Michael Morris, MD, Prostate Cancer Section Head, GU Oncology, Memorial Sloan Kettering Cancer Center, was interviewed by Akhil Saji, MD, urology resident at New York Medical College/Westchester Medical Center on the future of PSMA-targeted therapies in APC.

This is the second video in a two-part conversation with Dr. Morris. Watch part one of this discussion to learn more about PSMA-targeted therapies.

Akhil Saji, MD: So moving on to more advanced prostate cancer, we have this group of patients that we categorize as having non-metastatic castration resistant prostate cancer. And could you talk a little bit about how PSMA PET imaging can potentially change that diagnosis and what that holds for those patients?

Michael Morris, MD: Sure. We’re going to have a stage migration of those patients to metastatic disease if they’re high risk enough. So if you look at where those patients who are at risk dwell in terms of those risk strata, that’s basically rapid doubling times of 9 or 10 months or faster. And previous studies have shown that the majority of those patients have imageable disease. If you take those criteria, for example, from the SPARTAN trial, it’s been demonstrated that those patients that meet that criteria, basically all of them have imageable disease and about half of those patients have imageable metastatic disease.

So you’re going to have a stage migration from those patients to just calling them some terminology, which allows them to be designated as having visualized disease on a scan. From a treatment paradigm standpoint, nonmetastatic CRPC has drug approval that is quite overlapping for metastatic CRPC, enzalutamide, apalutamide, darolutamide, they’re all approved for both. So just diagnosing that disease earlier won’t necessarily open up some window of treatment opportunity that those patients were otherwise not able to access. But you will be recategorizing those patients and you just need to be careful when you do recategorize those patients that you’re not implying that they’re living longer with metastatic disease, you just diagnosed it earlier.

Akhil Saji, MD: Right. Okay. Very interesting. So moving on from diagnosis to more therapeutic options or utility of PSMA, can you talk about the mechanics of how PSMA is being utilized with therapeutic interventions?

Michael Morris, MD: Absolutely. So the field of theranostics is that which marries diagnostics and therapy. And in fact, the word theranostics is the marriage of therapeutics and diagnostics. The scientific basis of that is if you can image a molecule, then you can swap the radioactive payload from a PET tracer to a therapeutic dose of radiation. And that can be either a beta emitter or an alpha emitter, typical beta emitters are lutetium, typical alpha emitters are represented by actinium. And so if you can image the patient’s disease, you can treat that patient’s disease by virtue of moving from a diagnostic radioactive payload to a therapeutic one. Lutetium is the more commonly used, it’s a beta emitter, but actinium also looks like it’s very promising in terms of developing in the future and that’s an alpha emitter. The difference between the two being that beta emitters are generally lower energy, but have a longer pathway, alphas more energy, but through less tissue. So in boxing terms, alphas have a more forceful punch, but less reach.

Akhil Saji, MD: Very interesting. So I remembered reviewing the results of the VISION trial that was demonstrated last year. Do you mind briefly summarizing those results and also kind of talking about which ongoing trials for the results you’re most looking forward to?

Michael Morris, MD: Sure. So the VISION trial was the registration trial of lutetium 177 was the payload. The targeting molecule is called PSMA 617. It’s a small molecule that based on a urea core developed by Marty Pomper at Johns Hopkins. And the VISION trial was a randomized phase three study of patients with abiraterone or enzalutamide or some other androgen receptor pathway inhibitor, pretreated patients who had also received at least one regimen of a taxane based chemotherapy, if not two, who also had a positive PSMA PET scan. And these patients post ARPI and post-taxane chemotherapy with metastatic CRPC were randomized after their clinicians had put them on some standard of care, which could not be more chemotherapy or radiopharmaceutical therapy. They were randomized to either that standard of care plus lutetium or that standard of care alone and the lutetium was delivered in its conventional manner of four to six doses given every six weeks.

And those patients who received the standard of care did not receive lutetium. The primary endpoint was overall survival and there was an alternate primary endpoint of radiographic progression free survival as defined by Prostate Cancer Working Group 3. The trial to summarize showed really that all of its primary, as well as its secondary endpoints were met. The lutetium relative to just the standard of care alone, prolonged survival, prolonged radiographic progression free survival and preserved quality of life. And that was shown over the course of two meetings, one at ESMO and one at ASCO, and then in the New England Journal of Medicine publication. So it was the hazard ratio, we yielded about a 40% improvement in OS or put another way, a 40% reduction in the risk of dying and even greater gains in terms of RPFS, as well as prolongation of quality of life.

