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Alicia Morgans: Hi, I'm so excited to be here with Professor Michael Morris of Memorial Sloan Kettering. Thank you so much for being here with me today.

Michael Morris: Thank you for having me, Alicia. It's a pleasure.

Alicia Morgans: It is always a pleasure to talk to you too. And today, I really wanted to pick your brain on the prostate cancer highlights of ESMO 2023, a really exciting meeting.

Michael Morris: Well, I think a lot of attention at ESMO went to other diseases than prostate, but I would say that there really were some very key presentations at ESMO that there should be awareness about. One of those was a trial presented by Dr. Kevin Kelly of Jefferson of a drug called AMG 509, which is a bispecific antibody that is on one hand targeting a molecule called STEAP1, and on the other, CD3. And historically, immune therapy has not been a power hitter in prostate cancer. The age of checkpoint inhibitors yielded only for the MMR population, one meaningful application of immune checkpoint inhibition. And despite really thousands of patients and even more in resources, there hasn't been any strategy to expand that use or find some combination that turns prostate cancer into a hot tumor. But AMG 509 was a bridge into a possibility of an application for immunotherapy for prostate cancer.

This was a clinical trial. It's an early phase study. It's still in its dose finding phases right now, optimizing the dose and the schedule to either a one-week schedule or a two-week schedule. There's a series of priming doses that are given as an inpatient in order to mitigate CRS and be in a safe situation in terms of treatment. And from a side effect profile, CRS is part of that side effect profile as is fatigue, muscle aches, arthralgias and myalgias and fatigue. But really the key thing here is that it really looks like an active drug with significant reductions, not just in patients' bony disease, but also in some of our worst prognostic indicators, visceral diseases, even liver disease. Real responses, either PRs or CRs.

And whether or not AMG 509 is the drug that ultimately gets FDA approval as a first immunotherapy other than pembro in that really small population that has MMR or not, this is an entryway to a set of possibilities because there are a number of bispecific molecules out there that perhaps we really have a technology now, a platform on which to build to make immunotherapy part of the armamentarium for more than just a very select group of prostate cancer patients.

STEAP1 we had examined in an imaging trial in conjunction with a therapeutic trial that was led by Dan Danila at Memorial is expressed in most prostate cancer patients. So at least the early credentialing of the target's been done. But this is an intervention with a therapy that really holds the promise for patient benefit.

Alicia Morgans: So tell me a little bit about this too, because when we think about a phase 1 trial, these are usually patients who are heavily pretreated. Can you comment on that?

Michael Morris: Yeah. These patients were in essence similar to most of our phase 1 studies. Most of them were pretreated with chemotherapy. The trial did allow chemo naive patients. But I think that the profile, when you look at the demography of the patient population, it rings true that this has activity in very advanced disease. And so I don't think that this is a cherry-picked population where a therapy will only have a narrow lane to travel. And indeed, I think it would be very reasonable to begin those plans of moving this drug earlier. Because probably, if this class of drug follows all other classes of drugs in prostate, save for perhaps the radium experience, probably the most benefit's going to be in earlier patients. And I think it's a reasonable thing to think about that now that you have this early signal. And I guess usually we don't start talking about efficacy in phase 1.

Alicia Morgans: No.

Michael Morris: So you're seeing something here that the community is now talking about, because there really is a signal even at this early dose finding stage.

Alicia Morgans: Yes. To your point, that's extremely unusual. Phase 1 is really for dose finding and exploration of adverse events, and I want to dig into that in just one second. But to see signals suggestive of efficacy in phase 1 is highly unusual. So just to dig into the adverse events a little bit. Fatigue, obviously with so many of our studies, this is something we see, but cytokine release syndrome or CRS can be a little bit more difficult to manage. And in this study, this was something that the investigators had to do for those patients. What are your thoughts on cytokine release syndrome or CRS as this does move into hopefully phase 2, phase 3 trials?

Michael Morris: So a few things. First, CRS is something that I think as a phenomenon most prostate cancer doctors aren't familiar with, but CRS is part and parcel of other diseases and their treatments. So I think the prostate cancer community will need to learn how to manage CRS, and that's something that's going to be new and perhaps challenging to some. But we are a dynamic group. We didn't think we would need to know about PARP inhibitors and we did or how to interpret genetic studies, and we did. And we're going to need to expand our clinical skillset to manage CRS that especially in the hematologic world they see all the time.

