1813P Phase I/II trial of oral EPI-7386 in combination with enzalutamide (enz) compared to enz alone in metastatic castration-resistant prostate cancer (mCRPC) subjects: Current phase I (PI) results

EPI-7386 is a next generation aniten designed to inhibit androgen receptor (AR) activity by binding the N-terminal domain and blocking transcription despite resistance driven by point mutations and splice variants in the ligand-binding domain. In preclinical models, the combination of EPI-7386 with Enz results in a deeper blockade of the AR pathway and greater antitumor activity, prompting this trial. This phase I/II multicenter, open-label clinical trial (NCT05075577) is enrolling mCRPC patients on androgen deprivation therapy and naïve to second-generation antiandrogens (1 line of prior chemotherapy in the metastatic hormone sensitive setting allowed). PI examines escalating doses of EPI-7386 with Enz. Primary and secondary endpoints of PI evaluate the safety and pharmacokinetics (PK) of EPI-7386 and Enz when co-administered to establish recommended phase II combination doses (RP2CDs) and address possible drug-drug interactions (DDIs). Once RP2CDs are established, phase II (PII) will commence as a two arm, 2:1 randomized trial evaluating antitumor activity of EPI-7386 in combination with Enz versus Enz alone. To date, 11 patients have been enrolled in cohorts 1-3 (cohort 4 is currently enrolling). Safety is consistent with second-generation antiandrogens (e.g., Grade 1 or 2 AEs of fatigue and hot flashes). PK results demonstrate Enz exposure is minimally impacted by EPI-7386, allowing testing of the full dose of Enz (160 mg) in the current cohort 4. EPI-7386 exposure is strongly reduced by Enz (CYP3A4 inducer that metabolizes EPI-7386) but remains in the clinically relevant range seen in xenograft studies. EPI-7386 BID dosing shows an increase in EPI-7386 exposure and mitigates DDI caused by Enz. Data from the first 10 evaluable patients show 9/10 achieve a PSA90, and 7/10 patients reach PSA <0.2 ng/mL. With no safety concerns from cohorts 1-3, cohort 4 is currently enrolling at EPI-7386 BID + 160 mg QD Enz to evaluate optimal RP2Ds before the P2 component of the trial. Updated results, including cohort 4, will be presented.