Phase Ib study of enzalutamide with venetoclax in patients with metastatic castration-resistant prostate cancer

Purpose: Castration and enzalutamide induce BCL-2 to drive therapy resistance in prostate cancer (PCa). We conducted a phase Ib trial to test that metastatic castration-resistant PCa (mCRPC) can be effectively targeted by combining enzalutamide with the BCL-2 inhibitor venetoclax. Experimental design: This phase Ib single-arm trial of enzalutamide (160 mg/d) with venetoclax in patients with progressive mCRPC assessed dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Three dose levels (DL) of venetoclax (DL1 at 400 mg/d; DL2 at 600 mg/d; and DL3 at 800 mg/d) were evaluated using a 3 + 3 design. We also analyzed enzalutamide and venetoclax pharmacokinetics and conducted pharmacodynamic studies in peripheral blood mononuclear cells (PBMCs) to determine the impact of venetoclax on BCL-2 expression. Results: A total of 10 patients were enrolled across 3 DL and no DLT was observed. Mean duration on treatment was 29 weeks (range: 8–140 weeks). Treatment-related adverse events (TRAEs) were mostly grade 1–2, and Grade 3 TRAEs included fatigue (10%) and thrombocytopenia (10%). 1/10 (10%) attained PSA50 response and 4/10 (40%) had stable disease. Estimated median overall survival (OS) was 19 months (95% CI 5–28 months) and median time to next systemic therapy (TNST) was 5 months (95% CI 1–35 months). Pharmacokinetic results revealed sub-optimal plasma levels of venetoclax. Pharmacodynamic studies demonstrated that venetoclax enhanced BCL-2β generation and promoted BCL-2 degradation. Conclusions: Enzalutamide with venetoclax has an acceptable toxicity profile in patients with mCRPC. Despite sub-optimal venetoclax levels, the treatment elicited pharmacodynamic and clinical response in a subset of patients. Clinical trial ID: NCT03751436.