Now, having said that, earlier forms of these bispecific antibodies had much more frightening CRS. If you recall, before, this STEAP1 bispecific antibody, the same sponsor, Amgen, had a PSMA directed bispecific antibody. And there was significant CRS that was seen. I've had patients on both of these trials. The CRS that's seen with AMG 509 is really pretty modest relative to other levels of CRS. CRS can result in profound hypotension, organ dysfunction, and can be a really frightening event on the floor or even worse in your clinic. But having said that, I think that for the latest iteration of bispecific molecules, and I'm not just talking about this one because other companies have other bispecifics or Janssen, for example, has an hK2 bispecific. This CRS is manageable. It's lower grade CRS, and with a respectable skillset, I think most oncologists will feel comfortable managing these patients.

Alicia Morgans: That is definitely encouraging. And as you said, we can learn. We are educable people and we can learn and expand our skillset as we have countless times in the advanced prostate cancer setting. So not to dwell on this, but just to ask if you have any thoughts, pembrolizumab was also tested. As you said, additional immunotherapy data came out at this meeting, both in the metastatic castration resistant and metastatic hormone sensitive settings. Any thoughts on these trials?

Michael Morris: Yeah, there were several presentations of checkpoint inhibitors back to back, all negative. I think that the reiterative message is there's just not a role in combination or alone for anyone who does not have a mismatch repair defect.

Alicia Morgans: Okay. Well, that's short and sweet.

Michael Morris: Those were short and sweet presentations. It was like, this was a negative trial, overlapping survival curves, end of presentation.

Alicia Morgans: Yes, but important nonetheless.

Michael Morris: Oh, absolutely.

Alicia Morgans: Important for us to see this because I think there's been a lot of thought and hype and excitement around this, but in an unselected population, this role does not exist for this particular approach.

Michael Morris: I think that the only controversial thing that one could say after those two presentations, Misha Beltran provided the... It was to discuss it. And her last line was that this field warrants further study. But now that we have a new avenue to pursue immunotherapy, I personally am not sure that more resources on trying to get blood from this particular stone is going to be successful. And we now have some really active families of drugs that we could focus our energies on.

Alicia Morgans: Well, I think that's all fair. So let's move on to something else that was actually quite exciting. The ENZA-p trial was also presented. Can you explain the trial and then tell us your thoughts?

Michael Morris: Sure. The idea behind this trial is that as most will know PSMA is modulated by AR signaling. And so there are preclinical models, this literature has been around for a while now, that show that you can modulate PSMA expression by AR inhibition, especially in its castration resistant space. It's a little bit more complicated in the castration-sensitive space. The investigators of ENZA-p had the idea of bringing that known biologic relationship into contemporary therapy and applying as first-line therapy for metastatic CRPC. Applying enzalutamide, reducing AR signaling, and then applying radioligand therapy with lutetium-177 PSMA reactive treatment. It was a randomized phase 2 study.

One of the most interesting aspects of that trial as well, was an articulation of a new way of dosing radioligand therapy that I think needs to really be considered in all future radioligand therapy. And that is an adaptive dosing schedule.

First, in terms of the results of ENZA-p, we will need to see how those results play out. We know that, for example, in the therapy trial, there was an early signal that everyone was excited about in terms of PSA decline that did not result after enough follow-up time in a survival advantage. Interim or intermediate endpoints, they're always encouraging when they're positive, but they're not definitive. So I think we'll need to see what comes next from that group in terms of clinically validating the early results of this trial. Certainly it's encouraging, but we'll have to see how those play out in more definitive study with harder clinical endpoints like OS.

But even independent of that is this design issue, which if you think about how we right now are giving radioligand therapy, regardless of the response of the patient, we are giving six doses every six weeks. And in many respects, that is not rational. So let's say after two to three doses, a patient has a complete response. Their PSA is zero, their scans are clear. It's hard to understand why we would give another three doses because essentially you have no target and the dosimetry is such that since efficacy for this drug, which is essentially radiation is dependent on the delivery of radiation. If you can't see anything that you're treating, the dose is very low. So you're giving the patient a marrow exposure that's the same as every other dose, but the impact on the tumor is fractional.

A lot of us have been thinking about better ways to rationally deliver radioligand therapy. ENZA-p used an adaptive schedule, so that was a combination of looking at PSA and as well, And keeping your powder dry, so to speak, if the patient looked like they were really enjoying a good profound response and holding off on the next dose until the patient needed it, until there was evidence of relapse. So they give a few doses upfront, observe the patient, see what was happening, and then if the patient looked like they were having an incomplete response, then giving more. But if it looked like they were really enjoying a good response, then holding off. And I think that that is something that the whole RLT community is interested in exploring.

