ZEN-3694, Enzalutamide, and Pembrolizumab for the Treatment of Metastatic Castration-Resistant Prostate Cancer

Patients with metastatic castration resistant prostate cancer (mCRPC) who had prior disease progression on at least one second generation androgen signaling inhibitor, including abiraterone, apalutamide, darolutamide, and/or enzalutamide and have clinicogenomic evidence of transdifferentiated mCRPC (Cohort A) or mCRPC without transdifferentiation (Cohort B). Prior to enrollment in Phase 2 (Cohort A and B), a safety lead-in cohort of 6 patients with metastatic CRPC will be enrolled. Accrual will proceed to Phase 2 if \< 33% of patients (0/6 or 1/6 patients) experiences a dose-limiting toxicity during Cycle 1. OUTLINE: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1, BET bromodomain inhibitor ZEN-3694 orally (PO) once daily (QD) and enzalutamide PO QD on days 1-21. Patients not on enzalutamide prior to study enrollment or have previously discontinued enzalutamide receive BET bromodomain inhibitor ZEN-3694 beginning on day 1 of cycle 2. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and every 90 days until death or study completion or loss to follow-up, whichever occurs first. PRIMARY OBJECTIVE: I. To determine the composite response rate in Cohort A and Cohort B study population. SECONDARY OBJECTIVES: I. To determine the objective response rate and median duration of response in each study cohort. II. To determine the median progression free survival and 6-month progression-free survival rate. III. To determine the prostate-specific antigen (PSA) 50 (PSA50) response proportion in each study cohort. IV. To determine the median overall survival of each cohort. V. To determine the safety of the treatment combination. EXPLORATORY OBJECTIVES: I. To explore the association between baseline metastatic tumor characteristics including treatment-emergent small cell neuroendocrine carcinoma (t-SCNC), androgen receptor (AR), retinoblastoma tumor suppressor gene (RB1) loss, and immune response transcriptional signatures with clinical outcomes. II. To evaluate modulation of AR transcriptional activity, expression of t-SCNC markers, and immune parameters including tumor-infiltrating lymphocytes and PD-L1 expression in evaluable paired tumor biopsies. III. To evaluate the association between baseline and change from baseline in peripheral blood biomarkers including T cell subsets, T cell repertoire, and inhibitors of bromodomain extraterminal protein (BETi) whole blood ribonucleic acid (RNA) panel with clinical outcomes. IV. To evaluate the association between baseline or change from baseline in gallium Ga 68 citrate (68Ga-citrate) positron emission tomography (PET) with subsequent clinical outcomes. V. To compare efficacy outcomes (composite response, PSA50 response, objective response, progression-free survival (PFS), and overall survival (OS)) between cohorts.