Pedro Barata: Hey there, and welcome to another video from UroToday. We're here at AUA 2025. I'm really excited to be joined today by Dr. Scott Tagawa, really a key opinion leader in the GU world, particularly in prostate cancer. Dr. Tagawa is the director of the GU Research Program at Weill Cornell in New York. Thank you so much for joining us today.

Scott Tagawa: Thanks very much for the invitation.

Pedro Barata: Absolutely. I'm Pedro Barata, a GU oncologist and trialist out of University Hospital Seidman, Cleveland, Ohio. So today we're going to talk a little bit about the fantastic work that you presented here during AUA. And, of course, I keep following your work. You've been working on radioligand therapy for quite some time. You've acquired a huge experience on it.

And this goes way beyond lutetium PSMA, which is perhaps where most of us are more familiar with, a therapy approved for metastatic castration-resistant disease. And we'll talk a little bit about changes, but you have been working on different structures or different compounds that would turn diagnostic potential, not just beta particles, but also alpha particles.

Today, we're going to be talking about not just small molecules, but also antibodies. So can you please tell us a little bit about what is special about the construct here, your PSMA? Can you tell us a bit about the characteristics of that compound that make it an attractive therapy to use in prostate cancer?

Scott Tagawa: Sure. I like to think they're all special. So I think everyone knows, especially people that watch these videos, know what PSMA is. But very simply, a cell-surface target on the majority, but not all, of prostate cancer cells and some other normal areas in the body.

The first way that we, before me, were targeting PSMA was with antibodies. Those, capromab or 7E11, eventually became a marketed imaging compound—indium-111-radiolabeled capromab. That didn't work so well, in part, because it bound to the internal portion of PSMA so couldn't bind viable cells.

And then my friend and mentor, Neil Bander, came up with four different antibodies that bound to the external domain. J591, now called rosopatamab, is one of them. And a number of different compounds using that have been developed over the years. First, a couple of betas—yttrium and lutetium—and then, more recently, actinium.

So one thing that is different with antibodies versus small molecules is really the physical property—their size. So, by being larger size, they circulate through the bloodstream for a lot longer.

Pedro Barata: OK.

Scott Tagawa: And that has advantages and disadvantages. Advantages is it continues to target over days rather than just hours. So if I don't hit the tumor today, I have a chance tomorrow. And that's probably more important for the lower PSMA-expressing tumors. And then it's also too big to get into some of the areas where there's nominal expression of PSMA, such as salivary glands, small intestine, kidney, et cetera. But in exchange, it circulates longer through the bone marrow, is cleared through the liver, so there could be those other types of toxicities. That's loosely what is there.

The more recent version that we've been working on since 2017 is a version that has actinium-225. So it's an alpha emitter, emits four alphas, much higher linear energy transfer—something called potency—over a shorter range.

Pedro Barata: OK.

Scott Tagawa: And we're working through that really over the last several years, have now not necessarily completed but completed some and have ongoing work across five different clinical trials, and at AUA 2025, presenting two different analyses of these trials.

Pedro Barata: Perfect setup. So let's dive into that because you have dozens of patients—actually more than 100, I believe—patients treated with this therapy. And one of the works you presented here has to do with just comparing patients who got the actinium PSMA by itself versus tandem therapy, as we call it, or combination therapy of the alpha with a beta emitter, whether it's in I&T or lutetium. Can you give us a highlight? What did you find? Is it combining better than giving the drug by itself?

Scott Tagawa: So as a medical oncologist who treats all GU cancers, including testis cancer, I think that the main way, other than rare immunotherapy complete responses that are very rare in prostate cancer, really is combination therapy, I think, as long as we can do it safely. I think there's going to be the higher chance of cure, or, if that doesn't happen, at least the chance of a longer, deeper response. That's what I believe to get around heterogeneity, resistance, et cetera. That's what we've done in medical oncology for many, many decades.

So two of the combination studies, one of which I'm remembering was discussed by you at ASCO 2023, were two different PSMA targeting agents—using the antibody and using a small molecule. What they have in common is both targeting the tumor, but their other parts are not really overlapping, so the toxicity profile is overlapping. And then we also combine alpha and beta, and if you ask any physicist, alpha plus beta is going to cure more tumors than alpha alone or beta alone.

So we did that, and that was one of the combinations. And then many people are looking at radiation and immune checkpoint inhibitors across different diseases. One way to do that in prostate cancer or other cancers is to use systemic targeted radionuclide therapy. So it was an AR inhibitor plus pembrolizumab and actinium-225, and we've analyzed and presented the phase I portion, so that was also included in our combination studies.

