October 23, 2023
EPI-7386 & Enzalutamide Combination in mCRPC Holds Potential
By Dibash Kumar Das, PhD
In the relentless quest to find effective treatments for metastatic castration-resistant prostate cancer (mCRPC), a Phase I/II clinical trial of EPI-7386 in combination with enzalutamide has entered the spotlight, offering a glimpse of hope for patients grappling with this challenging condition.
Andrew Laccetti, MD, MS, study author and a medical oncologist focusing on prostate cancer and genitourinary cancer at Memorial Sloan Kettering Cancer Center, underscores that “to date, androgen receptor (AR) pathway inhibitors either competitively antagonize the receptor via the ligand-binding domain or block androgen synthesis.”
However, EPI-7386 represents a significant leap in the realm of antiandrogens. According to Laccetti, “EPI-7386 is a next-generation aniten, a new class of compounds designed to inhibit AR activity by binding to the N-terminal domain of the receptor, thus blocking transcription even in the presence of resistance mechanisms, including those centered at the AR ligand binding domain.”
This mechanism holds promise even in the face of resistance driven by point mutations and splice variants in the ligand-binding domain. The study was presented at the ESMO 2023 Congress held in Madrid, Spain (Abstract 1813P).
Preclinical models provided a compelling rationale for this trial, demonstrating that the combination of EPI-7386 with enzalutamide results in a more profound blockade of the AR pathway and enhanced antitumor activity. The ongoing Phase I/II multicenter, open-label clinical trial (NCT05075577) is enrolling mCRPC patients who are on androgen deprivation therapy and have not been exposed to second-generation antiandrogens. A single line of prior chemotherapy in the metastatic hormone-sensitive setting is permitted.
The Phase I component of the trial is meticulously examining escalating doses of EPI-7386 in conjunction with enzalutamide, focusing on primary and secondary endpoints related to safety and pharmacokinetics. This phase aims to establish recommended Phase II combination doses (RP2CDs) and assess potential drug-drug interactions. Once the RP2CDs are determined, the Phase II portion of the trial will proceed as a two-arm, 2:1 randomized study to evaluate the antitumor activity of EPI-7386 in combination with enzalutamide versus enzalutamide alone.
As of now, the trial has enrolled 11 patients across Cohorts 1-3, with Cohort 4 currently open for enrollment. Encouragingly, safety profiles align with second-generation antiandrogens, with mostly Grade 1-2 adverse events, such as fatigue and hot flashes. Pharmacokinetic results show that enzalutamide exposure is minimally impacted by EPI-7386, allowing for testing of the full enzalutamide dose (160 mg) in the current Cohort 4.
Importantly, EPI-7386 exposure is significantly reduced by enzalutamide, which acts as a CYP3A4 inducer metabolizing EPI-7386. Nevertheless, EPI-7386 levels remain within the clinically relevant range established in xenograft studies. Notably, data from the first 10 evaluable patients indicate that 9 out of 10 achieved a PSA90, and 7 out of 10 patients reached PSA levels below 0.2 ng/mL.
With no safety concerns arising from cohorts 1-3, cohort 4 is currently enrolling patients receiving EPI-7386, aiming to determine the optimal recommended Phase II combination doses (RP2CDs) before advancing to the Phase II component of the trial. Laccetti aptly concluded that “based on the current safety and pharmacokinetic data from the Phase I segment of this study through Cohort 4, we recommend Phase II combination doses of 600 mg twice daily for masofaniten and 160 mg daily for enzalutamide. Furthermore, the corresponding Phase II study, focused on delving into the safety and efficacy of these dose levels, is actively enrolling participants."
Dibash Kumar Das is a contributing writer