Utility of PSMA-PET in Intermediate Risk Prostate Cancer: Part 2

Neil Desai, MD, MHS, Associate Professor of Radiation and Oncology specializing in the treatment of GU malignancies at UT Southwestern Medical Center in Dallas, Texas, is interviewed by Daniel Tennenbaum, MD, chief resident at the Maimonides Medical Center urology residency program in Brooklyn, New York.

This is the second part of a two-part interview with Dr. Desai. Watch part one here.

Dr. Daniel Tennenbaum: Thank you for that. How do you think PET PSMA imaging is going to impact therapeutics in terms of whether radiation to metastatic disease, oligometastatic disease, using SABR technology? Where do you see radiation oncology utilizing this technology as a means for therapeutic treatment of disease?

Dr. Neil Desai: Yeah, so I think, again, same thing there, we’re finding things earlier, and so does that lead time give us actionability that improves the natural history… or affects the natural history disease? I think the jury’s still out, whether that’s true, right? We have certainly a couple different Phase II randomized trials, the STOMP trial by Piet Ost in the Belgian group, as well as Futran in the US, the ORIOLE trial, in which both randomized observation versus SBRT or SABR for oligometastates. And very interestingly, in Futran’s trial, he looked at a subset of patients who had PET PSMA, staging versus not, and it leads to the question being, “Well, if you got rid of all PSMA disease as compared to conventionally defined disease, you get better outcomes.” And yes, you did, in terms of delaying hormone therapy initiation, which is, I think, a meaningful endpoint, but not the same as survival.

So clearly, PSMA PET is going to help better define oligometastatic patients for treatment. Whether that, again, affects long-term natural history is a whole other question, but I don’t think we can ignore the fact that it changes treatment history at this point, which is important, right? It has quality life impacts. Secondly, I think in terms of the management of oligometastatic disease, and I think the question also is the question of treating the primary. In STAMPEDE, as we know, established level… at least level two data postop preplanned analysis based on stratification that primary site radiation improves survival in lower burden by conventionally defined imaging scans patients. But a lot of people are saying, “Oh, this patient has a lot more PET PSMA-defined disease than you saw on the conventional imaging.” I think you got to be careful there. I would advocate saying that you don’t know that those patients do not benefit to use double negative from primary site rated therapy, just because you found a lot more in PET PSMA. We know there’s more and we know that PET PSMA is insufficient. There’s more disease out there than you can see, okay?

And segueing from that, so I would say your low-burden metastatic patients cannot be defined by PET PSMA. It’s low-burden by conventional imaging for the selection of primary site radiotherapy. Last segue there is, in the metastatic setting, of course the question of, “Well, what do you do with these relapses after local therapy?” And I think there you’re seeing, again, the value of a negative PET PSMA scan. So in a PET PSMA scan, where you have these lymph nodes relapse, I think we’ve known long time now, from surgical series as well as SABR, that those single nodes you see is not all there is, there’s going to be more disease there. And I think we got to be careful, again, not to over interpret. I think you should treat these patients aggressively with regional salvage, but it has to be comprehensive in most healthy patients. I don’t think they’re going to be spot treatments. Spot treatments are more a philosophy for like the ORIOLE trial and STOMP, like I said in the beginning, for your delaying hormone therapy purely for a quality of life impact without really knowing if we’re going to impact survival long term. And that’s what’s worthwhile.

For radiopharmaceutical, as the last era on this continuum, certainly radiation, as we often say, is one of the best drugs we have for cancer in general. Now that’s a systemic therapy, I think we’re seeing the power of delivering a potent agent, like radiation, that’s not just cytostatic but actually cytotoxic, two areas of disease based on a highly specific, small molecule targeting, or antibody targeting, of PSMA, and I think that’s an area that’s going to explode for sure, and we’re just waiting to see what the big splashes will be in terms of CRPC in a CSPC setting.

And as you know, they’re moving into even the upfront, localized setting. And so very exciting times for us. I think we got to pair all this with an assessment of side effects, cost, and toxicity from the patient perspective. I don’t think we can get too excited, too early, got to test all these things. And certainly, we, in radiation oncology, have been guilty in the past about liking our new technology and throwing them out there. I think we can very quickly miss our window to validate the benefit of PET PSMA, in all these contexts I just listed out, if we don’t rigorously test perspectively. And I think people are doing a better job now than we did maybe 20 years ago.

Dr. Tennenbaum: When you’re mentioning radiopharmaceuticals, you’re mentioning things like Pylarify? Is that what you’re alluding to?

Dr. Desai: Pluvicto. So by radiopharmaceuticals, or therapeutic radiopharmaceuticals, will be what I was referring to, like Pluvicto, which is the trade name for the… which is in 177 targeting PSMA product by Novartis.

Dr. Tennenbaum: Got it, thank you. And yeah, actually, I’d read the ORIOLE study as well. Very theoretically appealing, although I can appreciate the nuance that you’re offering.

Dr. Desai: Yeah, and I think the PSMA targeting’s going to make an impact there. I think certainly, you’re right, if we have a PSMA stage patient with oligometastates, I feel a whole lot better that we’re going to drag out things.

