PURPOSE: Programmed death-ligand 1 (PD-L1) is overexpressed by dendritic cells in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing on androgen receptor pathway inhibitors. We tested whether checkpoint blockade could enhance antitumor activity in mCRPC. METHODS: In a multicenter open-label non-comparative randomized phase II study, patients with mCRPC treated with £ 1 prior cytotoxic chemotherapy, with measurable disease and progression on abiraterone and/or enzalutamide were randomized to durvalumab (D) 1500mg IV Q4 weeks ± 4 doses of tremelimumab (T) 75mg IV. The primary endpoint was objective response (OR) by iRECIST using a Simon 2-stage design. Correlative testing included PD-L1/CD8 immunohistochemistry on baseline tumour biopsies and deep targeted sequencing of plasma cell-free DNA. RESULTS: 52 patients were enrolled. Median age was 70 years (range, 50-83 years) and 52% had prior taxane therapy for mCRPC. In stage 1, 13 patients were randomized to D with no OR observed. D+T advanced to stage 2 with 39 patients enrolled (receiving a median 3 cycles, range 1-53). D+T related adverse events (AEs) were mainly £ grade 2 but led to discontinuation in 7 patients . There were seven OR (19.4% [95% confidence interval: 8.2-36.0%]; intention to treat (ITT) 17.9% [95% confidence interval: 7.5-33.5%]). Five responding tumours were PD-L1 positive and two exhibited DNA damage repair defects. Responses were observed without high tumour mutational burden or other genomic indices of immunotherapy sensitivity. CONCLUSION: D+T is active in mCRPC but patient selection remains a challenge. Further studies to develop predictive biomarkers are warranted.

中文翻译：

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Durvalumab 联合或不联合 Tremelimumab 治疗转移性去势抵抗性前列腺癌患者的随机 II 期研究。


目的： 程序性死亡配体 1 （PD-L1） 在接受雄激素受体通路抑制剂治疗后进展的转移性去势抵抗性前列腺癌 （mCRPC） 患者中由树突状细胞过表达。我们测试了检查点阻断是否可以增强 mCRPC 的抗肿瘤活性。方法： 在一项多中心、开放标签、非比较随机 II 期研究中，既往接受过 £ 1 细胞毒性化疗的 mCRPC 患者，在阿比特龙和/或恩杂鲁胺治疗后有可测量的疾病和进展，被随机分配到 durvalumab （D） 1500mg IV ± 4 剂 tremelimumab （T） 75mg IV 治疗。主要终点是 iRECIST 使用 Simon 2 阶段设计的客观缓解 （OR）。相关测试包括基线肿瘤活检的 PD-L1/CD8 免疫组化和浆细胞游离 DNA 的深度靶向测序。结果： 共纳入 52 例患者。中位年龄为 70 岁 （范围，50-83 岁），52% 的患者既往接受过 mCRPC 紫杉烷治疗。在第 1 阶段，13 例患者被随机分配到 D 组，未观察到 OR。D+T 进展到 2 期，有 39 名患者入组（中位接受 3 个周期，范围 1-53）。D+T 相关不良事件 （AEs） 主要是 £ 2 级，但导致 7 例患者停药。有 7 例 OR （19.4% [95% 置信区间： 8.2-36.0%];意向治疗 （ITT） 17.9% [95% 置信区间： 7.5-33.5%]）。5 例反应肿瘤为 PD-L1 阳性，2 例表现出 DNA 损伤修复缺陷。观察到的反应没有高肿瘤突变负荷或其他免疫治疗敏感性的基因组指标。结论： D+T 在 mCRPC 中活跃，但患者选择仍然是一个挑战。有必要进一步研究以开发预测性生物标志物。