A Phase Ib/IIa Study of the Pan-BET Inhibitor ZEN-3694 in Combination with Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Rahul R AggarwalJoshi J Alumkal

Abstract

ZEN-3694 is a bromodomain extraterminal inhibitor (BETi) with activity in androgen-signaling inhibitor (ASI)-resistant models. The safety and efficacy of ZEN-3694 plus enzalutamide was evaluated in a phase Ib/IIa study in metastatic castration-resistant prostate cancer (mCRPC). Patients had progressive mCRPC with prior resistance to abiraterone and/or enzalutamide. 3+3 dose escalation was followed by dose expansion in parallel cohorts (ZEN-3694 at 48 and 96 mg orally once daily, respectively). 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 abiraterone, 34 (45.3%) to enzalutamide, and 11 (14.7%) to both. ZEN-3694 dosing ranged from 36 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 fourfold mean difference at 4 hours post-ZEN-3694 dose; P ≤ 0.0001). The median radiographic progression-free survival (rPFS) was 9.0 months [95% confidence interval (CI), 4.6-12.9] and composite median radiographic or clinical progress...Continue Reading

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Citations

Jan 13, 2021·Current Oncology Reports·Yasutaka Yamada, Himisha Beltran
Feb 19, 2021·Journal of Medicinal Chemistry·Yi ZhangYuanxiang Wang
Mar 17, 2021·British Journal of Cancer·Tatiana ShorstovaMichael Witcher
Apr 1, 2021·European Urology·Anbarasu KumaraswamyJoshi J Alumkal
Jun 3, 2021·Cancers·Mayuko KanayamaEmmanuel S Antonarakis
Jul 25, 2021·Cancers·Samuel P BoysonKaren C Glass
Aug 11, 2021·Journal of Hematology & Oncology·Seyed Esmaeil AhmadiMajid Safa
Aug 21, 2021·Journal of Controlled Release : Official Journal of the Controlled Release Society·Yi ZhaoBowen Wang
Aug 28, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Qianqian WangXiaojun Yao
Jun 20, 2021·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Dae-Hwan KimJoshi J Alumkal

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