Phase 1/2 Study of EPI-7386 in Combination with Enzalutamide in Metastatic Castration-Resistant Prostate Cancer- Andrew Laccetti

March 3, 2023

Alicia Morgans is joined by Andrew Laccetti to discuss data on the combination of enzalutamide with the next-generation antigen EPI-7386 in chemotherapy-exposed patients with castration resistance in prostate cancer (CRPC) prior to exposure to any androgen receptor (AR) pathway inhibitor. EPI-7386 represents a new approach to disrupting the androgen receptor signaling pathway, the primary driver of prostate cancer growth. The combination trial and monotherapy study found favorable toxicity profiles, no dose limiting toxicities, and preclinical data suggests synergy with enzalutamide in a more durable response to androgen receptor pathway inhibition. The combination modality has the potential to help patients with CRPC if further investigation is conducted.


Andrew Laccetti, MD, MS, Medical Oncologist, Memorial Sloan Kettering Cancer, Center

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts

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Alicia Morgans: Hi, I'm so excited to be here with Dr. Andrew Laccetti. We're talking about a study that you presented at GU ASCO on an ESSA drug. Can you tell me a little bit about this?

Andrew Laccetti: Yes. Thank you very much for the opportunity to chat today. So EPI-7386 is a first in class N-terminal ligand inhibitor, part of a drug class called anitens. So as many in the audience are well aware, castration resistance is an eventuality for the vast majority of men with metastatic prostate cancer. Along with that, resistance mechanisms to second generation androgen receptor pathway inhibitors is a critical need for us to help overcome. So EPI-7386 is an N-terminal ligand inhibitor. So rather than binding to the ligand binding domain of the androgen receptor, it hits the back end of the molecule, antagonizing the effects of AR signaling through where the androgen receptor actually intercalates intracellularly through gene expression.

Alicia Morgans: Great. And is it expected to potentially have activity even after patients have been exposed to AR signaling inhibitors and may have developed AR mutations or multiplications, et cetera?

Andrew Laccetti: Yeah, no, we've got excellent preclinical data in-vitro and in-vivo that suggests that it has efficacy in wild type AR as well as AR mutations, including splice variants and point mutations in the ligand binding domain.

Alicia Morgans: Great. So tell me, how did you do this study? This was a phase one-two, right?

Andrew Laccetti: Correct. Yeah, so this is a phase one study, phase one-two study that's investigating EPI-7386 in combination with enzalutamide. This is in men with metastatic castration resistant prostate cancer who are naive to a second generation androgen receptor pathway inhibitor. So the study is subdivided into a dose escalation phase and then a phase two expansion. Essentially, the way the study was designed was understanding there's expected drug-drug interactions between EPI-7386 and enzalutamide. EPI-7386 is known to be a CYP3A inhibitor, which is one of the primary inducing metabolic proteins for enzalutamide.

Therefore, there was an expectation that enzalutamide may actually have a higher concentration in combination with EPI-7386. So the dose was set at 120 milligrams. Initially, the FDA labeling for enzalutamide in combination with CYP3A inhibit inducers is that it should be at 80 milligrams instead of 120. However, the expectation is that EPI-7386 is heavily protein bound and therefore we thought the exposure would be less, therefore 120 milligrams was targeted. Conversely, we expected enzalutamide as a CYP3A4 inducer to potentially reduce the level of EPI-7386. So we designed a dose escalation scheme with a fixed dose of 120 milligrams of enzalutamide in escalating doses of EPI-7386.

Alicia Morgans: Okay, and what did you see in terms of early responses and toxicity information?

Andrew Laccetti: Yeah, excellent. So to date, 10 patients have enrolled in the study. We have completed cohorts one and two through dose limiting toxicity analysis. That's a total of seven patients that were presented for analysis in this study. So the dose levels for EPI-7386 were 600 milligrams daily and 800 milligrams daily, and toxicity was very favorable. We saw it very much paralleling what we would expect with enzalutamide monotherapy. Fatigue, hot flashes were the most ... were very commonly appreciated. We also saw potentially a drug, an EPI-7386 specific effect of nausea, but generally that's grade one or two and well managed.

Alicia Morgans: Wonderful. So where do you go from here? What are next steps?

Andrew Laccetti: Yeah, no, that's a great question. So from a response rate, we've actually seen five out of six valuable patients demonstrating a PSA 90, so PSA reduction below 90%. So that 80% response rate is excellent and it's very much in line with historical results for enzalutamide as monotherapy. At this stage, it's very difficult, impossible, to really determine whether it's the enzalutamide or the EPI-7386 that's driving the efficacy we're seeing given the fact these patients are enzalutamide naive, or androgen receptor pathway inhibitor naive. So the next steps will be to continue through our dose escalation. We're currently enrolling to a 600 milligram BID cohort. We're eventually planning to expand to another cohort with a higher level of enzalutamide at 160 milligrams, because unexpectedly, we actually saw that EPI did not increase levels of enzalutamide. So we have room to increase that dose. Once a dose escalation is complete, we will transition into a phase two randomized component, which will include the combination versus enzalutamide alone.

Alicia Morgans: That's great and really exciting to think that this might potentiate the enzalutamide activity or even have some sort of synergistic effect that could be helpful for patients. So what would your message be to listeners as they're thinking about this potential treatment coming down the road, though it will be in a few years at earliest?

Andrew Laccetti: No, absolutely. So biologically, this is a very exciting drug. From a toxicity perspective, both in this combination trial as well as our monotherapy study, we found very favorable toxicity profiles, no dose limiting toxicities have been observed to date. The preclinical data is very encouraging to suggest synergy with enzalutamide in a more deep and potentially durable response to the androgen receptor pathway inhibition. And the combination modality really has a benefit to help patients with CRPC if the data bears out with further investigation.

Alicia Morgans: Wonderful. Well, I really look forward to hearing more. Congratulations on this work, and thank you so much for taking the time to share it with us.

Andrew Laccetti: Thank you very much.