Full abstract now posted:

CT095 / 19 - A Phase Ib/IIa study of the BET bromodomain inhibitor ZEN-3694 in combination with enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC)

Background: Abiraterone (ABI) and enzalutamide (ENZ) have significant activity in mCRPC yet demonstrate frequent cross-resistance limiting efficacy of sequential androgen receptor (AR) targeting. Bromodomain extra terminal (BET) inhibitors (BETi) down-regulate the expression of putative drivers of ABI/ENZ resistance. ZEN-3694 is an orally bioavailable, potent, and selective BETi with significant anti-tumor activity in ENZ-resistant pre-clinical models. The safety and efficacy of ZEN-3694 in combination with ENZ was evaluated in a phase 1b/2a study in mCRPC (NCT02711956).

Methods: Patients (pts) were required to have progressive mCRPC, prior resistance to ABI and/or ENZ, and no prior chemotherapy for mCRPC. A 3 plus 3 dose escalation schema was utilized, with a starting daily oral dose of ZEN-3694 36 mg plus ENZ 160 mg. Dose expansion was conducted in parallel cohorts at low and high-dose ZEN-3694 (48 and 96 mg daily, respectively). The primary objective was determination of maximally tolerated dose (MTD); key secondary endpoints included time to radiographic progression (TTP) and pharmacokinetic (PK) parameters. Pharmacodynamic (PD) markers included whole blood RNA expression of BETi targets including MYC, IL-8, CCR1, and IL1RN.

Results: 64 pts were enrolled. The median age and PSA at study entry was 70 (range 47 - 89) and 25.9 (range 0.1 ­- 1701.8), respectively. At study entry, 24 (37.5%) of pts were resistant to ABI, 29 (45.3%) were resistant to ENZ, and 11 (17.2%) to both. ZEN-3694 dose levels ranged from 36 mg to 144 mg daily without reaching a MTD. The most common treatment-related adverse events (AEs) (any grade) included transient photophobia (66%), nausea (40%), fatigue (31%), decreased appetite (22%), and dysgeusia (16%). Grade ≥ 3 related AEs (N = 8) and dose-limiting toxicities (N = 1 at 96 mg dose level) were uncommon. No Grade ≥ 3 thrombocytopenia was observed. Exposure to ZEN-3694 increased with dose without significant drug-drug interaction with ENZ. PD analyses demonstrated exposure-dependent, up to 4-fold decrease in expression of BETi targets. RNA-Seq of paired tumor biopsies demonstrated suppression of BET-dependent genes. The overall median TTP was 44.4 weeks, and was similar in subgroups with prior ABI vs. ENZ resistance. Durable responses were observed, including 3 pts with disease primarily refractory to ABI on study treatment for 21.3 +, 20.8 +, and 17.3 months, respectively, with > 90% decline in serum PSA. Early transitory serum PSA increases were associated with longer TTP.

Conclusions: ZEN-3694 demonstrates an acceptable safety and PK profile, robust target modulation, and encouraging disease stabilization in combination with ENZ in ABI/ENZ-refractory mCRPC. Analysis of paired metastatic tumor biopsies, circulating tumor cells and ctDNA is ongoing. Further investigation of the combination is warranted.