Read the Full Video Transcript

Zachary Klaassen: Hi. My name is Zach Klaassen, Urologic Oncologist at the Georgia Cancer Center in Augusta, Georgia. We're on UroToday at ASCO 2025 in Chicago. Delighted to be joined, as always, by Dr. Neeraj Agarwal, who's the Director of GU Oncology at the Huntsman Cancer Institute in the University of Utah. Neeraj, always good chatting with you. How are you?

Neeraj Agarwal: Always so pleased to be here.

Zachary Klaassen: So we're going to talk. There's a super exciting study, the MEVPRO-1 study. This is an mCRPC (metastatic castration resistant prostate cancer) first-line therapy. Just tell us about the study. What is mevrometostat? How did this trial come to be?

Neeraj Agarwal: So EZH2 inhibitors have potential in patients with metastatic prostate cancer. And just to take our viewers back a little, taking a step back, EZH2 inhibition has been discussed for the last more than a decade. If you look at enhancer of zeste homolog 2, which is EZH2, it has multiple effects or actions within the prostate cancer cells.

The most recognized one is the epigenetic regulation. And over time, EZH2 pathway has known to get upregulated in progressive prostate cancer and leads to suppression of tumor suppressor genes.

Zachary Klaassen: I see.

Neeraj Agarwal: Second, it can promote lineage plasticity. It can promote the prostate cancer transformation from adenocarcinoma to neuroendocrine prostate cancer. And then third, EZH2 pathway tends to interact with androgen receptors or somehow supports androgen receptor function. So if you combine all of these three, it makes sense to be able to block EZH2 pathway with EZH2 inhibitors and, hopefully, with the hope that it will improve outcome.

Zachary Klaassen: Right.

Neeraj Agarwal: So just talking specifically about this trial, the trial is using the drug mevrometostat, which is a novel EZH2 inhibitor. And I'll just focus on this one for now. There are other EZH2 inhibitors which are being developed. So mevrometostat was tested first in a phase I trial, in a dose-escalation study, where the investigators found encouraging progression-free survival rates.

And then in ASCO June 2025, Dr. Mike Schweizer, he presented the data from 80 patients, a randomized phase II trial where patients had disease progression on abiraterone. And they were randomized to enzalutamide versus enzalutamide plus mevrometostat. The results were quite striking. The progression-free survival was about six months with enzalutamide, which is expected.

Enza after abiraterone has some activity. But the progression-free survival in the combination of enza plus mevrometostat was 14 months. And it was translated into 50% reduction of risk of progression or death. So hazard ratio was 0.5. If you look at the PSA 90% responses, they were doubled in mevrometostat arm.

Objective responses and all those parameters favored the combination arm. I think these results were quite compelling, compelling enough to prompt the initiation of multiple phase III trials. So MEVPRO-1 is a phase III trial in metastatic CRPC setting. Patients have to have mCRPC. They have to progress prior with a prior treatment on abiraterone.

They could have received chemotherapy with docetaxel in the metastatic hormone-sensitive prostate cancer setting, but cannot receive docetaxel in CRPC setting. It is a 600-patient trial, so relatively large trial, where patients will be randomized 1 to 1 to enzalutamide versus enzalutamide plus mevrometostat. Just like to bring your attention to the dose of mevrometostat.

In previous phase II trial, it was 150 milligrams twice daily. Now, in the phase III trial, it is 875 milligrams twice daily really with food. So we saw that, although grade 3 for diarrhea was quite less, but not really remarkable, grade 1, 2 diarrhea or discomfort were present in a substantial or sizable number of patients. So to decrease the GI side effects, we decided to decrease the dose of-- to get mevrometostat with food so that we have to use less dose because food increases the absorption of mevrometostat.

Regarding the endpoint, radiographic progression-free survival is the primary endpoint. Overall survival is the key secondary endpoint, which will be independently powered. Just for the update, trial is actively enrolling in different parts of the world, including in the US.

Zachary Klaassen: Excellent.

Neeraj Agarwal: It's a very active combination based on the phase II data. And hopefully, the data will be replicated in the phase III trial.

Zachary Klaassen: Excellent.

Neeraj Agarwal: The control arm has both docetaxel and enzalutamide--

Zachary Klaassen: I see, OK.

Neeraj Agarwal: --which is different from the recently concluded study. So hopefully, we'll finish the accrual soon.

Zachary Klaassen: How many patients so far of those 600 patients?

Neeraj Agarwal: I don't have the most recent data. But because trial has just started, I'm pretty sure our patients who are out there and who are looking for trials, they should look at clinicaltrials.gov and look at the sites where they can find the information on where are those hospitals or places closer to their home where they can enroll in this trial. So again, clinicaltrials.gov.

Zachary Klaassen: Excellent.

Neeraj Agarwal: And of course, there are many other patient advocacy sites, including PCF UroToday, where they can get the information.

Zachary Klaassen: I want to ask you, Neeraj, in terms of a synergistic association between enzalutamide, mevrometostat, is there something there that perhaps is giving us these responses? What are your thoughts on that?

Neeraj Agarwal: Great question. Because although the action of EZH2 itself is not fully comprehended, this seems to have multiple actions on the cells, on the prostate cancer cells. One of those actions includes its support for androgen receptor. So it makes sense to me, although we don't have anything beyond this, beyond the phase II trial I just described, where we saw almost 50% reduction in risk of progression or death just by adding mevrometostat to enzalutamide, just mechanistically speaking, if it is helping androgen receptor and if you block both androgen receptor and EZH2, to me, as a clinician, it makes sense to expect some synergy.

Zachary Klaassen: Yeah, great point.

Neeraj Agarwal: Yeah.

Zachary Klaassen: Anything we haven't touched on from MEVPRO-1? You laid it out perfectly for our listeners. Any take-home points? Anything you want to mention again?

Neeraj Agarwal: Just to let you know that MEVPRO-2 and MEVPRO-3 trials are also coming up. MEVPRO-1 is in first-line mCRPC, where patients have not been exposed to an ARPI. These are going to be those patients who got radiation therapy surgery in the past and who had biochemical recurrence and who were treated with intermittent or continuous androgen deprivation therapy.

There are a lot of patients out there in the community who are progressing to mCRPC without having disease progression experienced in the pre-mCRPC setting. There is a hormone-sensitive trial, metastatic hormone-sensitive trial coming up where patients will be randomized to these two arms in a metastatic hormone-sensitive prostate cancer setting.

Zachary Klaassen: Excellent.

Neeraj Agarwal: So I think we are just seeing a start of the mevrometostat story. And hopefully, some of the trials will be positive or all the trials will be positive and we'll be able to impact the lives of our patients in a positive fashion.

Zachary Klaassen: I know. We started talking about the phase I a couple of years ago on the site, and it's exciting that the phase IIIs are enrolling multiple trials down the road. So it's like you said, just the beginning of the mevrometostat story.

Neeraj Agarwal: Yes. Or beginning of EZH2 inhibition--

Zachary Klaassen: That's right.

Neeraj Agarwal: --in prostate cancer.

Zachary Klaassen: Thank you, Neeraj. Always good chatting with you.

Neeraj Agarwal: Thank you very much.