Michael Morris: I think we're still in the beginning of the beginning of this field. Even though we think of Pluvicto as a very mature drug, now approved in the full spectrum of castration-resistant disease or APMR, as we announce, say according to work in group four, this is a period of really explosive discovery of both the optimal payload, the optimal targeting agent, and the optimal target. As Rana was just saying, the surfaceomics have created really new opportunities for bringing radiopharmaceuticals to a wide variety of disease states, ranging from adenocarcinoma to neuroendocrine prostate cancer.
So the question is what payload matches with what carrier molecule or targeting agent in what disease state, and in what disease distribution or volume? And it's definitely not going to be a one size fits all, and we definitely will need to think about not only combination studies, as Rana was saying, but also optimizing for a given patient that right molecule that targets the disease that they have, which may be very different from other prostate cancer patients, with the payload that's appropriate to that distribution and the place in the disease.
And as your question suggests, the different payloads will have a different role depending on where in the disease state a patient is. So for example, let's take the concerns around alphas that have come up. Is there long-term toxicity in terms of hemotox or is there long-term toxicity in terms of nephrotoxicity that would emerge in the very, very early patient that just is not a concern in the patient who is post ARPI, post-taxane? By the same token, where should those alphas be positioned? Will you get more bang for your buck if you do it as salvage after a beta or in the minimal disease state in conjunction with surgery radiation? Those are the two sort of extremes. I don't think we have the answer to that yet.
And then the last thing is in terms of selecting a payload. I wouldn't assume, for example, that Lead-212 and actinium-225 necessarily have the same side effects, even though they're both alphas. And I think that there are logistical issues that play a part here in terms of supply, manufacturing, transport to the patient. So what works for a center, for example in Indianapolis, which is the beating heart of payload synthesis, would that be the same as somebody in Nome, Alaska? I think that there are going to be a whole variety of issues that we have yet to really begun to scratch the surface of in terms of this right combination of feasibility, safety, and efficacy for a given patient.
Philip Kantoff: That's great. Let's be a little more specific, Michael, about the challenges in using actinium-225, challenges in using Lead-212.
Michael Morris: Lead-212 can be made quite easily with a small generator, but has a very short half-life. And so you can make it, but then you're confined to treatment centers within a certain radius of that generator, or you need to have a lot of generators that cover the country. So depending on the elimination half-life or the physical half-life of the tracer, those manufacturing issues really do come into play, much less also the biology of them.
If you look at some of the early trials of actinium small molecules versus early trials of Lead-212 molecules, these are small molecules, it does seem like there may be some differences in, at least for the PSMA-directed therapies, in salivary gland uptake, and so there may be different performance characteristics of these biologically as well.
Philip Kantoff: And on the Lead side, it seemed like the initial strategy was decentralization of production of Lead-212, but some of the companies are moving into a centralized facility and distribution model, and I don't understand that, how that will play out given the half-life being 10 hours. Do you have any insight into that?
Michael Morris: I think that for those that are working with Lead-212 who are looking at having a few centers that are producing the tracer, they're talking about having participating centers in those studies be within a feasible radius of those. But it's not like you have a single ... I remember in the old radium days, they make the drug over in Sweden and we wait a week for them to fly it over, clear customs in the US, and ship it by truck to the center that was participating in the trial. That can't happen with Lead-212. It has to get, as you point out aptly, it has to get to the treatment center quickly.
Philip Kantoff: Thanks, Michael. So Rana, let's move back to you, and you started talking about combinations, but let's specifically talk about combinations with radiopharmaceuticals. So what do you see as the most promising approaches with regard to combinations with radiopharmaceuticals? And how about the use of radiopharmaceuticals in early hormone-sensitive disease? Are you treating any patients in hormone-sensitive prostate cancer, to use the old terminology, Michael? And what are the opportunities there and what are the concerns? So combinations with radiopharmaceuticals and where do you see them evolving?
Rana McKay: Yeah, very good question. So I actually am super excited about combinations of radiopharmaceuticals with other agents, and I think if I had to bucket things, I would bucket into combining with other AR-targeted agents. I'd probably combine into targeting with potentially other DNA damaging agents, but we'll talk a little bit about that. And then I guess in the next bucket would be how do you target with immunotherapy and some of the exciting T-cell engagers that we just talked about? And Michael alluded to this a little bit, is can you actually combine alphas with betas and leverage different radiopharmaceutical properties of two different agents?
