Journal
CLINICAL CANCER RESEARCH
Volume 26, Issue 20, Pages 5338-5347Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-20-1707
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Funding
- Zenith Epigenetics
- Prostate Cancer Foundation
- Department of Defense Prostate Cancer Research Program [W81XWH1820039]
- NIH NCI Cancer Center Support grant [P30CA008748]
- Prostate Cancer SPORE [P50CA092629]
- Department of Defense Physician Research [W81XWH-17-1-0124]
- NCI [R01 CA251245]
- Pacific Northwest Prostate Cancer SPORE [NCI P50 CA097186]
- Michigan Prostate SPORE [NCI P50 CA186786]
- U.S. Department of Defense (DOD) [W81XWH1820039] Funding Source: U.S. Department of Defense (DOD)
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Purpose: 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 and Methods: 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). 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 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 exposuredependent 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 progression-free survival (PFS) was 5.5 months (95% CI, 4.0-7.8). Median duration of treatment was 3.5 months (range, 0-34.7+). Lower androgen receptor (AR) transcriptional activity in baseline tumor biopsies was associated with longer rPFS (median rPFS 10.4 vs. 4.3 months). Conclusions: ZEN-3694 plus enzalutamide demonstrated acceptable tolerability and potential efficacy in patients with ASIresistant mCRPC. Further prospective study is warranted including in mCRPC harboring low AR transcriptional activity.
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