Neeraj Agarwal: Hi, my name is Dr. Neeraj Agarwal. I'm a medical oncologist and a professor of medicine and oncology at the Huntsman Cancer Institute, University of Utah. It's such an honor to welcome our two guests on the UroToday during this 2025 USPCC meeting. First, Dr. Phil Kuo, who is a professor of radiology at the City of Hope, and he is specializing in nuclear medicine. And we have the Dr. Oliver Sartor, the well-known medical oncologist and a legend in our field. Thank you for being here today.

Oliver Sartor: Thank you, Neeraj.

Neeraj Agarwal: So a lot of new therapies are emerging. We saw PSMAfore data leading to Lutetium-177 or Pluvicto approval in pre-chemotherapy setting. Then we saw last year, P3 trials were presented, enzalutamide plus minus radium showing improved progression and overall survival by adding radium to enzalutamide, and then of course we have other options. But for this discussion I will focus on those patients who do not have HRR deficiency, do not have any other obvious genomic biomarkers which can be targeted. So this is a patient with metastatic hormone sensitive prostate cancer who was treated with ADT plus darolutamide plus docetaxel, and now is experiencing disease progression. You obtain a PSMA PET scan and it is positive. Obviously, for Dr. Sartor, Oliver, it's an easy question for you. What do you do next?

Oliver Sartor: Positive PSMA PET, meeting the criteria for VISION, post-ADT, post-ARPI, post-docetaxel, typically a PSMA-617 lutetium patient, VISION criteria met.

Neeraj Agarwal: Yes, of course, but docetaxel was given in hormone sensitive prostate cancer setting. It's a newly diagnosed MCRPC. Regardless of whether we look at VISION or PSMA-4, seems to be fitting the criteria for both.

Oliver Sartor: Not for PSMA-4. PSMA-4 specifically excluded the prior docetaxel treatment, so VISION was ADT, ARPI and a taxane, whereas PSMA-4 was only ADT and an ARPI.

Neeraj Agarwal: Great point. Thank you for pointing that out. Phil, what is your assessment of Oliver's viewpoint that patients should be getting Lutetium-177?

Phillip Kuo: Yeah, and Oliver and I have spoken on occasion [inaudible 00:02:52]. Oliver is an honorary nuclear medicine physician, he knows plenty, and we talk about as we move earlier and earlier in MCRPC or even earlier than that, it really provides an opportunity for more nuanced approaches. Things that are PSMA positive that meet the VISION eligibility criteria, Oliver knows as well as me, that was set intentionally as a low bar in VISION where patients had almost no options. We didn't want to exclude patients, a large number of them. We wanted to give them an opportunity. And just like in the PSMA-4 patient population and even earlier potentially, that I think is an even more opportune time to do a more nuanced way of selecting patients because they have more alternatives, and there's various ways to do that.
Oliver knows very well that there's multiple biomarkers that are very important. Some are imaging, some are non-imaging-based. Of course, as a nuclear physician, we focus more on the imaging-based markers and the PSMA expression, but I think that's a real way of fine-tuning who might be selected because after the NZP trial, I think the radium has returned to the discussion more than it has in the past.

Oliver Sartor: Let's talk a little bit about radium because we have level one evidence here, at least for the NCCN guidelines for three different alternatives. Number one would be the PSMA lutetium. Number two would be radium, but it'd be monotherapy and I'll come back to that, and would also be cabazitaxel as a second-line taxane. So the cabazitaxel I'll push to the side and focus on radium for a second. So radium in the original trial was looked at in metastatic CRPC, the ALSYMPCA trial.

Neeraj Agarwal: Which was also reported by you a long time ago.

Oliver Sartor: I happened to be the senior author of the manuscript and co-P on the trial. And what we found was that radium post either docetaxel or without prior docetaxel led to prolongation in survival, and that led in 2013 to the FDA approval, and so radium can be used as monotherapy.

Now, there was a new trial called the PEACE-3 trial led by Silke Gillessen, Bertrand Tombal, beautifully presented at ESMO last year, and what they showed in patients who had ADT plus or minus docetaxel but not prior ARPI, they used enzalutamide or enzalutamide plus radium, and you know what? It's a really nice result. The radium and enzalutamide had about a seven-month overall survival improvement over that of the enzalutamide alone, but that was front-line metastatic CRPC with no prior ARPI. That would be a great choice if this patient had ADT docetaxel but not a prior ARPI, as you mentioned with the darolutamide.