Akhil Saji, MD: And those are very once again, very interesting promising results. Are there any ongoing trials that you’re looking forward to?

Michael Morris, MD: Yeah, so that VISION patient populations really quite advanced, right? Those patients have very few remaining treatment opportunities that VISION represented, but in almost every other prostate cancer therapeutic that we’ve developed as a community, those gains are amplified in patients who receive therapy earlier, as opposed to later. So there are two large phase three studies that are testing lutetium, PSMA 617 in earlier clinical contexts than the one that VISION represented. So one is the PSMA4 trial that’s in metastatic CRPC post an androgen receptor pathway inhibitor, but pre chemotherapy. And that trial’s a randomization to either the androgen receptor pathway inhibitor that they didn’t receive for castration sensitive disease or lutetium for six cycles with an RPFS primary endpoint.

And then there’s a PSMA edition trial. That’s looking at newly diagnosed patients with castration sensitive disease metastatic, and that’s a randomization between ADT and the androgen receptor pathway inhibitor of physician’s choice plus or minus lutetium and that has an RPFS primary endpoint as well. So both of those will bring the lutetium basically from the latest phases of prostate cancer, to even the earliest diagnosed patients with metastatic disease. So all three of those trials, VISION, PSMA4 for and PSMA edition are looking at patients with metastatic disease.

There’s also a small exploratory studies even in the pre metastatic population. And then there are several combination study that are worth keeping your eye out on one is with PSMA 617 in combination with the PARP inhibitors and the other with immunotherapy, with the checkpoint inhibitors. So those are the trials I’m keeping my eye out for the combinations trials and the earlier studies. I think all of us as a community are interested in further developments in terms of actinium-225 so looking at the alpha emitters. Both in terms of upfront therapy with lower radioligand therapy and as salvage therapy after lutetium. So in other words, there’s a lot to keep your eye on.

Akhil Saji, MD: Right. Yeah, no, I will eagerly await the results of those studies. And going back to the VISION trial, this is my last question for you. I noticed that there was about 13% of the patients, they didn’t have PSMA positive disease. Could you comment on what role PSMA directed therapy has in these patients, if any, and what other targets or that are potential on the horizon?

Michael Morris, MD: Sure. The idea behind theranostics is that you’re not going to treat patients who don’t look like they have the target, because if they don’t have the target, it’s unlikely that patients will have a significant amount of radiation delivered to their cancers. And hence the VISION trial did exclude 13% of the patients because their cancers didn’t have enough PSMA expression. The criteria actually for the VISION trial were relatively conservative relative to other studies of PSMA 617, which had higher thresholds in terms of letting patients into those trials to receive therapy. So most of the other prospective trials that preceded VISION had more restrictive entry criteria based on the imaging and indeed those restrictions were not exclusively limited to PSMA imaging, but also included FDG PET imaging. Those other prospective studies, both of which were conducted in Australia and one of which was through [inaudible] as well used at combination of therapy. So they couldn’t, they couldn’t enter into those trials unless they both had PSMA rich tumors, and also didn’t have areas in which there was PSMA negative disease that was FDG positive.

And it’s possible that with that additional enrichment, those patients did have greater responses. Their PSA responses in those studies were somewhat higher than those seen in VISION. And so we have to sort through what the role is for really two questions. First, who’s going to be the best patient to respond to lutetium and radioligand therapy, how much PSMA expression do you need and how many PET scans should you have to establish those criteria. But also you don’t want to set barriers so high such that patients who have few other choices are precluded from getting potentially life prolonging therapy, even if they may not be the best responders, but look, some of those patients, that’s all that they have.

So there’s a balance there, and we’re trying to sort through as a field, what that balance is. Clearly though, there are some patients for whom this therapy is simply inappropriate. And if you don’t have PSMA expression at some level, you probably should move on onto other therapies. And those could be other therapies with other targets. And depending on what those targets may be, some patients will have genetic mutations that make them candidates for trials that target all the genetic alterations. Maybe there are MSI high patients and should get immunotherapy. Maybe those patients are HRD positive and so they should get PARP inhibition. Maybe those patients have neuroendocrine differentiated disease and they should get chemotherapy. So there’s still a whole world of other therapeutics than those that are PSMA directed that patients may be candidates for.