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 400 mg/d; DL2 600 mg/d; and DL3 800 mg) 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 hypertension (20%), 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-therapeutic 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-therapeutic venetoclax levels, the treatment elicited pharmacodynamic and clinical response in a subset of patients.

Clinical trial ID: NCT03751436

Translational Relevance

There are limited treatment options for mCRPC patients. Castration and androgen receptor (AR) targeted therapies cause significant cellular plasticity and exacerbate AR heterogeneity in mCRPC resulting in emergence of AR-positive (AR ⁺ ) and AR-negative (AR ⁻ ) PCa progenitor cells and metastatic foci. While AR ⁺ mCRPC can be targeted by AR pathway inhibitors (ARPIs) such as enzalutamide, AR ⁻ mCRPC cannot. Based on our recent findings that castration and ARPIs upregulate BCL-2 in both AR ⁺ and AR ⁻ CRPC models to drive castration resistance, here we conduct a prospective phase Ib clinical study to test that the heterogeneous AR ⁺ and AR ⁻ mCRPC can be holistically targeted by combining enzalutamide with the BCL-2 inhibitor venetoclax.