So first, I'll start with the AR-targeted. We already have actually a series of large studies that have looked at combinations. I think the first was ENZA-p that actually demonstrated that ENZA combined with lutetium not only improves PFS, but also overall survival in the context of that study. While not with a PSMA-targeting radiopharmaceutical, PEACE-3 is a landmark large phase-three study with a large OS signal in the context of combining radium-223, the first, I think, foray of radiopharmaceuticals in really solid tumor malignancies. I think it's the first agent ever to demonstrate a benefit in OS across any of the solid tumor malignancies, combining with ENZA in frontline mCRPC actually improved overall survival. I think some of the limitations of that trial has just been the context of the landscape evolving, and now our escalation of ARPIs in the metastatic hormone-sensitive setting. But we've been safely able to demonstrate that yes, actually, combinations work.
And I think to get to your point around hormone-sensitive disease, we've seen data presented from PSMAddition of course, which looked at the combination of lutetium plus ADT plus an ARPI for patients with mHSPC, and that study met its primary endpoint resulting in a statistically significant improvement in rPFS and an early trend in OS, so that data is still maturing. I think there's a lot of questions about integrating in the mHSPC setting, which we can get back to in the latter half of how much? Do you do adaptive dosing? How do you actually deploy the radiopharmaceutical?
I think with regards to the bucket of other DNA damaging agents, we've demonstrated in the context of our COMRADE trial, which looked at radium-223 in combination with olaparib, that actually, low-dose olaparib can be safely administered with a radiopharmaceutical with limited marrow toxicity. And that trial was positive, demonstrating improvement in progression-free survival of radium olaparib versus olaparib alone. That trial is not practice changing in any way, but it's certainly practice-informing, and I think it's one of the largest studies that demonstrated we can safely combine these two agents.
Of course, there's a lot of open questions about what's the impact of HRR-altered alterations in this context versus testing and unselected, and we really have to contend with the marrow toxicity and potential long-term marrow toxicity of those approaches. And I think the immunotherapy bucket, I think it's probably very immature. I think first, we've got to demonstrate I think that these agents have activity as single agents, as monotherapies, and there's appropriate rationale for combining, and similarly with the alphas and betas.
Shifting back to the hormone-sensitive space, right now, out of the context of the clinical trial, I'm not giving somebody a radiopharmaceutical for metastatic hormone-sensitive disease, but I think there's a lot of kinetics that need to be explored because the upfront response rate can be high. With PSMAddition, I think the PSA undetectable rate at 12 months was nearly 85%, so this is a highly effective therapy, and six cycles, is that sufficient? When should we scale back? When should we scale up? So I think these are all questions that are going to be really important to answer as the field evolves.
Philip Kantoff: I just want to add, in terms of combinations, Scott Tagawa has generated some really interesting data using CONV01-?, which is the radioantibody targeted at PSMA with actinium in combination with pembro, generating some very durable responses. Some patients three, four years without progression. And also data combining the radioantibody targeting PSMA coupled to actinium, along with a small molecule lutetium compound. And there's reason to think that at least preclinically, there might be synergy between the two, because the antibody which binds to the apical region of PSMA increases the uptake and retention of the small molecule, and you do see durable responses with that combination, even with low doses.
So let's move back to you, Michael, and talk about targets. We've really focused a lot of our attention over the past 20 years on androgen receptor, mismatch repair, PARP inhibitors, and most recently PSMA. And we talked about cell surface receptors and potentially internal receptors, which might become available to us even with radiopharmaceuticals. So what do you see as some of the more promising targets going forward?
Michael Morris: One thing that we haven't mentioned is our prostate cancer patient population that has no standard treatment options, that are really our greatest medical need, which is neuroendocrine prostate cancer. Now, there is a target for neuroendocrine prostate cancer that has a proof of principle in another disease that is small cell lung cancer, and that's DLL3 and tarlatamab. So I think as a target for neuroendocrine prostate cancer, DL3 is a really interesting target, not just for tarlatamab, but also for radiopharmaceuticals.
As you know, from our previous time working together, we have at MSK a DLL3 imaging scan, and we have a theranostic payer under development now as well. So I'd like to see some of our greatest patients in need of any effective therapy get a targeted therapy. That could be tarlatamab or another T-cell engager, could be a radiopharmaceutical, but I do think that those neuroendocrine prostate cancer patients have such a need for new therapies that targets, that focus on the neuroendocrine disease population are really important.
