A randomized, open-label, phase 2b study of the BET bromodomain inhibitor (BETi) ZEN-3694 plus enzalutamide vs. enzalutamide in patients with metastatic castration resistant prostate cancer (mCRPC).
Background: Androgen receptor signaling inhibitors (ARSI), such as enzalutamide (Enza), and abiraterone (Abi), are standard therapies for metastatic hormone-sensitive and metastatic castration-resistant prostate cancer (mHSPC, mCRPC). Patients who respond to the initial ARSI are frequently prescribed a 2nd ARSI upon progression. A suboptimal response to first line ARSI, including the ~ 20% treated with an ARSI for mHSPC who progress within 12 months of treatment initiation, may enrich for cancers harboring AR-independent mechanisms of resistance including treatment-emergent neuroendocrine prostate cancer (t-NEPC). BETi have been shown pre-clinically to block the neuroendocrine prostate cancer lineage plasticity program through modulating E2F1, a transcription factor involved in stemness and cell differentiation. Prior results from a mCRPC Ph. 1b/2a trial of ZEN-3694+ Enza support this notion, as lower AR transcriptional activity in baseline tumor biopsies was associated with longer radiographic progression-free survival (rPFS). Additionally, mCRPC patients who were primary refractory to 1st line abiraterone had prolonged rPFS with ZEN-3694 + Enza, suggesting that the patients with primary resistance may benefit from the combination. To test this hypothesis, a Ph. 2b randomized trial was initiated, enriching for mCRPC with suboptimal response to 1st line ARSI. Methods: This is a multi-national (USA and China), open-label, randomized, two cohort, Ph. 2b study of ZEN-3694 + Enza vs. Enza in mCRPC patients who have progressed on Abi (NCT04986423). Cohort A (N = 150): Patients with poor response to Abi defined either as progression in < 12 months or failure to achieve PSA nadir of 0.2 ng/mL while taking Abi in HSPC setting, or progression in < 6 months and/or failure to achieve a PSA50 response while taking Abi in the CRPC setting. Cohort B (N = 50): Patients who responded to Abi, defined as > 12 months duration without progression while on Abi in the HSPC setting and achieving a nadir PSA < 0.2 ng/mL, or > 6 months duration without progression while on Abi in the CRPC setting and confirmed PSA50 response. The primary endpoint is radiographic progression-free survival (rPFS) by blinded independent central review (BICR) in Cohort A evaluated by PCWG3. Key secondary endpoints include rPFS by BICR for Cohorts A + B, PFS by investigator assessment, overall survival, PSA50 response rate, objective response rate by RECIST 1.1, efficacy endpoints for only USA patients, and patient-reported health status and quality of life, evaluated in Cohorts A, and Cohorts A + B together. The trial, conducted in collaboration with Newsoara has dosed approximately 150 of 200 patients to date. Astellas is providing enzalutamide for this study.
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