We are so excited to have you here today, Dr. Agarwal. Thank you for joining us.
Neeraj Agarwal: Thank you for having me.
Leslie Ballas: Today we are interested in hearing about the MEVPRO-3 trial. Can you give us a little bit of background on that?
Neeraj Agarwal: Of course. So MEVPRO-3 trial is a trial in metastatic hormone-sensitive prostate cancer, 900 patient trial where patients are being treated with ADT plus enzalutamide versus ADT plus enzalutamide plus mevrometostat. So that's the overall view of this trial.
Leslie Ballas: Explain to me the EZH2 drug that is being used in this trial.
Neeraj Agarwal: Before I go into the trial design, I'd love to talk about EZH2 first.
So EZH2 is a major player facilitating prostate cancer progression, progression to castration-resistant disease, neuroendocrine differentiation, and unfortunately ultimately death. Metastatic prostate cancer is universally fatal disease if patients do not succumb to other issues.
And in this context, it is very important to understand what EZH2 does. So EZH2 is a part of Polycomb Repressive Complex 2. And what they essentially do is that they methylate the histone proteins at the lysine location. And once they do, tumor suppressor genes get suppressed. So to make it very simple for my patients, I tell them that EZH2 locks the tumor suppressor genes into suitcases inside the cancer cells. And because they're locked, they are disconnected from the normal cell functioning, they cannot exert their function and cells are allowed to multiply in an uncontrolled fashion and de-differentiate. So EZH2 inhibitor like mevrometostat can actually unlock those suitcases, allow those tumor suppressor genes to come out of those suitcases and do their job in the prostate cancer cell.
Now there's another mechanism which is unique to prostate cancer, unlike many other cancers, which is transcriptional coactivation of androgen receptor. So as we know, androgen receptor is a very prominent player in prostate cancer progression and continues to play a role in every stages of prostate cancer, every phases of prostate cancer. So as we block these androgen receptor with enzalutamide, EZH2 potentially can actually allow androgen receptors to gain refractiveness from the inhibitory effect of enzalutamide by activating that. So EZH2 inhibition has dual function in prostate cancer. So mevrometostat, when combined with enzalutamide, has strong preclinical rationale.
I like to talk about the prelim result of the phase-two trial, which was presented by Dr. Mike Schweizer in 2025 ASCO GU, where 80 patients who had progressed on abiraterone and they could have received one chemotherapy in either setting were randomized to ADT plus enzalutamide versus ADT plus enzalutamide plus mevrometostat. And the efficacy data were quite striking.
The radiographic progression-free survival, which was the primary endpoint, was six months with enzalutamide alone. So that's what we expect, but it was 14.3 months with the enzalutamide plus mevrometostat with the hazard ratio of 0.5. Even PSA-50% responses were more than double with enzalutamide plus mevrometostat. So these data were compelling, sufficiently compelling to allow activation of these three large phase-three trials to in metastatic CRPC and one in metastatic hormone-sensitive prostate cancer, the MEVPRO-3 trial we are talking about.
In that trial, diarrhea was the most common side effect. And based on the high incidence of Grade 3 diarrhea, the dose of mevrometostat was reduced in the MEVPRO-1 trial and MEVPRO-2 trial. And because of the food effect that lower dose, the PK data has shown that lower dose can be equally from the pharmacokinetic perspective, equally available for an antitumor action if you time this with food.
So the bottom line is the phase-three trials are using 875 milligram dose with a expected decrease in diarrhea. We don't know the results yet for these trials.
Other than diarrhea, the other side effects are altered taste. Fatigue is always a common symptom. It's hard to decipher. It's happening because of ADT or enzalutamide because you're starting enzalutamide along with mevrometostat, but I think fatigue is one of those side effects. So mostly gastrointestinal side effects, if you will.
And hopefully with many other drugs in oncology we use timely modification of the dosing of these medications will mitigate many of those gastrointestinal side effects.
Leslie Ballas: Thank you. Tell us about the trial design of MEVPRO-3.
Neeraj Agarwal: Yes. So MEVPRO-3 is a large phase-three trial. It's 1,000 patients with newly diagnosed metastatic prostate cancer. So metastatic hormone-sensitive prostate cancer are being randomized. So they will be recruited. They could not have been treated for metastatic hormone-sensitive prostate cancer setting in this setting and they are being randomized to enzalutamide ± mevrometostat. They have to be on ongoing androgen deprivation therapy and radiographic progression-free survival is the primary endpoint. And there are many other key secondary endpoints, including overall survival, objective responses, PSA responses, quality of life, and so on.
So we are really hoping trial is accruing very well actually worldwide. It's a worldwide trial and we really hope to show positive results with this new class of drug.
Leslie Ballas: Yes, it sounds very exciting. The phase-two data is compelling. What else should we as practitioners know about mevrometostat?
Neeraj Agarwal: So for now, waiting for the results of the trial and while the trial is open, it is extremely important for us to refer patients to the further trials. If the trial is not open in your cancer centers, I strongly recommend looking up clinicaltrials.gov website is a fantastic website where MEVPRO-3, M-E-V-P-R-O-3 trial. And then this video will be on the UroToday website.
So hopefully this will allow further dissemination of awareness about this trial and ultimately referring patients for the trial is the key to complete those trials as soon as possible so that we can see the data in the very near future.
Leslie Ballas: Well, we at UroToday cannot thank you enough for talking to us about the MEVPRO-3 trial and educating us about mevrometostat.
Neeraj Agarwal: Thank you.