Our registration trials that are currently ongoing, whether you're talking about VISION, which is done, PSMAfore, which has just resulted and was also discussed at the meeting. PSMAddition, which is now completely accrued. This is in the castration sensitive population or the SPLASH trial, which we expect to be resulted soon. These are all using fixed doses at fixed intervals, and it's time to think differently. I think that for a subgroup of patients, we're probably overtreating and we're also not leveraging the efficacy and power of radioligand therapy because we aren't saving a few doses for when the patient relapses and you could potentially reinduce a response and have the patient then be able to enjoy more tumor control over a longer period of time.

So that was really exciting to see. And I think that for those who may not be clued into the minutia of radioligand therapy, it might've just been passed off as sort of, "Oh, that was interesting." But there's actually something real there that we hope will be really explored in the next generation of registration trials.

Alicia Morgans: Well, and certainly there's work going into these sorts of adaptive designs on a larger scale. And I think in clinical practice, mostly based around AEs rather than response. We do have the power as the team to hold the doses and wait.

Michael Morris: Right.

Alicia Morgans: So if this is of interest to people in the clinic even today, this is something that you could potentially do.

Michael Morris: Yeah. I think most people feel really comfortable about dose reduction or holding a dose for toxicity.

Alicia Morgans: For toxicity, exactly.

Michael Morris: Because the message there from the patient is, "I'm not feeling well in one way or another."

Alicia Morgans: Or the cytopenias or other limiting factors.

Michael Morris: And so this is a little bit different because everything's going really well. And so instead of holding a dose because everything is not going well, you're holding a dose when everything is swimming along and that's a different paradigm. Let's say you're talking about for most solid tumors, let's say we continuously dose until you sort of relapse or reach intolerance for metastatic disease. Certainly in prostate cancer, you're on ADT for life, and as long as you're responding or you're tolerant of treatment for all of the next generation hormonal therapy, same thing, just keep going. Chemotherapy, a lot of people just keep on going every three weeks. And this would be a different paradigm.

Alicia Morgans: Absolutely. So one that we definitely need to explore.

Michael Morris: And I think that you could take that same paradigm and apply it to hormonal therapy and say, look, could we have for outstanding responders clinical trials that do explore pulling back on AR suppression and think about maybe taking those extraordinary responders and not treating them the same as we would for incomplete responders or progressors?

Alicia Morgans: Absolutely. And the DREAM Study is trying to work on this right now.

Michael Morris: That's a study that really is the brainchild and brought forth to the world by Atish Choudhury and Dana-Farber and he's done a great job.

Alicia Morgans: But it's difficult to disrupt the paradigm. And so we will see how all of this work goes. Some other work as we kind of wind down that I know you wanted to talk about, everybody's been talking about, the Presidential Symposium and PSMAfore. What are your thoughts there?

Michael Morris: PSMAfore was a randomized trial for chemo naive metastatic CRPC. This trial followed a paradigm that was really established by the PROfound trial in terms of its control arm, which is a switch in ARSI. So if patients were progressing on abi, they switched to enza and vice versa, enza to abi. They were either randomized to that switch or they were randomized to receive six doses of lutetium PSMA in the same vein as VISION, given every six weeks or four doses expandable to six. And the primary endpoint was rPFS. Secondary key endpoints were OS and quality of life, and of course safety was followed.

The trial showed a substantial improvement in radiographic progression-free survival. The hazard ratio was just slightly larger than 0.4, so it clearly hit on rPFS. The trial had an enormous crossover rate of over 80%, the highest crossover that most of us have seen in any contemporary trial, and only 45% of the OS events have hit yet. So it's very, very early to interpret overall survival.

It looked like the curves were beginning to separate in favor of lutetium, but I would say that in this circumstance, OS should not be over interpreted. A, the crossover rate was extremely high. B, the AE data and the quality of life data were really compelling in favor of lutetium as opposed to another ARSI. There were fewer treatment terminations. There were fewer toxicities overall. The hematologic toxicity of lutetium was actually less than half of that was seen in the VISION trial. Quality of life was preserved in favor of lutetium as assessed by FACT-P, and by the Brief Pain Inventory short form.

