Nobuaki Matsubara: Thank you very much, Neeraj, my friend. I'm very happy to join today's recording. Thank you.
Neeraj Agarwal: You have done so much work in the field, and you were very closely involved with the development of mevrometostat, a novel drug being investigated in prostate cancer patients, metastatic hormone-sensitive metastatic castration-resistant prostate cancer patients. Multiple phase three trials are ongoing. But this whole story started with your earlier work on the phase one study. So I'd like to ask you, Nobuaki, for our worldwide audience today, could you tell us more about mevrometostat first? What is mevrometostat? And what is EZH2?
Nobuaki Matsubara: EZH2 is a driver in prostate cancer, not only CRPC, especially in the HSPC. And also one of the recent mechanisms of the AR inhibition. Maybe a potential good target.
Neeraj Agarwal: So basically targeting EZH2 may allow these cancer cells to respond better and longer to ADT plus enzalutamide, for example.
Nobuaki Matsubara: Yeah.
Neeraj Agarwal: So, please tell about your phase one trial, how many patients were there, and what kind of treatments they had received in the past? Nobuaki Matsubara: Yes. Thank you very much, Neeraj. So this phase one trial includes a lot of the cohort, so from heavily treated patients to only one prior ARPI treatment. So interestingly, so after progression on the enzalutamide, add on that EZH2 inhibitor mevrometostat, we can observe the response again. So after resistance to the enzalutamide in the phase one trial. So at this year's ASCO GU, I presented both enzalutamide plus abiraterone exposure population and abiraterone only exposure population results.
Neeraj Agarwal: How many patients were there?
Nobuaki Matsubara: 14 and 15, relatively small cohorts.
Neeraj Agarwal: So, 14 patients and 15 patients were progressing on enzalutamide or abiraterone?
Nobuaki Matsubara: Yes, 14 patients progressed on the enzalutamide and abiraterone. And another cohort progressed on only abiraterone.
Neeraj Agarwal: What did you do? What was your intervention? You added mevrometostat as a single agent? Or you continued the previous therapy and added mevrometostat to the backbone?
Nobuaki Matsubara: Yes, that's a good point. So unfortunately, mevrometostat monotherapy unfortunately lacks efficacy. So we need a backbone ARPI continuous treatment. And then add on the EZH2 inhibitor.
Neeraj Agarwal: That makes sense because EZH2 inhibition will only work if these patients are being treated with androgen-signaling inhibitor. So what were the results?
Nobuaki Matsubara: Yes. So median follow-up period is now relatively short, just about 10 months. But median progression-free survival is 14 months and not yet reached, respectively. So this median PFS is encouraging to go to the phase three or larger phase two trial. And also, we would like to share the PSA response rate. So regardless of the previous treatment exposure, so PSA response rate is over 40%.
Neeraj Agarwal: That's very encouraging. These patients who are progressing on abiraterone, on enzalutamide, or enzalutamide, and then you are finding a median PFS or radiographic PFS of 14 months. And this is very similar to the other trial previously presented.
Nobuaki Matsubara: Yeah.
Neeraj Agarwal: Almost identical, if I'm not mistaken, in the randomized fashion, when patients were randomized to enzalutamide plus minus mevrometostat, after abiraterone, it was 14.3 months?
Nobuaki Matsubara: Mm-hmm.
Neeraj Agarwal: Any side effect you worry about? Or you have to focus on management? Because our colleagues worldwide are recruiting on these big phase three trials, and we like to hear from you. Any side effect we should be particularly concerned about? And should we take this drug with food or without food?
Nobuaki Matsubara: Thank you very much, Neeraj. So this is a very important perspective. So common side effect is GI toxicity such as nausea or dyskinesia. It is a very hateful side effect from patient perspective. But unfortunately, so our phase one study and also current phase three study, we chose the reduced dose of the mevrometostat and with food. So this change can reduce and improve tolerability. So as a result, treatment discontinuation due to the side effects is less than 10%.
Neeraj Agarwal: That's very encouraging that patients are able to tolerate the medication with food. So, like to emphasize with food because food increases the absorption of mevrometostat and also improves the GI tolerability of mevrometostat. So you take it with food with enzalutamide, and basically the discontinuation rates because of side effects is less than 10%. That's, I think, very encouraging. What is the dose of mevrometostat?
Nobuaki Matsubara: Choose the recommended phase three dose is 875 milligrams twice daily. So initially we chose the recommended phase dose at 1,215 milligrams, but as I explained earlier, we can succeed to reduce that dose, and it results in the lower side-effect rate and lower discontinuation rate.
Neeraj Agarwal: And that's why we need expert investigators like you who can figure out how to reduce the side effects without compromising on the exposure level of the drug in the blood. And this was, I thought was brilliant that the food, because it increases the absorption of mevrometostat and improves the GI tolerability of mevrometostat, reducing the dose and taking it with food have resulted already in improvement of side-effect profile. Well, Dr. Matsubara, Nobuaki, my friend, congratulations for doing these studies with cutting-edge therapies and moving the field forward. And thank you for everything you do, and thank you for joining us today.
Nobuaki Matsubara: Thank you very much, Neeraj. I'll see you soon.