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Daniel George: Hi, I'm Dr. Dan George and your host today for this section of UroToday. And I'm happy to introduce my guest today, Dr. Michael Morris, who is the section chief for prostate cancer at Memorial Sloan Kettering. Welcome, Michael.

Michael Morris: Thanks very much for having me, Dan. It's a pleasure to be here.

Daniel George: Yeah, me too. And looking forward to catching up with you. It's been now a little while since the VISION study and the TheraP study were published and now Pluvicto, or lutetium PSMA-617, has been used in practice. Tell me a little bit about these studies, because I think to some extent people may have forgotten a little bit what this indication was really based on.

Michael Morris: Sure. These are two very complementary studies. They address somewhat different questions. VISION was the registration study for Pluvicto. It was a phase-three trial in which patients who were registered were assigned a standard of care by their doctors. That could be anything that they wanted except for chemotherapy, immunotherapy, and radium. And then they were either randomized to that standard that their physicians put them on with Pluvicto, or that standard alone. So it's essentially a combination study. The primary endpoints were overall survival and radiographic progression-free survival. Either could have hit and the trial would've been declared a success. And all the patients had to have had positive disease on a Gallium-68 PSMA-11 PSMA PET. The results were a 60% improvement in rPFS, 40% improvement in OS, positive secondary endpoints in radiographic response, PSA 50 response, and preservation of quality of life and preservation of level of pain.

Daniel George: Perfect. Perfect. Let's stop there for a minute because that was really the pivotal study that led to the approval, and it was really, as you described, across the board positive for this population. But tell me a little bit about this population. These were PSMA-positive patients.

Michael Morris: They were.

Daniel George: How was that defined?

Michael Morris: So it was a pretty liberal definition actually. You had to have some lesion over and above the hepatic uptake. And the patients basically couldn't have PSMA-negative disease that met size criteria depending on whether it was the soft tissue component of a bony metastasis, a nodal metastasis, or visceral metastasis. And ultimately, most patients went on the study. So it's pretty practical criteria in which really the least likely patients to respond were excluded, but that really was just 13% of the patients that screen failed.

Daniel George: Interesting. So it's an eligibility criteria that really didn't change the population very much.

Michael Morris: Not much, no. No. Pretty typical real-world population as it turns out.

Daniel George: So, is it fair to say we should be treating pretty much everybody with a positive PSMA scan, or do you use that kind of criteria in your selection?

Michael Morris: I do use it, and I think that it's important to get that pre-treatment PSMA scan. First of all, if you have a patient who has PSMA-nil liver metastasis, I think there are better therapies than lutetium PSMA to go on. And so, I think from a treatment selection patient population, it is important. This is advanced disease. As you pointed out, all these patients were post at least one ARPI, and post at least one or two chemotherapeutics. So, this patient population really is in a difficult situation. They may not have PSMA-avid disease, and there have subsequently, we've presented data that shows that in terms of a nomogram or model that will predict for benefit, the PSMA uptake makes a difference. And it's good to know what your expectations are, both for you as a physician and your patient of the likelihood of responding and benefiting from this therapy. And that pre-treatment PSMA scan is part of that information, not exclusively. There are other elements that look in the nomogram to be important predictors, but the PSMA scan is probably the single most important predictor.

Daniel George: So, that's really helpful. So, just knowing that someone's got a lot of uptake on their PSMA, or uniform uptake on their PSMA, really helps you gauge the patient what they can expect going down from this therapy. And then, of course, there's PSA response and other things, but just talking about that upfront before-treatment expectation for the patients. What about the people, though, that have a little bit less than hot PSMA, but it's still present? How do you talk to those patients?

Michael Morris: I think it's a key issue because every patient's going to ask you, "Well, Doc, what's the likelihood I'm going to benefit from this?" Now, certainly, those who have PSMA avidity, of SUVs that are greater than 10, are your most likely to respond. Now that's SUV mean that we use, and that's not readily available. But on a routine scan, you could use SUV max, which is standardly reported, so that's at least some guidance. But what of those patients, what about those who don't have SUVs in that 10 or higher range? Well, if you look at those patients, they have a lesser likelihood of responding, and they don't have the greatest overall survival benefit relative to those who do have the highest SUVs. But everybody did better if they got Pluvicto, regardless of their SUVs than not getting Pluvicto.

Daniel George: And that's an important message, right?

Michael Morris: Yeah.

Daniel George: I mean, even if the benefit isn't as great, look, we don't get to choose this. Any benefit is a benefit. This is a patient population, on average, with a survival of less than a year.

Michael Morris: Yes.

Daniel George: Now, you made one other important point here, and that's that chemotherapy was excluded as a standard of care.

Michael Morris: Yes, it was.

