Background: EPI-7386 is a next generation aniten designed to inhibit androgen receptor (AR) activity by binding to the N-terminal domain (NTD) of the AR while effectively blocking transcription despite AR resistance mechanisms driven by the ligand-binding domain (LBD), including point mutations and splice variants. Preclinical models demonstrate the combination of EPI-7386 with enzalutamide (enz) results in a deeper blockade of the AR pathway (per RNAseq and ChIPseq data) and greater antitumor activity, prompting initiation of this trial. Methods: This Phase 1/2 multicenter, open-label clinical trial (NCT05075577) is enrolling mCRPC pts on androgen deprivation therapy and naïve to second-generation antiandrogens (one line of prior chemotherapy allowed). Phase 1 (P1) of the trial examines escalating doses of EPI-7386 in combination with a fixed dose of enz. The primary and secondary endpoints of P1 are to evaluate the safety and pharmacokinetics (PK) aspects of EPI-7386 and enz when administered in combination to establish the recommended Phase 2 combination doses (RP2CDs) and address any possible drug-drug interactions. Once the RP2CDs are established, Phase 2 of the trial will commence as a two -arm, 2:1 randomized trial evaluating the antitumor activity of EPI-7386 in combination with enz versus enz alone. Results: Seven pts have been enrolled in the first 2 cohorts: 3 in cohort 1 (600 mg QD EPI-7386 + 120 mg QD enz) and 4 in cohort 2 (800 mg QD EPI-7386 + 120 mg QD enz). No DLTs were observed, and the safety profile was consistent with second-generation antiandrogens (e.g., Grade 1 or 2 AEs of fatigue and hot flashes). PK results demonstrated enz exposure was minimally impacted by EPI-7386, while, as expected, EPI-7386 exposure was reduced 60-80% by enz (well-established CYP3A4 inducer). The observed EPI-7386 exposures remained in the clinically relevant range suggested by preclinical xenograft studies. 4/6 evaluable patients showed a PSA decrease >90% at/before week 12 regardless of the pt’s previous chemotherapy status and 5/6 evaluable patients achieved a PSA decrease of at least 85%; all 6 patients showed stable disease by imaging. Conclusions: With no safety concerns from cohorts 1 and 2, cohort 3 is enrolling at 600 mg BID EPI-7386 + 120 mg QD enz to assess if the exposure of EPI-7386 can be further increased in light of the augmented metabolism of the drug induced by enz. Clinical trial information: NCT05075577.