And then the single agent was the first-in-human phase I, which was a single dose of the drug. And then the study that was partly presented at AUA last year, which was the fractionated dose—half today, half two weeks later—and the spread-out every six weeks multiple dose. So those two combined were the single-agent combinations, and we looked at efficacy and safety combining those two—the two that had more than one drug and the two that had one drug.

Pedro Barata: Right.

Scott Tagawa: So basically, what we found is that responses—measured by PSA—were a little bit more with the combination than the single agent, but not when we corrected for multivariate analysis. So similar multivariate analysis, but PFS, and especially OS, were different with the combination—small phase I/II studies, hypothesis-generating, but it is in line. It does give credence to the hypothesis that a combination is going to be better in the long run.

Pedro Barata: Right.

Scott Tagawa: So I found that interesting. In terms of the other side, the adverse-event rate—not a huge difference across the board—but it did look like the combinations had a little bit more in terms of the high-grade adverse events, which is not surprising. More than one drug may have a little bit higher toxicity profile than a single agent. So none of those were really surprises.

Pedro Barata: Got you. So let me touch on the safety piece because that has been, obviously, an important consideration. It always is, particularly when we bring novel therapies to the table. We want to make sure that the toxicity is OK in the short term, but it's also safe to do whatever systemic therapies coming next need to be offered to the patient.

So I'm sure that it will cross the mind of many of us—do you have follow-up? What can you tell us about what is going on with the patients as far as long-lasting cytopenias if that's the case, as far as maybe renal toxicity, because there's a limit to how much radiation you can get, and the ability to receive subsequent therapies is also a topic incredibly relevant in the context of cancer because we try to talk about sequencing. And if we're moving these agents early on, perhaps that conversation makes a lot of sense.

So what have you learned—and I'm asking you a question because you have dealt with these therapies for a long time, so you actually are in a very good position to provide thoughtful insights about—is that considered real? Is it not? How do you see the long-term impact of doing combination approaches, if you will, or even monotherapy with these particular regimens, using an antibody that stays in the body longer? How do you see that?

Scott Tagawa: So the AUA 2025 presentations are not focused on long-term adverse events. We are literally doing an analysis right now in preparation, perhaps for ESMO, where we are looking at this. And so, yeah, we do have some patients that are more than a decade out after lutetium PSMA.

Pedro Barata: Wow.

Scott Tagawa: Because we started—actually before me—in 2002-2003 were the first lutetium, yttrium patients. So we're looking at that. Importantly, some of the adverse events for certain organs that we worry about, really the kidney and the bone marrow. Yes, things can happen within months or one or two years, but the major problem—if it happens—could be 5 to 15 to 20 years. So definitely is there. There are now published reports of MDS and AML. Hard to know.

Pedro Barata: Right.

Scott Tagawa: If it was causal or not because we don't have long-term randomized data, but we certainly know it's a risk for chemotherapy, for when we used mitoxantrone for a long time, PARP inhibitors. So it definitely is a risk. It does look like it is a small subset, but hard to know what is that subset.

More directly answering your question about the combination, I think combinations such as upfront AR plus PSMA are going to be at risk for longer term in a good way, because I think we're going to do much better. They're going to live a lot longer.

Pedro Barata: Because they're going to be around with tumor control.

Scott Tagawa: So that's my hypothesis. We'll see what happens with ongoing studies, but I think that's something that we'll have the fortunate problem of needing to monitor.

Pedro Barata: So I guess my last question before I let you go, Scott—amazing thoughts, by the way—is, do you envision a world, and if you do, how far are we from there, where we might actually be talking about combining a beta with an alpha—not necessarily actinium, lutetium, but maybe other companies? Do you envision a world of combination, not just combining with an ARPI, in advanced prostate cancer?

Scott Tagawa: I think so. So one study—the phase I—was already presented. Another study, I think, finished accrual, called AlphaBet. So alpha-beta but different targets—PSA and hydroxyapatite in terms of radium. So that's the study being done in Australia. That is, I think, fully accrued, and we'll see some data probably in the next year or so.

That makes sense because there are two approved agents with that. So I was using investigational agents; these are two separate approved agents that theoretically I could prescribe today. I won't until I see the efficacy-safety data.

Pedro Barata: The efficacy data.

Scott Tagawa: But one of the possibilities we think about—testis cancer, other cancers—is with combinations backing off slightly, with some of the drugs having better efficacy and maybe not so much in the way of excess toxicity. So it's possible that some of the combinations might actually be safer in the long run, but we need the data.

Pedro Barata: Well, this is wonderful. I want to congratulate you because you are really pushing the envelope in this area. Obviously, it's a very hot area measured in many different ways, and I want to congratulate you for actually pushing the agenda forward on the RLT world. It's a pleasure always to talk to you. I always learn talking to you. So thank you for taking the time being here with us today.

Scott Tagawa: Great to be here. Thanks.