Neeraj Agarwal: Thank you for having me, Tanya.
Tanya Dorff: So today we wanted to talk about MEVPRO-3, which is a phase III trial that's ongoing in advanced prostate cancer using a new drug, mevrometostat. So I was hoping you could explain why epigenetics and EZH2 has been such an attractive target in prostate cancer.
Neeraj Agarwal: Tanya, first of all, thank you for having me talk about MEVPRO-3 trial. It's a very important trial, phase III trial, and giving the shout-out to an ongoing phase three trial really helps with accrual. Patients need to know about this, doctors need to know about this, clinicians need to know about this, so thank you for doing it. Just to take a step back, what is mevrometostat? Mevrometostat is a novel drug which targets EZH2. Now, this is, maybe, unfamiliar terminology for most of our colleagues worldwide, but what I have learned over the time is EZH2 pathway allows prostate cancer cells to gain independence from androgen signaling inhibition. So as we know, ADT plus ARPI is a backbone of therapy for patients with metastatic prostate cancer, both in hormone-sensitive, and even later, androgen signaling continues to play a role. And I will come to the castrate-resistant setting for a moment. But going back to the mevrometostat and EZH2, in theory, if you block EZH2, you may allow these prostate cancer cells to remain dependent on androgen signaling and thus respond to ADT plus ARPI therapy for much longer time. So that's the scientific rationale in a very simplified fashion.
Tanya Dorff: So is it something that works well on its own or better together with an AR pathway inhibitor?
Neeraj Agarwal: That's a great question. Just looking at it mechanistically, EZH2 pathway enhances responsiveness to androgen receptor signaling inhibition. So it has to be combined with an androgen pathway inhibitor, ADT plus ARPI. But yes, it has to be combined with the backbone of ADT plus ARPI.
Tanya Dorff: And what does the side effect profile look like for a drug like this?
Neeraj Agarwal: Yeah. So before I go to the side effects, I'd like to highlight the early-phase trial presented by Mike Schweizer and team in 2025 ASCO GU just a year ago. And this was a relatively small trial, less than 100 patients who had progressed on ADT plus abiraterone. And these patients had metastatic castrate-resistant prostate cancer and they were randomized to enzalutamide plus/minus mevrometostat. Now, I have never seen this magnitude of difference in radiographic progression-free survival in such early-phase trial.
Tanya Dorff: Yeah, I remember it was quite striking.
Neeraj Agarwal: Yeah. If you look at enzalutamide, how it performed after abiraterone, it was 6 months, which we expect. Enzalutamide retains some activity trial, randomized trial from Vancouver, Kim Chi and colleagues have shown in the past, and based on our own experience, enzalutamide retained some activity after abiraterone. And that's what we saw. 6 months. But if you look at the other side, enzalutamide plus mevrometostat, it was 14.3 months. Quite unprecedented. And I think that really excited the field and obviously led to three phase III trials. MEVPRO-1 is ongoing in castrate-resistant setting, which is exactly similar to the early-phase trial. Patients who had progressed on ADT plus abiraterone, they are being randomized to enzalutamide plus/minus mevrometostat.
Then there is a phase III trial in the hormone-sensitive setting, which is MEVPRO-3 trial, which we are presenting as trial in progress in ASCOGU 2026. So as expected, this is a large trial. 1,000 patients with newly-diagnosed metastatic hormone-sensitive prostate cancer. And these patients will be randomized to ADT plus enzalutamide versus ADT plus enzalutamide plus mevrometostat. Radiographic progression-free survival is the primary endpoint, and obviously many other key endpoints are overall survival, quality of life, and adverse event profile. So we really are excited about this ongoing trial and really hoping that our colleagues and patients know about this trial so that they can have the opportunity to enroll in this trial.
Tanya Dorff: Are there particular patients you think are a good fit? Are you screening out for patients with BRCA alterations who maybe should get a PARP inhibitor in the upfront setting?
Neeraj Agarwal: That's a great question. So first of all, the indication for BRCA2 patients just came not even 3 months, I think. It has been few weeks. So obviously that is definitely a consideration. This is a global trial which is recruiting in Asia, Europe, South America, so we'll have to keep in mind the indications which are available, the approvals which are there in all these countries in this global trial.
Tanya Dorff: Not everyone can access NGS, let alone these drugs. Yeah.
Neeraj Agarwal: Exactly. So you talk about NGS, talk about availability of PARP inhibitor. So I'm really hoping if these patients have BRCA2 mutation, they have the opportunity to avail PARP inhibitor, but they're also allowed to enroll in this trial. Now, coming back to your question about side effects. So if you look at the side effect in this early-phase trial presented last year, what really stood out was the gastrointestinal side effect, which was the main portion of grade-1/2/3 side effects. And based on the side effect profile of side effects in that clinical trial, the dose of mevrometostat has been reduced to 875 milligram. So enzalutamide reduces the exposure of mevrometostat because of drug-drug interactions. So careful studies, PKPD studies, and then association with food, which also can impact absorption, the dose in the phase III trial is lower than the dose of phase I trial. So we really hope that side effect profile is better. Obviously trial is ongoing. I'm recruiting patients on the trial, so I cannot talk about the side effects which we are experiencing in this ongoing trial, but diarrhea, altered taste are the two main side effects. Fatigue is hard to decipher if it's coming from enzalutamide or coming from mevrometostat.
Tanya Dorff: Or the ADT. Yeah.
Neeraj Agarwal: Or ADT itself. I mean, you have published studies on the side effects of ADT, and fatigue stands out as one of the most common side effects. But I'm really hoping that first 3 months, I tell my patients, "Every single drug has side effects and a progressing prostate cancer has a lot of side effects." So how to achieve this balancing act of controlling the disease progression, allowing these diseases, aggressive prostate cancers to retain sensitivity to ADT plus ARPI while maintaining quality of life. So first 3 months are crucial. Like any cancer drug, we start them on treatment, careful monitoring. If you have terrible side effects, grade-3 side effects, reduce the dose, marginal side effects, grade 1/2, symptomatic management. And based on my personal experience, it has not been any unusual experience compared to many other cancer drugs we use in our clinic.
Tanya Dorff: And it sounds similar, maybe, even to capivasertib and CAPItello-281. We heard the quality of life PROs presented by Dan George at this meeting, and similarly, there are side effects that happen early. It's our job to manage them so our patients can stay on drug and continue to try to access the benefit. But I totally agree with you. It pays dividends in the long run. The better remission we achieve upfront, the longer it takes for the cancer to progress and cause harm and symptoms for our patients.
Neeraj Agarwal: Absolutely. I agree with you. And again, I want to encourage my colleagues worldwide, this is a worldwide forum with a very high, deep penetration across the community of urologists and medical oncologists across the world, I really encourage our colleagues out there to consider this trial for enrollment.
Tanya Dorff: Great. Thank you so much for being here today to share that with us.
Neeraj Agarwal: Thank you