Data from Phase Ib Study of the BET Inhibitor GS-5829 as Monotherapy and Combined with Enzalutamide in Patients with Metastatic Castration-Resistant Prostate Cancer

<div>AbstractPurpose:<p>A phase Ib study (1604) was conducted to evaluate the safety and efficacy of GS-5829, an oral bromodomain and extraterminal inhibitor, alone and in combination with enzalutamide in metastatic castration-resistant prostate cancer (mCRPC). A phase I study (1599) in solid tumors/lymphoma was also conducted.</p>Patients and Methods:<p>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 nonprogression rate at week 24; secondary endpoints included prostate-specific antigen reduction from baseline, progression-free survival, and GS-5829 pharmacokinetics (PK). PK and safety were also evaluated in Study 1599.</p>Results:<p>Thirty-one men, with a median of five prior regimens, received at least 1 dose of study drug in Study 1604. Treatment-emergent adverse events (TEAE) were reported in 94% of patients; 16% discontinued for TEAEs. There were no dose-dependent increases in the AUC_tau or <i>C</i>_max after once-daily administration of GS-5829 2 to 9 mg, and biomarkers <i>CCR2</i> inhibition and <i>HEXIM1</i> 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 nonprogression at week 24, estimated by Kaplan–Meier model, was 25% (95% confidence interval, 10–42) for all treated patients.</p>Conclusions:<p>GS-5829 was generally tolerated but demonstrated limited efficacy and lack of dose proportional increases in plasma concentrations in patients with mCRPC.</p></div>

Duke Scholars

Author Andrew John Armstrong Medicine, Medical Oncology