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Zach Klaassen: Hi, my name is Dr. Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. And I'm pleased to be joined today by Dr. Andrew Laccetti, who is a genitourinary medical oncologist at Memorial Sloan Kettering Cancer Center. Thanks so much for joining us today.

Andrew Laccetti: Happy to be here today. Thanks for the opportunity.

Zach Klaassen: So we're going to be talking today about EPI-7386, Masofaniten, which has generated some really interesting results in some of the early data that's been presented at previous meetings. And so just tell our listeners a little bit about what this is mechanistically.

Andrew Laccetti: So yeah, EPI-7386, most recently branded Masofaniten, is a first-in-class anti-androgen drug referred to as an N-terminal domain ligand inhibitor. So as much of the audience is aware, hormonally based testosterone-directed therapies have been the mainstay of treatment in prostate cancer. When it comes to androgen receptor antagonists, to date, we've only developed drugs that work at the ligand-binding domain. So Masofaniten actually operates on the back end of the receptor, referred to as the N-terminal domain. And it's an attempt to overcome much of the resistance mechanisms that have been observed in response to drugs like ADT and some of the novel oral hormonal therapies. This includes things like splice variants and ligand-binding domain mutations. So biologically, we're very excited for this drug and eager to see how it performs in patients.

Zach Klaassen: Absolutely. So take us through some of the previous data that's been presented in, I know, last year at GU ASCO, ESMO 2023. What's the lead-up into what we've already seen with Masofaniten?

Andrew Laccetti: Yeah, so the report that's specific for GU ASCO 2024 and has also been reported at prior meetings as you mentioned, is a study in which Masofaniten is combined with enzalutamide. We also have a monotherapy study that's underway, but for purposes of the discussion today, our combination study with enzalutamide is what we'll discuss. So there's some preclinical data that suggests that Masofaniten may in fact synergize with enzalutamide, creating a more deep and hopefully durable response to hormonally directed therapy. Therefore, a study has been designed in collaboration with ESSA Pharmaceuticals to explore Masofaniten in combination with enzalutamide.

Zach Klaassen: So speaking of GU ASCO, this was recently presented as you mentioned, what was the update and the highlights from the data presented recently?

Andrew Laccetti: Yeah, so the study itself was designed in two phases. It's a phase one, phase two study. Initially, enzalutamide and Masofaniten were combined using a dose-escalating design in order to determine the optimal combination for phase two exploration. So at GU ASCO 2024, we're presenting results from the phase one component, and in this portion of the study, patients received an escalating dose of Masofaniten with a fixed dose of enzalutamide. Initially, the cohorts were started with 120 milligrams of enzalutamide, anticipating a drug-drug interaction that would actually boost the level of enzalutamide in serum.

Zach Klaassen: I see.

Andrew Laccetti: So that's why we didn't initially select for 160 milligrams daily of enzalutamide. After the first several cohorts, we realized that the pharmacokinetic interaction was not observed, and in the later cohorts of the phase one study, we actually incorporated enzalutamide at full dose, 160 milligrams daily.

So the data that is being presented at this meeting incorporates that dose escalation program. It incorporates 18 patients, 13 of whom actually still remain on trial with a median follow-up of about 11 months. And what we've observed is a very favorable safety and toxicity profile that mimics that of enzalutamide as monotherapy. With the one exception, we're maybe seeing a little bit of GI side effects, some nausea, and some diarrhea, although it's generally mild, low grade.

So speaking to the efficacy that's been observed to date, of the 18 patients enrolled, we're seeing a PSA90 rate of 81%, which is excellent. I will give the caveat that included in this study are men with castration-resistant metastatic disease; however, they cannot have been exposed to an oral anti-androgen yet. So no abiraterone, enzalutamide, apalutamide. With that said, that PSA90 response rate is responding really favorably to historical averages.

Zach Klaassen: That's great 'cause we know that deep PSA response, especially early, means a lot as these patients go forward. So if we extrapolate where this study design goes, maybe to a phase three, let's say there's a positive phase three trial, how do you see this fitting into this very complicated sequencing network of MCRPC?

Andrew Laccetti: Yeah, so first and foremost, we're very excited to extend the study into its randomized phase two portion-

Zach Klaassen: Excellent.

Andrew Laccetti: ... in which we're comparing the combination, 600 milligrams of Masofaniten with 160 milligrams of enzalutamide, and that's compared to enzalutamide alone. So that study is currently underway. But yes, we are hopeful that if we receive favorable results from the phase two study, eventually a phase three could emerge, and I anticipate this drug would be beneficial for men, likely those that are still within a circumstance where chemotherapy is not a dire or urgent need, or men who are interested in avoiding chemotherapy. So enriching for folks that have AR-driven disease, that we're able to overcome some of the resistance that has developed, is really the position that we're hoping to place Masofaniten in. But certainly, the future will show us how the drug is best utilized, and there's the opportunity to even explore it in other disease settings.

Zach Klaassen: Yeah. I think you mentioned the combination of really strong efficacy, but that tolerability. When I look at this data, that's what's really exciting is we may have something that could really drive home deep PSA responses with minimal toxicity.

Andrew Laccetti: Yeah, exactly. And I think it's important to recognize that hormonal therapies, even in the castration-resistant setting, we still have the opportunity to really make a difference and do some rational, sound drug development, as you said, to hopefully care for patients with better-tolerated drugs.

Zach Klaassen: Absolutely. It's been a great discussion. Anything we haven't hit on that you want to discuss, or any take-home messages for our listeners?

Andrew Laccetti: Yeah, so just as mentioned, Masofaniten is a first-in-class N-terminal domain ligand inhibitor. We're showing good toxicity and early efficacy data in our phase one component of the combination study with enzalutamide, and we're eagerly anticipating the results as we move forward into the phase two portion.

Zach Klaassen: That's great. Awesome discussion. Thanks so much for your time.

Andrew Laccetti: All right, thank you.