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Andrea Miyahira: Hi, everyone. I'm Andrea Miyahira here at the Prostate Cancer Foundation. Joining me today is Dr. Michael Schweizer, an associate professor at Fred Hutch Cancer Center. Dr. Schweizer just presented an ASCO poster on Mevrometostat, an EZH2 inhibitor in a trial for metastatic castration-resistant prostate cancer. Dr. Schweizer, thanks for joining me today.

Michael Schweizer: Yeah, thanks for the invitation.

Andrea Miyahira: So, NEPC neuroendocrine prostate cancer arises in about 20% of patients who develop castration-resistant prostate cancer, and it's thus far incurable. Studies have found that EZH2 may be a driver of NEPC and therefore may be a treatment target. So tell us about this trial and what you guys were looking at.

Michael Schweizer: Yeah, so this is a Phase I/II study. The preliminary data that we presented at ESMO in 2022 outlined some of the results from the initial dose escalation, the monotherapy cohorts, and they enrolled patients with follicular lymphoma, small cell lung cancer, and also castrate-resistant prostate cancer. The follow-up data that we're presenting here is really on the combination data using Mevrometostat with enzalutamide for castrate-resistant prostate cancer. We did not specifically enroll patients with small cell prostate cancer or neuroendocrine prostate cancers. They were excluded. But you're right, I think a lot of the enthusiasm about this target in prostate cancer really stems from data showing that EZH2 is likely a key mediator in that trans-differentiation process that promotes adenocarcinoma switching to neuroendocrine cancers. There is also data that EZH2 likely suppresses factors that are involved in negatively regulating the androgen receptor as well. So it gives a little bit of rationale to use it in these resistant prostate cancers that have progressed on prior abiraterone, enzalutamide, and other androgen receptor pathway inhibitors.

Andrea Miyahira: So tell us about the results from this part II trial in the dose escalation. What did you find?

Michael Schweizer: Yeah, so we brought some preliminary results in 2022 as mentioned, but here we have longer follow-up and more patients on the study, 47 patients in total. Overall, we found that there was very encouraging signs of activity with this combination and a fairly tolerable side effect profile. Overall, this was a heavily pretreated population of men. I believe about half of them had received taxane chemotherapy in the past. 75% had received enzalutamide previously and then a third of them received abiraterone and enzalutamide before enrolling in this study. So these are patients that have been exposed to a lot of standard drugs already, and what we found was that the progression-free survival with enzalutamide was really pretty encouraging. Overall, it was around 17 months for the entire population and almost a year for patients that had already progressed on enzalutamide, which speaks to the probable activity of this combination as opposed to just some effect of enzalutamide by itself.

Andrea Miyahira: And how about tolerability? Were there any safety concerns?

Michael Schweizer: No, I would say that the drug is fairly well tolerated. High-grade, grade three and above, adverse events were rare in general. There are some GI side effects including dyskinesia, some issues with diarrhea, but these are generally manageable and lower grade. So for the most part, this was a fairly well-tolerated drug. I'd also mention that cytopenias were generally lower grade as well. There was I think just a very small handful of patients that had higher grade anemia, thrombocytopenia, etc. But in general, the drug seems to be very well tolerated. My personal experience in using it for my patients is that they generally do quite well once you figure out how to deal with some of the GI things using drugs like Imodium and such.

Andrea Miyahira: Okay, thank you. And did your team do any genomics or other correlative biomarkers to identify patients that may be more likely to respond or not?

Michael Schweizer: Yeah, so we're working on that now and I think that's a really important question. So in the poster we present some data specifically focused on androgen receptor mutations and also TP53 mutations. And I think that's relevant because we know that TP53 is often one of the earlier events that happens in driving cancers towards these neuroendocrine subtypes. And what we found within the subset of patients that had loss of function mutations in that gene, that a little over 40% of them had really prolonged, progression-free survival. I believe it was about 44% stayed on the study for over 12 months in spite of having one of these high-risk mutations. So one could imagine that maybe if you have a TP53 mutation that that's sort of priming this cancer to head towards that prostate cancer trans-differentiation process where the tumor cells undergo lineage plasticity and emerge with this neuroendocrine phenotype. Maybe you're catching it early and you're stopping that from happening. That could potentially be one of the ways that this drug helps patients to do better than just enzalutamide alone.

Andrea Miyahira: EZH2 has been found to be a major driver of NEPC. So has your team looked at whether this combination could prevent progression to NEPC or possibly reverse NEPC?

Michael Schweizer: So it's a good question. I think that looking at whether or not there's some emergence of that that could potentially be targeted by this drug is key. And right now we don't have a lot of data in that respect. Patients didn't undergo baseline metastatic biopsies to answer that question. What our site's interested in looking at is whether or not we can use blood-based assays to phenotype cancers and see whether or not there is a subpopulation of emergent neuroendocrine prostate cancer in patients enrolled in this study.

So in collaboration with Gavin Ha, a researcher at Fred Hutch, we're doing some ctDNA-based fragmentomics work to see if we can develop blood-based signatures to see if there are subpopulations of NEPC emerging. Or maybe if patients already had evidence of NEPC that's already present at baseline. I think that that's going to be really key. If you can identify a patient population that's heading down that pathway and use a drug to effectively blunt it, that's going to be I think one of the major selling points of this drug.

Andrea Miyahira: And are there any next steps of the clinical development of this?

Michael Schweizer: Yeah, absolutely. I think based on the really encouraging results, the drug is moving forward and there's a Phase III study combining Mevrometostat with enzalutamide, in comparison to enzalutamide alone in patients who've already progressed on abiraterone. This is a Phase III study and should hopefully open up in the near term. So we'll have more definitive evidence whether or not an EZH2 inhibitor, Mevrometostat, can potentially be included as a standard of care for our patients in the future.

Andrea Miyahira: Thank you so much. And do you have any final thoughts or take-home messages?

Michael Schweizer: I think these epigenetic targets are really, I think, important in prostate cancer. I think they've been implicated for a long time and to date we really haven't been able to capitalize on that basic science knowledge and translate it into drugs. But it's exciting to see Mevrometostat and other epigenetic regulator therapies really coming forward and showing a lot of promise in terms of being viable therapies.

Andrea Miyahira: Thank you so much Dr. Schweizer for sharing this with us today.

Michael Schweizer: Yeah, my pleasure. Thanks again for the invite.