But think about radium as that bone-targeted therapy, and by the way, one of the things I'm going to mention a little bit later is if you do a PSMA PET scan and it's bone only, then you want to look at the bone scan because that osteoblastic metastatic process you see on the bone scan is the biomarker for radium. If you've got a robust expression of the osteoblastic lesion on the bone scan, good radium patient.

Phillip Kuo: Yeah, and that's what's so awesome about Oliver. He really understands our radiopharmaceuticals. Radium goes to that mineral component of the bone, not the cellular, and that's why we have to use our standard technetium bone scan agents versus PSMA targeted therapies which are going after those PSMA targeted cancer cells. So we use our PSMA. It's still theranostics but requires another level of understanding clearly. And the other thing to emphasize is that we talk about enzalutamide and the radium, but it was actually enzalutamide, radium and a bone health agent.

Oliver Sartor: Thank you. Very important point, Phil, and let me elaborate on that.

Phillip Kuo: Yes, please.

Oliver Sartor: It's so important. The way the trial was constructed, initially, there was a bit of an option on the bone health agent. That would be zoledronic acid and denosumab, but they had a monitoring committee, noted fairly early on an excess number of fractures were occurring and mandated the use of the bone health agents. And if you did not use the bone health agents, the fracture rate was exceptionally high, and by using the bone health agents, it turned out that you dramatically lowered that fracture rate and the outcome for overall survival was very favorable.

Neeraj Agarwal: Thank you for bringing this up.

Oliver Sartor: Thank you. Thank you, Phil.

Neeraj Agarwal: So bone modifying agents become more and more critical as we get more data to be used in the clinic. Coming back to the lutetium use, so this patient, you use lutetium because they fulfill the criteria for VISION trial having received or progressed on ADT plus ARPI plus having received docetaxel chemotherapy. I have two quick questions. Number one, what is the utility of radium after lutetium? Both are good drugs, both are associated with overall survival benefit during at least one phase of prostate cancer, and radium seems to be a very well tolerated drug to me, in my patients.

Oliver Sartor: We only have small anecdotal series. We don't really have full trials, and so at this point, I'd have to say the data would say that radium is safe, but we don't really know if it's effective.

Neeraj Agarwal: Phil, your viewpoint on this?

Phillip Kuo: Yeah, very much agree. Obviously, safety is very individualized, you need to see what their bone marrow reserve is, but one of the huge advantages of radium is it's very well tolerated by almost everybody. At least I consult patients that they shouldn't necessarily expect dramatic drops, for example in PSA like they may have experienced with Pluvicto before. That shouldn't necessarily discourage them, but it's one of the challenges I find with radium, is monitoring response to therapy. We can always get, for example, serial bone scans, but we don't quite have, I think, the robust personalized theranostics that we can do with lutetium and PSMA-617 that we can do with radium. It's certainly worth that attempt in a lot of patients, especially if they already have associated toxicities from chemotherapy before, you don't want to add to that, so it's certainly in our armamentarium to consider.

Oliver Sartor: Yeah, Phil, just to let you know, I agree completely. Monitoring post-radium is tough, and by the way, we're still struggling a little bit with even monitoring post PSMA lutetium because the way the trial was constructed, the prospective trials, we didn't build in the specs, we didn't build in the PET, and we had the conventional imaging, we had the PSA of course, but we're feeling our way forward and I think we're getting better.

Phillip Kuo: Yeah, absolutely.

Neeraj Agarwal: Any last comments?

Phillip Kuo: Well, it's been a real honor to be here at this first USPCC for me. As a nuclear medicine physician, I'm learning every minute and it's just been a really dynamic meeting and exciting to be here.

Oliver Sartor: Agreed, Neeraj. Great meeting and a pleasure to be able to work with you and Phil and the others that are here, because the truth is we're all teaching each other and that's fun.

Neeraj Agarwal: Yes. Well, thank you for being here.

Oliver Sartor: Thank you.

Phillip Kuo: Thank you.