Daniel George: That wasn't the case with the TheraP trial, right? Walk us through that one a little bit.

Michael Morris: That's why I think it's a really nice complementary study. Design-wise, it was quite different. It was a randomized phase II, not a phase III. The primary endpoint of that study was an absolute difference that was anticipated to be 20% or greater. That would be declared a positive trial in the PSA-50 response rates. These patients were doubly selected to be good candidates for radioligand therapy. So, they had both a PSMA scan and an FDG scan, and they were excluded if they had FDG-positive disease that was not PSMA-positive. They would be declared unlikely to benefit from this therapy. And indeed, the screen failure rate was 30% rather than the 10% that was seen in VISION. So, these were more rigorously selected. The control arm here was cabazitaxel in the patient population where those who had received docetaxel.

So, they were previously taxane-exposed, but they had not received maximal therapy in terms of chemotherapy. So, the control arm was cabazitaxel at 20 milligrams per meter squared. And the dosing of the Pluvicto was slightly different than in VISION, but still good doses of Pluvicto. They started at 8.5 gigabecquerels and then had decreasing doses with each subsequent dose. And the data for that trial was clearly, it was a positive study based on its primary endpoint. The PSA-50 response rate was more than 20% better in favor of Pluvicto. And it looked like that after six months, progression-free survival was also better in favor of Pluvicto. However, and again, this was a secondary endpoint, overall survival was about the same between the two treatment arms. And again, this speaks to having some circumspection about using PSA-based data to declare success or failure clinically, which we've learned so many times in prostate cancer.

Daniel George: And what about side effects? Were there differences in those profiles?

Michael Morris: There were. So, it really highlights the differences between PSMA-based radioligand therapy, especially with small molecules, and chemotherapy. So, more xerostomia and some GI side effects that were associated with lutetium. More neuropathy and neutropenia associated with cabazitaxel than with radioligand therapy. So, what we all see as the differences between chemotherapy and PSMA, small molecule-directed radioligand therapy were highlighted in this trial. And you could really see that, in particular, in the rates of neuropathy and neutropenia that you don't really get with radioligand therapy.

Daniel George: Right. Right. So, kind of pick your poison here. And it's nice to have a choice for our patients. I think, you know, it does suggest cabazitaxel, a reasonable alternative here to Pluvicto, but certainly, we can make the case that for patients that maybe we think fit that criteria, albeit without the FDG component, this is still really active therapy...

Michael Morris: Absolutely.

Daniel George: ... for this population.

Michael Morris: Now, I think what's important to recognize, as most of the clinical audience of this video know firsthand, most patients aren't eager to get chemotherapy, and most don't get cabazitaxel.

Daniel George: That's right.

Michael Morris: And I suppose the flip side of that TheraP trial is, if they are wanting lutetium, they're not giving something up that would otherwise confer a superior survival advantage. So, I think that there is a message there that usually we think about, well, shouldn't lutetium be superior to chemotherapy because the PSA decline rate is higher? Well, it's not. And by the same token, these are two legitimately valid options for this patient population. They're not mutually exclusive. Of course, some patients will get both, but patients do have a preference. And I think that TheraP, at least indirectly, sort of indicates whatever their preference is, is probably legitimate. But in a subsequent analysis with looking at who lived longer and who responded better in TheraP, and again, it's not quite like the model for VISION, which was a formal phase III with a survival-based endpoint, but still the PSMA scan avidity was the major determinant of response.

Daniel George: Good take-home message. One last quick question for it to end on. Are these overlapping? Are the patients that respond to Pluvicto the same patients that are going to respond to cabazitaxel? Or are we looking at potentially complementary strategies? You mentioned using them in sequence. What's your experience?

Michael Morris: So, we really don't have all the biomarker data that we need. And I guess the question is, which would be better, especially for the PSMA low-avidity population, the neuroendocrine differentiated population, those patients who have visceral versus non-visceral disease, which therapy might be better. I wish we had that perfect answer and the perfect dataset by which to analyze that. But I think we all in our heads are making that calculus with each patient who comes in, looking at their genomic profiling and looking at their mutational profile, looking at what the IHC on the pathology has shown in terms of Chromogranin and other stains. Looking at how well they responded to prior therapies and that pre-treatment PSMA scan, and ultimately making the best decision that we can as to which therapy should go up front, what does the next move.

Daniel George: Right. But more data for sure need to come.

Michael Morris: Yeah.

Daniel George: Wow. This has been great, Michael. Thank you so much for your time.

Michael Morris: Thank you, Dan.

Daniel George: My pleasure. On behalf of UroToday, appreciate you being here. Thanks.

Michael Morris: Thanks for having me. It's always a pleasure.