Zachary Klaassen: Hello, UroToday. My name is Zach Klaassen. I'm an Augusta, Georgia urologist. I'm delighted to be joined by Dr. Neal Shore, a urologist in Myrtle Beach, South Carolina. Neal, thanks so much for joining us post-AUA on UroToday.

Neal Shore: Thanks, Zach.

Zachary Klaassen: So we're going to discuss one of your exciting posters that you had on the Tuesday of AUA, looking at PSMAfore. Not just the data-- we've heard about that. I'm going to get you to maybe run through some of the highlights of PSMAfore, but really focusing on the health‑related quality outcomes that were collected. So before we get into it, just give our listeners a high‑level overview of what PSMAfore showed and led to the subsequent FDA approval.

Neal Shore: Yeah, thanks so much. The VISION trial, which was approved by the FDA and now in the guidelines, clearly demonstrated a statistically significant rPFS and OS benefit in patients who had-- with mCRPC-- who had progressed after a taxane, sometimes two different taxanes, and at least one, sometimes at least two ARPIs. So this is the first and only phase III trial that demonstrated that, and this really is a landmark trial.

So the Fore trial was basically same lutetium‑177 PSMA‑targeted radioligand therapy. But the patient population in Fore was pre‑chemotherapy mCRPC patients who had to have progressed after an ARPI. And we presented these results at ESMO last year. It was a markedly successful trial, meeting the primary endpoint of the rPFS-- a lot of crossover in that study. So the OS is trending positively. We actually have a publication pending on the final OS results in PSMAfore.

But our presentation at AUA 2025, Zach, was really looking at three different interesting aspects in the population. And just to remind our colleagues, patients received six administrations at the six‑weekly interval of lutetium‑177 PSMA‑617 versus sequencing from one ARPI to another. And that was the control arm.

I just told everybody what the positive results on rPFS were and a trending benefit in OS in the Fore. But what we looked at was SSEs, Symptomatic Skeletal Events-- typically, the things we're familiar with-- symptomatic pathologic bone fracture, cord compression, surgical orthopedic intervention, and palliative requirement for radiation for pain. And it was markedly favoring the lutetium arm over the ARPI switch or change, as we called it, in the poster-- markedly beneficial, a hazard ratio of 0.38.

The second key parameter that we looked at was the time to first SSE and looking, as I just mentioned. And then overall, looking at health‑reported quality of life, looking at FACT‑P and EQ‑5D‑5L. Again, a hazard ratio of 0.63 favoring the lutetium over the sequencing arm.

And so these were really broken down in time to worsening. And these were broken down additionally into other metrics inclusive of the bone pain index or the brief pain index, pain intensity, pain interference.

And so I think this is reassuring for colleagues, essentially, that in our conclusions, that the treatment arm, those getting the lutetium‑177 PSMA‑617 as opposed to sequencing, which is a common real‑world phenomenon in our resistant prostate cancer patients, really demonstrated a delay to time to worsening for patient‑reported health‑related quality of life pain, shorter median time to improvement after worsening in pain intensity as well, and a really consistent good safety profile that we're familiar with and similar profiles that you would see with sequencing ARPI.

Zachary Klaassen: Yeah, that's a great summary, Neal. And I think we've had a lot of excitement with PSMAfore, obviously getting FDA approval in the end of March of 2025. And I guess two questions.

When we look at this data that you presented at AUA, looking at quality of life, when we pair that with the rPFS benefit, how does that help position Pluvicto in that sort of post‑ARPI mCRPC setting?

Neal Shore: Yeah. So I think it's-- from my standpoint, I'm always thinking about if a patient's progressing on a line of therapy, I like the idea of offering them a novel MOA, Mechanism of Action. And I tend to really feel, and always have, that going from one ARPI to another is a fairly lateral move. You can make the argument maybe going from abiraterone to an ARPI has a little bit more value proposition. I don't think that's unreasonable.

But for our patients who are PSMA PET positive, which is about 9-- a little over 90% in the Fore trials, about 87% in VISION, so it's the overwhelming majority. And plus, we're using more PSMA PET now anyway with CT, certainly in earlier stage disease, you can offer patients now lutetium‑177 PSMA‑617, which is, by and large, pretty well‑tolerated.

I mean, you do the CBC beforehand. There's a small but real risk of myelosuppression, especially depending upon their tumor burden. It's not very giant, and it's very manageable. And there's a very small but important monitoring of both some low‑grade GI side effects, very low‑grade salivary gland effects and/or renal effects. So like other radiopharmaceuticals that we're familiar with, for example, radium‑223, it's a well‑tolerated drug. And it doesn't preclude you from other therapies.

Zachary Klaassen: Yeah, that's great. I think we're about six weeks from post‑FDA approval, as we're speaking today. Have you seen-- have you treated patients in this disease space? Have you talked to patients about it? Where are you seeing it in the real world already?

Neal Shore: Yeah, it's a great question. It's early. It's now incorporated into NCCN guidelines approved by FDA, which I think was really very forward‑thinking on their part. I think it's great for patient care.

Interestingly, we presented a poster at ASCO GU in 2023. Xiao Wei was the first author. I was second. A lot of the same steering committee folks were authors. And we looked at a couple of thousand patients who had commercial receipt of Pluvicto in the US. This is back in 2023. And even then, about 40% of the patients had only progressed on either a taxane or an ARPI.

So our colleagues were already starting to use it. I think we're going to-- this is going to really be an incredible impetus for many of our colleagues to now offer patients mCRPC post‑ARPI, which they could get when they're sensitive. Most are getting it then anyway-- low‑ or high‑volume mHSPC. And it can arguably now move into almost first‑line mCRPC.

You have other things to think about, too-- sipuleucel‑T, radium, possibly, a PARP inhibitor. But I think it's really going to open up a lot of options for patients and health care providers.

Zachary Klaassen: Yeah, you're absolutely right. And I think we could have a whole nother discussion on sequencing based on what they got in the mHSPC setting, what their genetic profile looks like. But great insight, Neal. Any final thoughts before we wrap up?

Neal Shore: Well, I just think it's really important to work with your multidisciplinary team. You have to have an authorized user to administer radioligand therapy. Could be a nuc med, a radiation oncologist, or even some med oncs and uro‑oncologists in a small percentage. But it's working together and I think optimizing patient options.

Zachary Klaassen: Yeah. Well said, Neal. Thanks, as always, for joining us on UroToday.

Neal Shore: Pleasure. Thanks, Zach.