For today's discussion, I'm joined by two leading experts in GU oncology, Dr. Rana McKay, who's a medical oncologist specializing in GU cancers. She leads the multidisciplinary prostate cancer clinic at UC San Diego Moore's Cancer Center, and is a professor of medicine and urology at the UC San Diego School of Medicine. Also joined by Dr. Michael Morris, who's the section head of prostate cancer of the genitourinary oncology service at Memorial Sloan Kettering. He's a full member of the Memorial Sloan Kettering Cancer Center and a professor of medicine at Weill Cornell Medicine.
Today is the last of a four-part series on radiopharmaceutical therapy in prostate cancer. I'm excited for today's discussion, which will focus on future directions, unmet needs in prostate cancer, particularly in radiopharmaceuticals. We'll explore the critical gaps that remain in care for patients with prostate cancer and discuss how various potential therapies, including radiopharmaceuticals, are beginning to shift the field away from more traditional standards of care.
So let's get right into it. Let's start off with you, Michael, and you've done a terrific job in leading the field and developing endpoints and regulatory standards in your leadership of the Prostate Cancer Working Group and in your roles as the medical director of the Prostate Cancer Clinical Trials Consortium and co-director of the joint unit that partners with the FDA to accelerate drug development. In the setting of metastatic castration-resistant prostate cancer, the current standard for regulatory approvals is the overall survival. How do you see this changing over the next few years?
Michael Morris: Thanks, Phil, and thanks for the kind introduction. I think that as a field, we've been migrating for some time now, especially with the adoption and validation of Prostate Working Group 3's rPFS definition. And indeed, if you look at the approvals of our most recent round of registration trials for ARPIs, for PARPS and for radiopharmaceuticals, rPFS has been if not the co-primary endpoint that has been part of the registration package, that's TITAN, ARCHS, PROFOUND, ARANOTE, VISION, PSMAfore, PROPEL, TALAPRO-2, MAGNITUDE, AMPLITUDE, all had rPFS as either the key or a key endpoint which led to registration. I think the challenge for the future is how is PSMA PET going to be part of that?
Now that we have a validated regulatory endpoint, what do we do in an era in which we have an interim endpoint based on the technology we really don't know how to use as a response or progression criteria?
We've tried to incorporate that into Prostate Cancer Working Group 4 to do what we did with bone scintigraphy in 3 and bring imaging up to the current contemporary standards, which would be PSMA PET, moving on from bone scintigraphy, but we are not there yet. It's not really ready for prime time as a regulatory endpoint, but it's incumbent on us all to work with the Prostate Cancer Working Group 4, incorporate PSMA PET into future prospective registration studies, and collect the data so we can get to endpoints other than OS or old rPFS ever more rapidly for future use.
Philip Kantoff: So how many years, Michael, do you think it's going to take before we incorporate PSMA PET scans as a regulatory endpoint?
Michael Morris: The truth is that around working group three, it didn't take that long. It was really the first registration trials for abiraterone and for enzalutamide that provided enough data to convince the agency that at least for selected agents, especially those that already had a clinical trial demonstrating overall survival, that rPFS was a legitimate endpoint.
So that was with real cooperative buy-in by multiple industry sponsors, big phase-three studies, all activating at the same time using the same criteria. If we can get the same level of collaboration between industry academia and the regulatory bodies, it could happen relatively quickly, but PSMA PET has to be paid for, which bone scintigraphy did not for this purpose, and so that is a singular challenge that we need to overcome.
Philip Kantoff: I just want to clarify something you said. You said rPFS can be a regulatory endpoint, but for that particular drug, there has to be some study that demonstrates an overall survival advantage, either as a co-primary endpoint or as a solitary endpoint, before you can use rPFS alone as an endpoint in a different stage of disease. Is that correct?
Michael Morris: Well, let's take VISION as an example, because this is about radiopharmaceutical. So if you look at the original design of VISION, it had dual endpoints, either rPFS or OS, and either could have hit for it to have been considered a positive study. But as it happened, we didn't have enough rPFS events for a variety of reasons, and so the trial essentially was driven as an endpoint with OS, but it could have gone the rPFS way had we had enough data in terms of rPFS events. So I think that there is some movement even in terms of first in disease trials without an OS primary endpoint, but as it turns out, you're absolutely correct. OS drove the VISION trial to its approval, and PSMAfore, which has an rPFS primary endpoint, does in fact have a trial showing an OS advantage preceding that.
