Phase Ib trial of enzalutamide (Enza) with venetoclax (Ven) in metastatic castrationresistant prostate cancer (mCRPC).

182 Background: Androgen receptor (AR) signaling is critical to prostate cancer (PCa) cell survival and proliferation. Androgen ablation leads to expansion of both AR−/lo and AR+/hi resistant clones in CRPC xenografts. Most current therapies for mCRPC are directed towards AR+/hi cells. BCL-2 is highly up-regulated in CRPC xenografts and human tumors post-Enza. Ven, a selective BCL-2 inhibitor, inhibits Enza resistance in AR−/lo and CRPC models. We hypothesize that co-targeting AR−/lo and AR+/hi clones with Ven and Enza may inhibit Enza resistance in human mCRPC. Methods: This is a phase 1b single center, single arm trial of fixed dose Enza (160mg/d) with escalating doses of Ven in patients with mCRPC that has progressed on multiple lines of prior therapies including antiandrogens to evaluate pharmacokinetics, safety and recommended phase 2 dose. A total of 10 patients were enrolled in the study. Three dose levels of Ven (400mg (DL1), 600mg (DL2), and 800mg (DL3)/d q28d) were evaluated using a 3+3 study design. Kaplan Meier method was used to estimate median overall survival (OS) and time to next systemic therapy (TNST). Results: Median age was 71.3 years and mean duration on treatment was 28.7 weeks (range: 8-140 weeks). On an average, each patient received 3 lines of treatment prior to enrollment(range:1-8). The most frequent treatment related adverse events (TRAEs) (>10%) were mostly grade 1-2 as listed. Grade 3 TRAEs included hypertension (20%), fatigue (10%), and thrombocytopenia (10%). Grade 3 fatigue as DLT was reported in one patient in DL3. Only 1/10 (10%) attained PSA50 response; 4/10 (40%) patients had stable disease and 6/10 (60%) had disease progression as their best radiographic response. Median OS for the study population was 18.8 months (95% CI 5.3-28.2 months) and median TNST was 5.4 months (95% CI 0.9-34.6 months). Conclusions: This phase 1b trial demonstrates an acceptable toxicity profile for the combination of Enza and Ven in refractory mCRPC. PK evaluations and correlative biomarker studies are currently ongoing. Clinical trial information: NCT03751436 . [Table: see text]