Dr. Tennenbaum: For a few instances through our conversation, we’ve alluded to upfront treatment, focal therapy, lesional therapy. Do you envision or foresee a future where we’ll be using PSMA technology, maybe in combination with MRI technology, to offer lesional treatment as precise as possible to maintain the prostate gland without whole-gland therapy?

Dr. Desai: I think it’s already happening. And there’s two parts to this. One is the higher-risk patients where you’re trying to figure out, is there a sub-volume of the whole pros that you need to boost a higher dose? That way you can get the same benefits without side effects of higher-dose boosting the whole gland? And on the lower-risk side, can you just do focal therapies, like you said, to have… which is very in vogue right now, to get better quality life outcomes without sacrificing outcome. So on the higher-risk side, clearly MRI’s already established the principle, because there’s a Phase III randomized trial called the FLAME trial, that established a biochemical control benefit without increased side effects by doing lesion-only dose painting. This has now been written into our ongoing NRG-GU010 Phase III trial in the United States. We’re allowing micro boost, which is what’s called where you’re just boosting dominant lesion. And you’re planning the radiation as if you’re not doing any boost at all. So all the normal organs at the same dose, basically, as if you were not doing the boost, so you’re taking what’s free, as it were with the modern technology. And I think that’s very interesting.

The addition of PSMA to this will be, it’s very clear that if you look at the whole-mount versus MRI or PSMA imaging correlate studies, the MRI dominated disease is not one-to-one and it pixel to tissue. There’s going to be more disease than you can see on the gland, even with high-quality MRI programs. PSMA, when you add it to MRI, clearly is more sensitive to picking up the microscopic extent of the disease and better defining things about lesion boost. There’s ongoing German Phase II trial that’s using PSMA for that lesion boost through that purpose now as well. I’m very interested to see how their outcome will be, whether they get even better outcomes long term.

Lastly, in the converse side, like you said, for focal therapies, like HIFU, TULSA…a big program here at UT Southwestern, cryo, a lot of work being done in this area. Everyone’s focused on MRI right now, but you’re clearly under-treating disease, and that’s maybe okay in the lower-risk patients, because we don’t really see a major benefit of treating them anyways, which is my big criticism of a lot of focal therapy approaches. But PSMA should technically help the marginal failure risk in those patients. And yes, I know it’s more uptake in higher-risk disease, but you see it in your Gleason 7s as well. So if you’re stepping into the Gleason 7 world of focal therapy, which I think is highly controversial, I think PSMA has a role making sure you’re not missing the marginal disease.

Dr. Tennenbaum: How was PSMA utilized in your trial design? You mentioned about the NRG-GU010 trial, in our discussions before we started this interview, you had mentioned that PSMA technology was utilized in the design of the trial. I’m curious how you used it?

Dr. Desai: Yeah, so it was definitely… it was part of the discussion. So everything in our trial is based upon… anything in the current Phase III trials, most trials going through NCINC TEP are going to be, for good reasons, saying, “Well, wait a minute, you got to make sure you’re picking endpoints that are validated surrogates of survival as much as possible.” And that PSMA PET-detected metastasis is not necessarily the same thing as conventionally detected metastasis in terms of impacted survival. Like we just talked about, many trials before us, we would’ve picked up a lot of things on PET PSMA that you did not pick up now on conventional, or would not have picked up on conventional before. And so are those surrogates of survival in the same way conventionally-defined metastasis? Clearly not. And so right now, at least in the NRG-GU010 trials, as well as the other radiation trials that I’m aware of, almost all of them require a conventionally imaging-defined metastasis endpoint or metastasis trial endpoints as surrogates.

PET PSMA, however, people acknowledge is going to impact everything. We knew it was coming out. Certainly, other investigators knew it was coming out. And again, it’s going to impact both the stage migration end, and so there we’ll say, “Be careful. Give people the benefit of the doubt, don’t stage migrate them out of curable therapy based upon an iffy finding in the retroperitoneum, which may not be real.” So pretest probability’s important. And secondly, on the backend, for detecting relapses, you’re going to detect more of them earlier. So you can drop your metastasis rate by stage migrating people, but you might increase your metastasis rate by detecting it earlier. And I think people very smart people have modeled all this and come to the conclusion, we’ll see.

So I think the cleverest thing we saw from very discerning advisors on all these trials, I got to sit in as a junior investigator and listen of the very smart people designed this, is they basically make these as correlate endpoints, right? So they’re not the primary endpoint, but they’re very acknowledging this could be an experimental or sort of exploratory endpoint or secondary endpoint for that matter, where you’re looking at PSMA-defined endpoint and we’ll see how that all impacts everything in the future.

Dr. Tennenbaum: Sounds like there’s a lot that we are going to find out very excitingly in the future, hopefully not too far along. Not too far away. All right, well, Dr. Desai, I think that about wraps it up for us. I want to thank you for taking the time to speak with us and for educating all of our viewers, and me in particular. I very much value your time. Thank you so much.

Dr. Desai: Thank you so much for your time and being patient with me. And you have a great day.

Dr. Tennenbaum: You too, all the best.