The first patient has been dosed in a phase 1/2 trial assessing the combination of the investigational NTD androgen receptor inhibitor EPI-7386 and enzalutamide (Xtandi) in patients with metastatic castration-resistant prostate cancer (mCRPC).1
The phase 1 portion of the study (NCT05075577) is a single-arm dose-escalation study of EPI-7386 combined with a fixed dose of enzalutamide. The study is enrolling patients who have not received second-generation anti-androgen therapies (eg, enzalutamide, abiraterone acetate [Zytiga], apalutamide [Erleada], and darolutamide [Nubeqa]), and has a target enrollment of up to 30 patients. The goal of phase 1 is to examine the safety and tolerability of the combination and determine the recommended phase 2 dose for the regimen.
Phase 2 of the trial will be an open-label, 2-arm design in which patients are randomized in a 2:1 ratio to either EPI-7386 plus enzalutamide or enzalutamide alone. The enrollment goal for phase 2 is 120 patients, with 80 patients randomized to the combination and 40 patients randomized to the control arm of single-agent enzalutamide.
"The initiation of this combination trial with [enzalutamide developer] Astellas is a watershed moment for ESSA as we investigate the potential clinical benefit of inhibiting the androgen receptor through two independent pathways in the treatment of patients with mCRPC who have not yet received treatment with a second-generation antiandrogen drug," David. R. Parkinson, MD, CEO, ESSA Pharma, stated in a press release. "Combining our two therapies will simultaneously target both ends of the androgen receptor. In preclinical models, we have seen that combining EPI-7386 with current antiandrogens can lead to deeper and broader inhibition of androgen biology. This phase 1/2 trial marks the first of a series of clinical studies to evaluate EPI-7386 in combination with current antiandrogen therapies in patients with mCRPC, with additional phase 1/2 combination trials anticipated to begin in 2022."
The small molecule inhibitor EPI-7386 previously demonstrated preclinical activity in models of antiandrogen-sensitive and -resistant prostate cancer. In September 2020, it was announced that the FDA had granted a Fast Track Designation to EPI-7386 for the treatment of patients with mCRPC resistant to standard-of-care treatments.2 In an interview with Urology Times at the time of the designation, J. Brantley Thrasher, MD, explained that EPI-7386 is part of a new class of AR-targeting compounds known as anitens.
“These compounds differ from currently available AR-blocking compounds because they bind to the N-terminal domain of the AR instead of the ligand binding domain. Due to its novel binding and mechanism of blocking the AR, it appears to work well in those patients who are progressing on current standard of care treatments,” said Thrasher.
1. ESSA Pharma Announces First Patient Dosed in a Phase 1/2 Clinical Trial of EPI-7386 in Combination with Enzalutamide in Patients with Metastatic Castration-Resistant Prostate Cancer. Published online January 19, 2022, Accessed January 19, 2022. https://prn.to/3AefzL4
2. ESSA Pharma announces fast track designation granted by the FDA to EPI-7386 for the treatment of metastatic castration-resistant prostate cancer. Press release. Essa Pharma. September 14, 2020. Accessed Sept. 16, 2020. https://bit.ly/3iCGsyL.