Enzalutamide With Venetoclax in Treating Patients With Metastatic Castration Resistant Prostate Cancer

PRIMARY OBJECTIVES: * To determine the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of enzalutamide in combination with venetoclax in patients with metastatic castrate resistant prostate cancer (mCRPC). (Phase Ib) * To characterize the safety and tolerability profile of enzalutamide in combination with venetoclax in patients with metastatic castrate resistant prostate cancer (mCRPC). (Phase Ib) * To evaluate the efficacy of venetoclax in combination with enzalutamide in patients with metastatic castrate resistant prostate cancer (mCRPC) that are enzalutamide-naive, as measured by 12-month progression free survival rate. (Phase II) SECONDARY OBJECTIVES: * To assess PSA50 response as well as circulating tumor cell (CTC) response in patients who received venetoclax + enzalutamide. (Phase II) -To estimate the proportion of patients who received venetoclax + enzalutamide and remain radiographic progression free at 6 months. (Phase II) * To estimate the time to first skeletal-related event (SRE) and the time to first symptomatic skeletal event (SSE). (Phase II) \- To estimate the time to clinical progression. (Phase II) * To estimate the time to initiation of new systemic treatment for prostate cancer. (Phase II) * Assess the effect of venetoclax + enzalutamide on overall survival. (Phase II) PHARMACOKINETIC OBJECTIVES: I. To characterize the pharmacokinetic (PK) profiles of enzalutamide and venetoclax when given in combination to patients with metastatic castrate resistant prostate cancer (mCRPC). II. Comprehensive analyses of venetoclax levels to assure that they are in the therapeutic range. EXPLORATORY BIOMARKER OBJECTIVES: I. To identify non-inherited biomarkers that are predictive of response to study treatment (i.e., predictive biomarkers), are associated with progression to a more severe disease state (i.e., prognostic biomarkers), are associated with acquired resistance to study treatment, are associated with susceptibility to developing adverse events, can provide evidence of study treatment activity, can increase the knowledge and understanding of prostate cancer biology or study treatment mechanism of action, or can contribute to improvement of diagnostic assays. OUTLINE: This is a phase Ib, dose-escalation study of venetoclax followed by a phase II study. Patients receive venetoclax orally (PO) once daily (QD) and enzalutamide PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 1 year and then every 3 months.