B7H3 might be one of those. Rana mentioned B7H3 in her discussion earlier. A very good target for adenocarcinoma, but it does look like B7H3 expression extends into the neuroendocrine spectrum as well, which is unlike, for example, a target like TROP-2, which is I think underutilized, underexploited in prostate and in the radiopharmaceutical world. But TROP-2 does seem to need AR. Whether it's functional and AR dependent or not, it doesn't look like it necessarily needs to be. You could have non AR-driven but AR-present disease, but it still does express TROP-2. So TROP-2 still covers, if not outright neuroendocrine disease, a fair degree of the adenocarcinoma spectrum of disease as well.
KLK2, Rana mentioned in the context of Pasritamig. We did work on a KLK2 alpha antibody therapy, and as we had presented a few years ago, it did have some toxicities that I think were dose-limiting. And probably if we're going to explore KLK2, I would favor going with a small molecule as opposed to an antibody. Some of those toxicities I think were related to the long elimination half-life of the antibody.
And we do have an active therapy with T-cell engagers with STEAP1. We don't have a radiopharmaceutical yet, but I think that it could certainly be a legitimate radiopharmaceutical target. I do get a little concerned in terms of STEAP1 because of the musculoskeletal side effects that we see with the T-cell engager, and if that is an on target effect, maybe a radiopharmaceutical isn't so great to be targeting connective tissue and skeletal tissue.
So that I think is the targets I think of most as needing further exploration and further clinical leverage and exploitation as we move forward in radiopharmaceuticals.
Philip Kantoff: That's great, Michael. Thank you. So Rana, I remember giving a talk at ASCO some 15 years ago about sequencing therapies, when life was a lot simpler than it is now. Now we have so many more therapies and so many potential therapies, and there's a paucity of really good predictive biomarkers still. Maybe you can speak to that. We need more, obviously. Tell us how you're thinking how this is going to play out in the next five years, how sequencing of all these therapies, existing and future therapies, are going to play out?
Rana McKay: Oh, very good question. I think this is a very challenging area that we as a field need to contend with because the way that we design our trials, it's very difficult to design studies that truly test the sequencing question, this better before this, that after this, so forth. What we're clearly seeing is an evolution with treatments moving earlier and earlier into the treatment landscape, particularly the ARPIs. Just today, ASCO plenary titles released on the 21st year of April, if you will, and PROTEUS is going to be presented of neoadjuvant ADT apalutamide in the perioperative space. We've seen data from EMBARK with a OS benefit of enzalutamide ADT in the BCR setting.
We're going to see this evolution of ARPIs moving much earlier on and potentially people being on therapies for even longer periods of time, and so I think actually the dynamics of the disease is also going to evolve, but these are big questions to contend with. And even for PARP inhibitors, for example, we've seen data from Amplitude that's going to be with the FDA approval for niraparib in the hormone-sensitive setting. We're going to see data from TALAPRO-3 with talazoparib enzalutamide for hormone-sensitive disease. So I think everything is shifting earlier, or shifting in those very high-risk patients to actually escalate, but there's going to be a lot of questions of how to do it right.
And there's going to be a lot of questions about where can we peel back? We're going to see data at ASCO as well from deescalation strategies in the mHSPC for patients that are exceptional responders, and so when do we need to escalate? When do we need to de-escalate? I think the integration of PSMA PET into all of this is also further complicating, and so I don't have an answer for you other than I think it's dramatically going to change and the ARPIs are going to move into localized disease. They've already moved into hormone-sensitive disease or BCR disease. We're only going to see more of that, and I think it's going to open up what do we do in late-stage with regards to some of these novel therapies we've been discussing.
Philip Kantoff: Yeah, I'm as optimistic as you are about moving some of these therapies into early disease, curing more people, prolonging survival, but as I think we would all agree, the biology that emerges for those patients who have been through all these therapies early is going to be really challenging and will need even more therapies in the future to attack those cancers that emerge. So on that note, I think we're running out of time here. This has been a fantastic session and appropriate for the last session of our four-part series. We're talking about the future. Michael, Rana, thank you so much. You're terrific. Appreciate your time and thank you all for watching this session.
Rana McKay: Thank you.
Michael Morris: Thank you, Phil. Thanks for having us.