A Phase 1b study (1604) was conducted to evaluate the safety and efficacy of GS-5829, an oral bromodomain and extra-terminal inhibitor, alone and in combination with enzalutamide in metastatic castration-resistant prostate cancer (mCRPC). A Phase 1 study (1599) in solid tumors/lymphoma was also conducted.
Men with confirmed mCRPC and disease progression despite abiraterone and/or enzalutamide treatment were enrolled in a 3 + 3 dose-escalation paradigm starting at 2 mg daily with GS-5829 alone and in combination with 160-mg daily enzalutamide. The primary efficacy endpoint was non-progression rate at Week 24; secondary endpoints included prostate-specific antigen (PSA) reduction from baseline, progression-free survival (PFS), and GS-5829 pharmacokinetics (PK). PK and safety were also evaluated in Study 1599.
Thirty-one men, with a median of 5 prior regimens, received at least 1 dose of study drug in Study 1604. Treatment-emergent adverse events (TEAEs) were reported in 94% of patients; 16% discontinued for TEAEs. There were no dose-dependent increases in the AUCtau or Cmax after once-daily administration of GS-5829 2 to 9 mg,and biomarkers CCR2 inhibition and HEXIM1 induction were increased only at higher doses of monotherapy. A high degree of interpatient variability existed across all doses in PK and pharmacodynamic parameters. The proportion with non-progression at Week 24, estimated by Kaplan-Meier model, was 25% (95% confidence interval [CI] 10, 42) for all treated patients.
GS-5829 was generally tolerated but demonstrated limited efficacy and lack of dose-proportional increases in plasma concentrations in patients with mCRPC.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2022 Jul 11 [Epub ahead of print]
Rahul Aggarwal, Alexander N Starodub, Brian D Koh, Guan Xing, Andrew J Armstrong, Michael A Carducci
University of California, San Francisco, San Francisco, CA, United States., The Christ Hospital Physicians, Cincinnati, OH, United States., Gilead Sciences (United States), Foster City, CA, United States., Gilead Sciences, Inc, Foster City, CA, United States., Duke Cancer Institute, Durham, NC, United States., Johns Hopkins University, Baltimore, MD, United States.