Abstract

Purpose: ZEN-3694 is a bromodomain extra-terminal inhibitor (BETi) with activity in androgen signaling inhibitor (ASI)-resistant models. The safety and efficacy of ZEN-3694 plus enzalutamide (ENZ) was evaluated in a phase 1b/2a study in metastatic castration-resistant prostate cancer (mCRPC).

Experimental design: Patients had progressive mCRPC with prior resistance to abiraterone (ABI) and/or ENZ. 3+3 dose escalation was followed by dose expansion in parallel cohorts (ZEN‑3694 at 48 and 96 mg orally once daily, respectively).

Results: Seventy-five patients were enrolled (N = 26 and 14 in Dose Expansion at low- and high-dose ZEN-3694, respectively). Thirty (40.0%) patients were resistant to ABI, thirty-four (45.3%) to ENZ, and eleven (14.7%) to both. ZEN-3694 dosing ranged from 36 mg to 144 mg daily without reaching an MTD. Fourteen patients (18.7%) experienced grade ≥ 3 toxicities, including three patients with Grade 3 thrombocytopenia (4%). An exposure-dependent decrease in whole blood RNA expression of BETi targets was observed (up to 4-fold mean difference at 4 hours post-ZEN-3694 dose; p ≤ 0.0001). The median radiographic progression-free survival (rPFS) was 9.0 months (95% CI: 4.6, 12.9) and composite median radiographic or clinical progression-free survival was 5.5 months (95% CI: 4.0, 7.8). Median duration of treatment was 3.5 months (range 0 -- 34.7+). Lower AR transcriptional activity in baseline tumor biopsies was associated with longer rPFS (median rPFS 10.4 vs. 4.3 months).

Conclusions: ZEN-3694 plus ENZ demonstrated acceptable tolerability and potential efficacy in patients with ASI-resistant mCRPC. Further prospective study is warranted including in mCRPC harboring low AR transcriptional activity.