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Zachary Klaassen: Hi, my name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I am delighted to be joined on UroToday with Dr. Neeraj Agarwal, medical oncologist at the Huntsman Cancer Institute in Salt Lake City.Today, we're going to be discussing an SUO 2024 presentation from Doctor Agarwal, The Phase III Randomized MEVPRO-1 Study. And this is looking at mevrometostat, in combination with enzalutamide in patients with mCRPC previously treated with abiraterone acetate. Neeraj, thanks, as always, for your time on your show today.

Neeraj Agarwal: Absolutely. It’s such a pleasure, Zach, to discuss these trials with you and for our patients and colleagues out there.

Zachary Klaassen: Absolutely. Before we get going through the trial, this is an important target that we're discussing today. A novel target, EZH2. I think for the majority of folks, I would surmise they would like background on what this molecule is and really what this trial is targeting.

Neeraj Agarwal: Yes. I think you raised a critical question about how EZH2 works. And for our audience, for our colleagues, for our patients out there, I'd like to simplify this. So if you look at the full form of EZH2, this is enhancer of GST homolog 2, which is a key component of what we call as Polycomb Repressive Complex II or PRC2.

So what is actually—what does it do actually in simplified fashion, if I will? So EZH2 is an enzyme that adds methyl group to the histone proteins. And this modification, this methylation leads to the repression of the gene expression. So by adding these methyl groups, EZH2 compacts the chromatin structure, making it less accessible to the transcription machinery. And if transcription machinery cannot access those parts of the DNA, those genes get silenced.

Now, the problem is many of those genes are tumor suppressor genes or regulatory genes. And if you silence them, it can lead to uncontrolled cell growth and cancer progression. EZH2 pathway is involved in multiple cancers, including prostate cancer. So it makes sense that if you block the EZH2 with drugs like mevrometostat, that can lead to control of cancer progression and shrinkage and improve survival outcomes in our patients.

Zachary Klaassen: Excellent, excellent. That's a great background for our listeners. And so maybe this will just lead into the background of how we're thinking about this from a clinical trial perspective.

Neeraj Agarwal: Absolutely. So if we look at the earlier phase trial reported by Dr. Schweitzer, and hopefully we'll see more data in the coming meeting. Mevrometostat, which is a potent and selective small molecule EZH2 inhibitor, was combined with the enzalutamide in those patients who had prior exposure to abiraterone, and in those patients who had received ARPI, just to keep it simple. And in this earlier trial, and of course, we will be seeing more data hopefully in the coming meeting.

If you look at the radiographic progression-free survival, it was 17 months in patients who had received prior abiraterone. And in patients who had received even prior enzalutamide, the median progression-free survival, radiographic progression-free survival was 11 months. So what I gather from these data, even though a small trial, early phase trial, if you combine mevrometostat with enzalutamide, there is a promise out there. And of course, as I said, we will be seeing more data in the coming meeting from this trial.

So now let's come to the Phase III Trial, which has been launched based on these exciting data, solid preclinical rationale, solid biological rationale, and of course, the Phase I Trial and early Phase II Trial. So here is the design of the Phase III Trial. This is a patient population which has metastatic castration resistant prostate cancer, who have had disease progression on androgen deprivation therapy, and they have also had disease progression on abiraterone.

And these patients will be randomized to enzalutamide plus mevrometostat, a potent EZH2 inhibitor, versus physician choice of enzalutamide or docetaxel chemotherapy. The primary endpoints are radiographic progression-free survival, and an important secondary endpoint is overall survival. And of course, there are multiple other secondary endpoints, such as patient-reported outcomes, which is important for all of us to assess quality of life of these patients, response rates, and many others.

I would like to bring your attention to the fact that the control arm does have the choice of chemotherapy, in addition to enzalutamide, which we know has activity after prior failure of abiraterone. And this is a relatively large trial—hundreds of patients. And I'm happy to report that the trial has started recruiting and it is being opened in several centers across the world, in many centers across countries and continents.

So for our viewers, the take-home message is EZH2 inhibition is a promising area of drug development in advanced metastatic prostate cancer. And this Phase III Trial, also known as MEVPRO-1 of enzalutamide with and without mevrometostat, may establish concurrent EZH2 and AR targeting as a standard of care for our patients with mCRPC in the near future. And I look forward to accruing in this clinical trial.

And thank you very much for giving the shout-out to this clinical trial through this, one of the best, I would say, digital media channels in our world, which is UroToday.

Zachary Klaassen: Thanks so much, Neeraj. Great, great overview of this trial. When I was looking at your presentation at SUO, it really sort of—I had to take a step back from a very high-level view. We're moving into 2025, for our listeners, it’s just incredible we're finding these new targets.

A target that is somewhat responsible for adenocarcinoma to neuroendocrine differentiation, and we are now targeting with specific inhibitors in a Phase III Trial. I mean, we've come such a long way in a decade from the chartered stampede, maybe just a 30-second response on how incredible this really is.

Neeraj Agarwal: Firstly, I feel very optimistic. The earlier trial data are very promising. And as I said, we look forward to seeing more data in the coming meetings. And all I can tell you right now is that it is very promising and I look, really looking forward to a positive trial which will establish EZH2 inhibition as an integral part of treatment armamentarium in our clinic for our patients with metastatic castration-resistant prostate cancer in the very near future.

Zachary Klaassen: Yeah, absolutely. And I think, just to spin off of that last point you made, let's fast forward. This is what the beauty of UroToday is. We can have these discussions. Let's say that the MEVPRO-1 trial is a positive trial. Where do you think mevrometostat plus enzalutamide may line up in this growing armamentarium of treatment options we have for mCRPC?

Neeraj Agarwal: The best part of this drug is that this is an oral pill which allows our patients to stay at home, not worry about coming to the cancer centers or their doctor's office for long infusion chemotherapies, or like we see with chemotherapies and many other intravenous injections.

So that's number one. Number two, based on what we have seen so far, is pretty well tolerated. And number three, one of the most attractive parts is the combination with enzalutamide, which is one of the most widely utilized ARPI, or androgen receptor pathway inhibitor, in our patients—not only in metastatic castration-resistant prostate cancer but also in earlier phase or phases of advanced prostate cancer.

So if this trial is positive, which I really hope it is, it will open the avenue for combining mevrometostat with enzalutamide in many other settings, even in metastatic hormone-sensitive prostate cancer setting. So I think the scope is quite wide here. And again, as I said, an oral pill combined with a widely utilized pill definitely gives a lot of autonomy to our patients.

And ultimately, we'll have to see the data. How the data are. But assuming everything goes well, I think this will, as I said, become an integral part of our treatment armamentarium for our patients.

Zachary Klaassen: Yeah, absolutely. Well, we certainly look forward to subsequent results from the MEVPRO-1 trial. As always, Neeraj, thanks for your time and expertise on UroToday.

Neeraj Agarwal: Thank you very much for having me, Zach.