Philip Kantoff: So just to be clear, let's say we had co-primary endpoints of rPFS and OS. OS does not hit, rPFS does hit. Is that an approvable-
Michael Morris: No, no. That has never been tested as a case study, and I'm not sure any sponsor wants to be the first to test that, but at least to date, all agents that have used rPFS as a primary endpoint in a trial have some study that preceded that study to show an OS benefit.
Philip Kantoff: Thanks, Michael. So let's move over to you, Rana, and talk about immunotherapies. Although we have a couple of immunotherapy approvals in prostate cancer, including Sipuleucel-T and checkpoint inhibitors in the context of high mutational burden, prostate cancer is generally considered a cold tumor. Are you optimistic about any of the potential developments in the IO space?
Rana McKay: Yeah. No, thank you so much for that question. Yeah, the track record for unselected immunotherapy in the form of PD-1, PD-L1 has really been humbling in the experience in prostate cancer, but that being said, I think we're really seeing a emergence, a renaissance of novel immunotherapy strategies for advanced disease. What is genuinely exciting me in this context are the T-cell engagers and the bispecifics. I think it's been a long road of working on refining the chemistry and the biology and the mode of administration of these T-cell engagers. This is not the first time that these are being developed, but a lot of really exciting agents.
Xaluritamig, which is a STEAP1 CD3 2+1 bispecific, showed really promising responses in early-phase studies and heavily-pretreated patients that is now advancing into phase-three. Another agent, which I think is one that I'm also really excited about and predominantly also really excited about this target, is Pasritamig. It's a KLK2 targeting T-cell engager, and what's really interesting about KLK2 is it's got almost 80% homology with PSA. It's actually PSA3, if you will, almost, and it's very specific to prostate cancer. And there's not a lot of expression of KLK2 on normal tissue. We don't really see much background above what's in prostate, and it's been modified to be able to be administered as an outpatient IV infusion every six weeks with a really mitigated CRS profile. So that's really advancing in several phase-three studies in mCRPC.
We're also seeing T-cell engagers to PSMA. I think some of the initial T-cell engagers have had issues with regards to mode of administration and CRS, and most recent data that were presented on a compound called VIR-5818, which again, the science and the chemistry continues to get even more and more exciting. And they have basically, the way that the drug is designed, there are proteins that mask the agent when it's in circulation to limit the toxicity profile, and when it actually enters into the tumor microenvironment, there are proteases within the tumor microenvironment that'll cleave the masking proteins so that it has an intratumoral effect, and we've seen quite impressive responses in very late-stage refractory disease.
So I think I'm super excited about these T-cell engagers, and honestly, not just in mCRPC, but their evolution across the landscape, even in hormone-sensitive and biochemically recurrent disease. So we're going to see a lot come down the pike in that regard.
Philip Kantoff: Thanks, Rana. So it does seem, I agree with you, that the CRS problem is becoming less of a prominent issue. We're seeing less hospitalizable CRS, maybe Grade 1, a little bit of Grade 2, so this masking technology, I'm speaking as a non-immunologist, seems to be taking hold. The issue that I see is one of durability. I don't know if it's an issue of T-cell exhaustion or something else going on, but what are your thoughts about the durability of responses and how do we extend the durability of these T-cell engagers?
Rana McKay: I think that's an excellent question. I think that's the holy grail is can we put people into deep remission when they have late-stage disease? I think the durability question is still early. I will say that at GU ASCO just this past February, there were data that were presented on the combination of docetaxel plus Pasritamig. We're seeing PSA-90s in 75% of patients, and when you look at the swimmer plots, many patients are still remaining on therapy even with the docetaxel being discontinued, and this is late-stage. This is early. This is phase-one, early data, but I think there are some signals of potential durability that I think the phase threes are going to really have to be positioned to really definitively answer those questions.
Philip Kantoff: So you're optimistic about combinations getting around the problem of durability, but maybe some more work on actually monotherapy improving durability would be in order as well.
Rana McKay: Yeah. And I think too, I think the Achilles heel of this targeting of the surfaceome, we've gotten so excited about targeting the surfaceome. There's so many cell surface proteins, STEAP, KLK2, STEAP1, STEAP2, KLK2, B7-H3, and now the drugs, the conjugated therapies are getting so great. You've got radiopharmaceutical conjugates, you've got now T-cell engagers, you've got ADCs and this whole concept of ... But I'd love to see a Venn diagram of all these cell surface targets and what the heterogeneity looks like in all the different disease settings, because I think the less heterogeneity I think is going to be key, the bystander effect is going to be important. So I think these are things that we'll have to contend with. I'm actually enthused about these agents in the earlier setting, potentially the hormone-sensitive setting when the disease is less heterogeneous.