So if you look at it from a patient perspective, you've got more durable disease control and your quality of life and side effects were clearly in favor of lutetium at a dose of just the six doses as opposed to what you and I were just talking about, which is every day taking an ARSI. So if you did that strategy, you would be taking a drug daily in which you would have more side effects and less durable tumor control. I think the main OS event that needs to be established is that OS wasn't any worse and that you're not getting some false readout by rPFS. I don't know that in this early juncture with a high crossover rate, you'd necessarily see OS improve. But that I don't think is the main point. It's better disease control, better quality of life, a lesser treatment burden, and fewer AEs. As long as OS is even the same, I think that's a winner.

Alicia Morgans: I would have to agree with you. So just to make sure that everyone's aware, crossover was built into this trial. This is what made this trial ethical from my perspective, because we were randomizing to what we knew was potentially based on multiple other studies, a lesser therapy. Now, we didn't know that for sure, we had to do the trial, but this is what was suggested by multiple other studies. And so if we did not build in that crossover, I don't know that enrollment would've been as robust just because maybe other physicians would've said, "I don't know if I can randomize in this setting," but this made me feel comfortable with this randomization, one person putting patients on the trial.

Secondly, to your point, if OS is at least the same, you're not harming the patient. And third, I would say it is unfortunate when we have a control arm that because there's a delay of three to six months in that active treatment leads to such a decrement in their overall disease trajectory, especially when we're this early in the disease setting and when we can rescue a patient with a therapy that is so powerful that it can overcome six months of delay, I think that speaks more for the power of the therapy that you're testing and less so that it's an ineffective therapy.

So I think this is actually quite an encouraging result. And as you said, I completely agree that as long as overall survival is not worse, we actually have a winner.

Michael Morris: Yeah. The one thing I would point out is this was not a negative placebo controlled trial.

Alicia Morgans: True. Yes, of course.

Michael Morris: Those patients did have over a 20% response proportion in terms of PSA decline, which is consistent with the literature. So it's not like they received placebos, but it was clearly less effective therapy.

Alicia Morgans: True. And for any individual patient, they may respond to that second AR signaling inhibitor. And so I don't mean to say that. I just am very glad that the control arm appears to potentially have been able to, at this early data, catch up, and that's important for our patients.

Michael Morris: I think the other thing to point out is that practice pattern, the second ARSI is the dominant real world practice pattern. And so you might say, "Well, I don't believe that the dominant real world practice pattern is ethical," but that is what it is.

Alicia Morgans: It is what it is. Yeah.

Michael Morris: Most patients are not going on to chemotherapy. And I would say that there's a whole class of patients that probably do warrant an alternative to chemotherapy because not everybody is progressing in a rapid way with multiple new lesions. Many patients, they may have had years of durable control on an ARSI and now their PSAs are rising, their scans haven't changed. They may have a nominal tumor burden and neither patient nor physician are really looking for chemotherapy to treat that circumstance.

Alicia Morgans: Sure.

Michael Morris: And indeed, I would expect a responsible investigator if they think that their patient needed chemotherapy, would not register the patient to that trial.

Alicia Morgans: Yes.

Michael Morris: That does mean that PSMAfore will represent a segment of prostate cancer that doesn't need chemotherapy, presuming that those responsible investigators wouldn't put their patients on a study in which they could have been randomized to a treatment that they felt was inappropriately weak.

Alicia Morgans: Well, besides that, I should also encourage that the control arm on progression was getting lutetium faster than they would get this in any other setting. And so this was a good trial design and I definitely don't mean to refute that. I just mean-

Michael Morris: No, I know it's a topic of heated discussion.

Alicia Morgans: It is a topic of heated discussion, but it is a positive trial. And I don't think that the lack of OS benefit at this early time point means that this is an ineffective therapy. And I think we agree on that at least.

Michael Morris: And we should be talking about these issues because control arms are very important. But prostate cancer is a really diverse disease. And some patients have rapidly progressive disease and some do not. And we understand that. And most of us have trials that are open. In any given segment of the disease, some trials will be appropriate and some inappropriate for patients. Very few trials would we say, "You know what? Everyone at this stage of the disease should just be going on this trial." So you have to, as an investigator and as a physician, be responsible. And just because patients are eligible for a club doesn't mean that they should enter it.

Alicia Morgans: I could not agree more. Well, thank you so much for taking the time to walk through what was a very exciting ESMO in 2023 from a prostate perspective. Even if there was a lot of data in other disease types, we had our own data there as well.

Michael Morris: We had our own small moments there, even though there was a lot of thoracic data and a lot of bladder data as well.

Alicia Morgans: It's very exciting for so many, which is great for everyone in the end. But thank you so much for your time and your expertise.

Michael Morris: Thank you, Alicia. It's a pleasure being here.