important issues that are at the forefront of everyone's consciousness, that as we go into this really earliest disease setting, the potential over years to have either toxicity to normal organs that otherwise wouldn't declare itself or themselves and also secondary malignancies that would now have the time to manifest over the course of if not years, then decades—one has to be cognizant of the potential for toxicity that would really be, in an early patient, potentially debilitating or preclude further therapy.

And there, of course, the xerostomia is really quite relevant. You take a patient who has many decades to live, and you do need to protect their salivary glands. So the toxicity issue is an important one. I think as we get more data in the later disease states, we'll perhaps have a larger database with which, in terms of dosing and dosing schedule, knowing how to move earlier, better, and safer. And so I wouldn't necessarily start exploring the alphas in these early, early, early disease spaces in terms of large clinical trials.

And then the endpoints will depend on two factors. First, those early trials need to really be enriched for patients who are at highest risk for relapse. So you reach either an MFS or other progression of disease declaration of treatment failure as quickly as you can. Granted, that means smaller studies than just all comers, but that's probably most appropriate.

Lower-risk or even low-intermediate-risk patients, they don't necessarily need this therapy in order to be rendered free of disease. Or some of those patients don't need any treatment. And then, as we go into those early spaces, that might be a place where we might explore qualifying even earlier endpoints, such as minimal residual disease within the primary itself.

And those clinical trials to qualify those endpoints are ongoing with other therapies right now. But that's where it's really important to establish some of those intermediate endpoints that, with further study, might justify a drug approval if they're shown to be clinically relevant.

Oliver Sartor: Lots of attention to the PROTEUS trial, which you alluded to without the name.

Michael Morris: Yep.

Oliver Sartor: And how the FDA will react to that particular data set, of course, we haven't seen it. We don't know what it is. I think Mary-Ellen Taplin will have the opportunity to present it at some point. We don't know when.

But yeah, that'll be very provocative. So you touched on the possibility of even a neoadjuvant study with the radiopharmaceuticals, which is an eye opener. We're talking about post-lutetium, post-taxane, post-ARPI. And now we're all the way into neoadjuvant. So that's a lot to talk about. Mike, we probably need to wrap it up here in just a minute. But let me ask you, do you have any final comments or things that you'd like to say that we didn't cover? We covered antibodies, actinium, toxicity, clinical trial space, lots of cool stuff. Any comments you'd like to make to wrap up?

Michael Morris: As you open this discussion, we are presenting as a poster at this meeting the first trials-in-progress poster for CONV01-Alpha, which is the term now for actinium J591. It's somewhat of a new synthesis for making the molecule, and it's a dose optimization study for those with advanced disease that is castration-resistant disease.

There's a cohort that's pre-Pluvicto, and there's a cohort that's post-Pluvicto. Those have somewhat of a different dose escalation or dose optimization schedules. But I think that it's time for this drug to move into formal clinical trials and explore the potential of actinium radiolabeled antibodies.

We look forward to seeing what the results are. The trial is open and accruing. And on behalf of all the investigators, we'll be presenting this study at the meeting.

Oliver Sartor: Terrific. Mike, thank you for sharing your expertise—

Michael Morris: Thank you, Oliver.

Oliver Sartor: —deep, deep expertise in this space and helping to educate our viewers today. Thank you very much.

Michael Morris: Thank you, Oliver.