Neeraj Agarwal: Thank you, Dr. Ballas. Call me Neeraj, please.
Leslie Ballas: Call me Leslie.
Neeraj Agarwal: Let's make it informal, to make it really easy for our audience and viewers today. So MEVPRO-1 trial is a metastatic CRPC trial, and I will use this opportunity to also talk about MEVPRO-2 trial, which is also an mCRPC trial. So before we go to discuss these trials and design and endpoints, I'd like to take a minute to talk about mevrometostat, which is a EZH2 inhibitor. First, as we know, prostate cancer ultimately progresses. Metastatic prostate cancer progression is universal, and one of the key factors, players in this progression, is EZH2.
And it's a mouthful to elaborate on EZH2, but Enhancer of Zeste Homolog 2 is a transcription repressor, which actually doesn't allow tumor suppressor genes to express themselves. So technically speaking, EZH2 is a part of PRC2 complex, what we call as Polycomb Repressive Complex 2, and it puts methylation, methyl groups, at the lysine location of the histone proteins. And to keep it simple, the way I explain to my patients when I recruit them on the trial, I tell them that all our cancer, all the cancers, partly originate because the tumor suppressor genes stop working very well, and it partly happens because this EZH2 puts those tumor suppressor genes into suitcases and lock them from outside.
Leslie Ballas: I like that. That's good.
Neeraj Agarwal: So when we use EZH2 inhibitor, that essentially unlock those suitcases inside the cancer cells and allow those tumor suppressor genes to exert their effects, thereby decreasing proliferation, transformation to neuroendocrine phenotype, which is mostly one of the most lethal forms of prostate cancer, and so on.
Now, the second, less-discussed mechanism of EZH2 is that it can act as a transcriptional coactivator for androgen receptor. Now, androgen receptor we know is the major player in prostate cancer, and we block them with enzalutamide-like drugs. But then if EZH2 activates androgen receptor, it can make drugs like enzalutamide less effective, because now androgen receptor has another partner to stimulate this action. So mevrometostat, by inhibiting EZH2, is unlocking those suitcases where tumor suppressor genes have been hidden so they exert their effect better, and also allows drugs like enzalutamide to work better on androgen receptor.
Leslie Ballas: Tell us about the work that led to this trial.
Neeraj Agarwal: The preclinical data are strong, but then there was a trial presented by Dr. Mike Schweizer and team last year, and this is a phase-2 trial, which was also built on phase-1 data. In this phase-2 trial, 80 patients with metastatic castration-resistant prostate cancer progressing on abiraterone were randomized to enzalutamide versus enzalutamide plus mevrometostat, and they could have received one chemotherapy in the past.
The signals were quite striking. If you look at the efficacy endpoint, the radiographic progression-free survival, the rPFS was six months in those patients who received enzalutamide alone, and that's what we expect post-abiraterone. We also saw this red data from a similar trial presented earlier, and that's what our clinical experience is, that enzalutamide retains some activity after abiraterone, so six months radiographic progression-free survival. But if you look at those patients who got enzalutamide plus mevrometostat, the progression radiographic PFS was 14.3 months. Hazard ratio of 0.51, but 50% reduction risk of progression or death.
In such a small trial, I think this is one of the most striking signals or efficacy signals we have seen in any of the phase-2 trials with these novel agents in the recent past. Even PSA-50% responses were almost doubled ... more than doubled actually, so 15% versus 34% ... in patients who received enzalutamide plus mevrometostat. So obviously these signals were striking enough, compelling enough, to these two phase-3 large randomized controlled trial in the CRPC setting.
Leslie Ballas: And is the endpoint for MEVPRO-1 and -2 also radiographic progression-free survival?
Neeraj Agarwal: Yes. So radiographic progression-free survival is acceptable. FDA has accepted this endpoint, like many other cancers, so as to not delay the approval of drugs for our patients for too long if overall survival is an endpoint. But in pretty much all these trials, many of these trials, overall survival is a key alpha-protected secondary endpoint. So we will have robust information on the overall survival within due course of time, yes.
Leslie Ballas: And is the radiographic progression-free survival based on conventional imaging? How does it integrate PSMA?
Neeraj Agarwal: That's a great question. Yeah, so it's a PCWG3 guideline. I know PCWG4 is out, but PCWG3 is what was used for determining radiographic progression-free survival in these two trials. So MEVPRO-1 is post-abiraterone trial. As we know, about 30% of patients who receive ARPI, first ARPI, 30 to 40% of patients receive abiraterone across the world in many settings. Even now, localized prostate cancer setting, abiraterone is used now. So patients who are progressing on abiraterone, they have to have disease progression while receiving abiraterone or prior therapy of abiraterone. So after they have been failed by abiraterone, they are randomized to enzalutamide versus enzalutamide plus mevrometostat. So exactly the same design, but just a larger number of patients, 600 patients in this trial.
Now, MEVPRO-2 is slightly earlier in the course of disease. So these are those patients who have received only ADT before progressing to mCRPC. That population may sound trivial in medical oncology clinics, but if you look at the overall number of patients in America, if you have 100 patients diagnosed with prostate cancer, 90 of them are diagnosed in the localized form because of the relatively high PSA screening, unlike many other parts of the world, where metastatic disease is the most common way for prostate cancer to present. In U.S., only 10% of patients present with de novo metastatic prostate cancer. So all these patients who present to their urologists or radiation oncologists like you, they are treated with definitive radiation therapy, prostatectomy, and they have biochemical recurrence. The most common therapy used for those patients in biochemically recurrent setting is ADT monotherapy, either intermittent or continuous.
So there is a large number of patients out there, also based on our own real-world data from Flatiron and on many other databases, that there is a significant number of patients out there who are developing mCRPC without actually progressing on a ARPI, so the MEVPRO-2 trial is for those patients. So patients who have newly diagnosed mCRPC have not been exposed to an ARPI, they are being randomized to ADT plus enzalutamide versus ADT plus enzalutamide plus mevrometostat. It's a larger trial because we needed more effect size, so a 900 patients trial. Ultimately again, very standard endpoints, radiographic PFS and other OS, PFS responses, objective responses, quality of life. There are multiple other important secondary endpoints.
Leslie Ballas: How are you integrating metastasis-directed therapy into the patients who are either going to go onto MEVPRO, would be candidates, or on MEVPRO?
Neeraj Agarwal: Metastasis-directed therapy is probably not a very common option for patients who are metastatic CRPC progressing on abiraterone, but patients who have progressed on ADT and they have oligoprogression, I use metastasis-directed therapy in my clinic in many patients. It's not very unusual treatment, but in this trial, metastasis-directed therapy is not allowed.
Leslie Ballas: Great.
Neeraj Agarwal: So once patient go on the trial, unless they have symptoms, baseline symptoms, they may be allowed to receive radiation therapy, but once they enroll on the trial, because radiographic progression-free survival is the primary endpoint, obviously it is not allowed. But this will also allow I think more eligible patients to go on these trials, patients with high-volume disease, even in mCRPC setting who really need systemic therapy, are the ones who will be enrolled and who should be enrolled in this trial.
Leslie Ballas: Well, I look forward to seeing what these results are in the future, and I thank you very much for joining us today.
Neeraj Agarwal: Thank you for having me. It's a pleasure.