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Oliver Sartor: Hi, I'm Dr. Oliver Sartor with you here today. And here we have Michael Schweizer, Associate Professor at UW, as well as the Fred Hutch. And he gave a really cool talk on mevrometostat—if I pronounced that properly—here at ASCO GU. So welcome, Michael.

Michael Schweizer: Thank you. Good to be here.

Oliver Sartor: You know, it's interesting, and your presentation caught a lot of publicity because of the RPFS. But let's not start there. What is mevrometostat, because probably the vast majority of our listeners have no clue. What is it? What does it do?

Michael Schweizer: Yeah, so it's an EZH2 inhibitor. And so EZH2 has been implicated in promoting lineage plasticity. And it also has a noncanonical role in regulating androgen receptor activity and probably plays a role in driving resistance to drugs like enzalutamide and abiraterone. And so as a target, it's been something that's been implicated in multiple different studies in the past. And so that was the rationale for testing it here.

Oliver Sartor: People have been playing around with EZH2 for a while. This is not a totally new concept. Why is this different than what came before?

Michael Schweizer: Yeah, as far as I know, there's only been data presented with tazemetostat in terms of looking at randomized data using an EZH2 inhibitor in patients with metastatic castration-resistant prostate cancer. And that study was ostensibly negative. Why is this drug working better? It could have better pharmacology. It might hit the target better. I don't think we really know the answer to that. We did present some translational work looking at pharmacodynamic modulation of H3K27 trimethylation marks, which is the target of EZH2. And it shows that it modulates it very well in the periphery. And importantly, in a handful of patients who had matched pre-post biopsies, you show that it has the expected on-target effects in terms of regulating transcriptional output too.

So the drug is clearly hitting its target and doing what we think it should be doing in terms of a mechanism of action. It's hard for me to comment regarding other drugs and why they may not have been able to do that as well. The clinical activity wasn't as good as you would have anticipated.

Oliver Sartor: It is an EZH2 inhibitor. Let's talk about the trial design first, and then we'll go on to the results and findings.

Michael Schweizer: Yes, so this was part of a randomized dose-expansion cohort from the original phase I dose escalation study. And so in this randomized expansion, they enrolled patients with metastatic castration-resistant prostate cancer. Everybody progressed on prior abiraterone, and they were only allowed up to one prior line of chemotherapy. They were randomized between either mevrometostat plus enzalutamide or enzalutamide alone. And the primary endpoint was RPFS and safety.

Oliver Sartor: And what did you find?

Michael Schweizer: Yeah, so the take-home was that the RPFS showed a large difference between the mevrometostat–enzalutamide arm versus enzalutamide. Overall, it was a 49% reduction in the risk of radiographic progression with the combination.

Oliver Sartor: And the hazard ratio is 0.49. What are the absolute magnitudes of the effect?

Michael Schweizer: Yeah, so in terms of change in median, progression-free survival was an eight-month difference. It went from six months to about 14 months.

Oliver Sartor: Fourteen months is pretty good.

Michael Schweizer: Yeah.

Oliver Sartor: How many of the patients had prior docetaxel?

Michael Schweizer: A little less than half in both arms.

Oliver Sartor: OK.

Michael Schweizer: Yeah.

Oliver Sartor: But that's active.

Michael Schweizer: It's active, yeah. It's a very large difference. And I think that effect size was justification for moving forward with two international phase III studies which are currently open.

Oliver Sartor: Let's talk about toxicity before we get to the phase IIIs. What kind of toxicities were found in the study?

Michael Schweizer: Yeah, so in terms of key toxicities, the biggest one that was an issue was GI toxicity, including diarrhea, dysgeusia, low appetite, nausea, that kind of thing. So that was the big one. And there was a decent number of patients that had treatment-related adverse events as well. I think it was like 10 in the mevrometostat–enza arm compared to the single agent.

Oliver Sartor: What was the discontinuation rate?

Michael Schweizer: Discontinuation rate due to toxicity was really, really low. Only one person in the combo arm discontinued because of a toxicity.

Oliver Sartor: Oh, wow, only one discontinuation.

Michael Schweizer: Only one, yeah.

Oliver Sartor: How many dose reductions? Just trying to get a handle on that.

Michael Schweizer: Yeah, I believe it was around a third or so had a dose reduction due to a toxicity. But the take-home for me is that they're manageable, whether you need to dose reduce or if you go in and use things like Imodium to control diarrhea, et cetera. I think the other important part of the abstract was they, originally in the randomized portion, dosed it at 1,250 milligrams on an empty stomach. They did a food effect cohort study, which showed that you can essentially achieve the same plasma concentration at a lower dose with food—875 milligrams. And so you're getting the same exposure. But importantly, they saw the rates of diarrhea basically cut in half—

Oliver Sartor: Oh, wow.

Michael Schweizer: —when they did that.

Oliver Sartor: So that's a big change.

Michael Schweizer: Yeah, and there was no grade 3 or higher diarrhea events at that drop. Now, that data is still maturing. We hope to present it at a future meeting and have a better picture in terms of the safety profile. But because of that encouraging safety signal—doing it with food at the lower dose—that's the dose being tested in the phase III trials.

Oliver Sartor: Oh, cool. So just for clarity's sake, how many of the patients in your randomized portion of the trial received the lower dose with food?

Michael Schweizer: None.

Oliver Sartor: None, zero.

Michael Schweizer: No.

Oliver Sartor: Zero there.

Michael Schweizer: Exactly.

Oliver Sartor: OK. So this is a separate food effect looking at PK.

Michael Schweizer: You got it.

Oliver Sartor: Got it. OK, great. Thanks for clarification. All right, going to phase III, two of them—tell me about it.

Michael Schweizer: So similar population. So the MEVPRO-1 study is enrolling patients who progressed on abiraterone, sort of identical essentially to the patients we enrolled in the randomized expansion data that I just discussed. The randomization there is they get either mevrometostat plus enzalutamide versus either enzalutamide or docetaxel. It's dealer's choice.

The second study, the MEVPRO-2 study, is looking at patients who have not been exposed to a prior androgen receptor pathway inhibitor. So they haven't had treatment intensification with an ARPI. And the randomization there is either mevro plus enzalutamide or placebo enzalutamide.

Oliver Sartor: Got it. And global trials?

Michael Schweizer: Both of them, yeah.

Oliver Sartor: Phase IIIs. Tell me about the endpoint.

Michael Schweizer: Endpoints are PFS and OS for both.

Oliver Sartor: OK. Great. Very interesting. We have a new mechanism of action—I'm going to call it new despite the prior studies because we didn't really have a good signal in those. Now we've got a signal, already moving to phase III. This could be a big deal.

Michael Schweizer: Yeah, and I think it's great to have a new class of drugs that is actually moving forward, because in addition to showing activity in combo with an ARPI, I think there's a lot of interesting biology there. And I'd love to see novel combinations coming out of this. There's some preclinical rationale for maybe combining them with immunotherapies, for instance. It might do things in terms of remodeling the cell surface antigen phenotype, which could be advantageous depending on whether you want to use a novel radioligand or an ADC or a T-cell engager. And so I think having these drugs hopefully get approved is going to allow us to start looking at maybe extending it beyond that and looking at these more novel ways to incorporate them into our treatments.

Oliver Sartor: Gosh, Michael, thank you. Important work leading to phase III—could be practice changing. Appreciate all you're doing for the field. Thanks for being on here today.

Michael Schweizer: Yeah, of course. Thanks for having me.