Purpose: 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. Patients and Methods: 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. Results: 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 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 nonprogression at week 24, estimated by Kaplan–Meier model, was 25% (95% confidence interval, 10–42) for all treated patients. Conclusions: GS-5829 was generally tolerated but demonstrated limited efficacy and lack of dose proportional increases in plasma concentrations in patients with mCRPC.

中文翻译：

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BET 抑制剂 GS-5829 单药及联合恩杂鲁胺治疗转移性去势抵抗性前列腺癌的 Ib 期研究

目的：进行 Ib 期研究 (1604)，以评估 GS-5829（一种口服溴结构域和末端抑制剂）单独或与恩杂鲁胺联合治疗转移性去势抵抗性前列腺癌 (mCRPC) 的安全性和有效性。还进行了实体瘤/淋巴瘤的 I 期研究 (1599)。患者和方法：尽管接受阿比特龙和/或恩杂鲁胺治疗，但确诊为 mCRPC 且疾病进展的男性被纳入 3 + 3 剂量递增模式，从每天 2 mg 单独使用 GS-5829 开始，并与每天 160 mg 恩杂鲁胺联用。主要疗效终点是第 24 周的无进展率；次要终点包括前列腺特异性抗原较基线减少、无进展生存期和 GS-5829 药代动力学 (PK)。研究 1599 还评估了 PK 和安全性。结果：31 名男性，在研究 1604 中，接受过至少 5 种既往治疗方案的患者至少接受过 1 剂研究药物。94% 的患者报告了治疗引起的不良事件 (TEAE)；16% 停止使用 TEAE。每天一次给予 GS-5829 2 至 9 mg 后，AUCtau 或 Cmax 没有剂量依赖性增加，并且生物标志物 CCR2 抑制和 HEXIM1 诱导仅在较高剂量的单药治疗时增加。所有剂量的 PK 和药效学参数均存在高度的患者间差异。根据 Kaplan-Meier 模型估计，所有接受治疗的患者在第 24 周无进展的比例为 25%（95% 置信区间，10-42）。结论：GS-5829 总体上具有耐受性，但在 mCRPC 患者中显示疗效有限，且血浆浓度未按剂量比例增加。