Today I have the honor of having Dr. Neal Shore to talk about the MEVPRO-2 trial, the phase-three randomized trial, which Dr. Shore is leading. So Neal, welcome.
Neal Shore: Thanks very much, Neeraj. And let me just say great to see you.
Neeraj Agarwal: So Neal, you have been leading MEVPRO-2 trials, and there are multiple MEVPRO trials, but this time the focus is on MEVPRO-2 trial. So we'd like to start with some background. Why do you think this trial is important? But before we go there, we can talk about the rationale which came from the phase-one/two trial presented by Mike Schweizer a few years ago. And then we can briefly touch upon the MEVPRO-1 and then MEVPRO-2. But focus is on MEVPRO-2 today.
Neal Shore: Sure. Sure. So MEVPRO-2, this is a phase-three trial, as you say, Neeraj. And this is going to look at patients receiving Mevrometostat and Enzalutamide versus Enzalutamide alone. And these are patients who have developed resistant biology, who were otherwise only receiving monotherapy ADT by and large. So they're treatment-naive to an ARPI.
Taxane or Docetaxel is permitted as long as it's received in the sensitive setting. It's going to be about 900 patients, it's a one-to-one randomization. They'll get the Mevrometostat, it's 875 milligrams twice a day with food versus Enzalutamide, the traditional 160 milligram dose with a placebo. So it's a classic prospective double-blind control randomized trial.
I think it'll be interesting because probably most of these patients will come from outside the United States, where we do see a lot of doublet therapy, but that's okay. It's a global study and I think we will accrue pretty quickly. And the reason or the basis behind it, which you're very much well aware, is the notion of adding this EZH2 inhibitor, Mevrometostat. There's several other types of EZH2s that are in the field. It's a very exciting area. This EZH stands for enhancer of zeste homolog 2, so it's easier to just say EZH2.
What we know is EZH receptors are typically more highly expressed in neuroendocrine prostate cancer. And so part of the thought process is by adding this selective EZH2 inhibitor, Mevrometostat, it inhibits methylation and it suppresses EZH2 cancer growth. And there's a theoretical possibility and an enhanced AR inhibitor effects. It sort of works to reactivate co-express genes, preventing the development of NEPC, perhaps restoring anti-androgen sensitivity. And this was actually nicely shown in preclinical models. So this is what the MEVPRO-2 trial is trying to get to.
I'm excited about it. I'm also excited about we have other trials. There's the MEVPRO-1, which is in the similar resistant biology. Abiraterone progressors, basically, getting ENZA-MEVPRO versus just ENZA. It's a 600-patient trial. And then there's even the MEVPRO-3, not to confuse our audience, which is looking at the sensitive biology or what we now call the APMS, or the mHSPC traditionally, and that'll be a randomization of the ADT ENZA-MEVPRO versus ADT ENZA placebo.
So it's pretty cool. There's a real commitment on behalf of sponsor and us. And as you mentioned, Mike Schweizer and many of our other colleagues globally who are really excited about these trials. But we're always trying to figure out a way, how do we either inhibit resistance or correct resistance to the AR pathway. You've done a tremendous amount of work in this, particularly with the PARP inhibitors. So now we're adding to that repertoire.
Neeraj Agarwal: Thank you, Neal. That's such a nice description of all these trials.
And just for the viewers, like to just clarify, or again emphasize that MEVPRO-1 was the first trial which was launched based on the earlier phase two data where patients who are progressing on Abiraterone in mCRPC setting, they were randomized to Enzalutamide plus Mevrometostat versus Enzalutamide alone. 80 patients were randomized, and the progression-free survival, the rPFS on Enzalutamide was six months, which is expected after Abiraterone. But what was striking was Enzalutamide plus Mevrometostat, the rPFS was 14.3 months with a hazard ratio of 0.51, and PSA-50% responses were also double. And this were striking responses.
If you look at the radiographic PFS with ENZA plus MEVRO, it was very similar to earlier phase one trial, which was seen in a phase one trial earlier. And I think these two trials really motivated the sponsor here ... Pfizer is the manufacturer of Mevrometostat to start three phase-three trials. So MEVPRO-1, as you mentioned, is Post-abiraterone on mCRPC. MEVPRO-2 is ARPI-niave CRPC, and MEVPRO-3 is mHSPC. And the new terminology for is, because we all love to avoid castration terminology, so we like to use the word now metastatic androgen pathway modulation sensitive prostate cancer, and androgen pathway modulation resistant prostate cancer, APMS and APMR.
Did I say it correctly, Neal?
Neal Shore: I think you did. And I think the repetition is important. A, because there are three different trials, and even our nomenclature is starting to change too. I think at the end of the day, what's exciting about the whole class of EZH2s, there's some EZH2s and EZH1s is how can we diminish the development of resistance regardless of whether it's insensitive or resistant biology. I think overall the oral medication, it's a little bit easier to administer both in the clinic and even for patients by and large. We're always looking at DDI interactions and PK and PD very carefully. I think these doses have come about through some really very nice earlier phase work that you mentioned, and that's why we're really happy to be part of the trial both in the hormone sensitive as well as in the resistant biology.
And this is how we can potentially make some significant advances. And I don't think being subjected to this particular molecule and this MOA will preclude any other already approved life-prolonging therapies, the radiopharmaceuticals or taxane therapy. So the tox safety profile is actually pretty good on this. There's some GI things, but nothing that's difficult to manage.
Neeraj Agarwal: And I'm glad you mentioned the GI side effects, including altered taste and diarrhea, nausea.
So in the phase one trial, Mevrometostat was used at 150 milligram twice daily, empty stomach. And in the phase-three trials, MEVPRO-2, MEVPRO-1, MEVPRO-3, Mevrometostat is being used at a lower dose, but with food. So both are expected. It's being used at 875 milligram twice daily with food, and it is expected to reduce the GI side effects with that strategy.
So I have been using Mevrometostat-Enzalutamide combination in the trials. Obviously we are not going to be talking about the trial data which have not been published yet, but I can assure those investigators who are thinking about using this combination for their patients through one of these three trials, they will not have to worry about the gastrointestinal side effects. Like many targeted therapies, dose modification is the key. And as long as we can recognize who are those small number of patients who are going to develop grade three side effects, monitor them closely upfront, and decrease the dose of Mevrometostat in a timely fashion, allow most of these patients to receive Mevrometostat with Enzalutamide for a long time.
Neal Shore: I think that's exactly right. And the nice thing too, always with oral medications, and even with Enzalutamide, which there's more than a decade of experience with it now, one can always dose modify. And I think we'll see that I'm sure on these trials, and that's built into the protocol. But the most important thing is extending the rPFS and the usual secondary endpoints that we're going to look at. PSA, we'll look at in time to pain progression, additional next antineoplastic therapy. And I think we're always feeling if we can add an oral therapy that demonstrates the clinical benefit of lowering resistance, keeping the benefit of the RP, in this case Enzalutamide, then we've done something really good without precluding additional therapies. There really is not going to be much of any kind of a marrow issue here like we see with some of the other therapies, the radiopharmaceuticals and the PARP inhibitors and the taxanes.
So I think we'll wait and see. It's why we do these phase-three trials. I'm certainly optimistic.
Neeraj Agarwal: Thank you.
And just for those who are interested in referring patients, the trial is already referenced in the clinicaltrials.gov, NCT number 06629779. And there are sites which are actively enrolling the patient, so let's give our patients opportunity to enroll in another clinical trial, a very promising clinical trial and a strategy. Thank you, Neal.
Neal Shore: My pleasure. Thank you, Neeraj.