Immune checkpoint inhibitors (ICIs) have limited efficacy in prostate cancer (PCa). Better biomarkers are needed to predict responses to ICIs. We sought to demonstrate that a panel-based mutational signature identifies mismatch repair (MMR) deficient (MMRd) PCa and is a biomarker of response to pembrolizumab. Clinico-genomic data was obtained for 2664 patients with PCa sequenced at Dana-Farber Cancer Institute (DFCI) and Memorial Sloan Kettering (MSK). Clinical outcomes were collected for patients with metastatic castration-resistant PCa (mCRPC) treated with pembrolizumab at DFCI. SigMA was used to characterize tumors as MMRd or MMR proficient (MMRp). The concordance between MMRd with microsatellite instability (MSI-H) was assessed. Radiographic progression-free survival (rPFS) and overall survival (OS) were collected for patients treated with pembrolizumab. Event-time distributions were estimated using Kaplan-Meier methodology. Across both cohorts, 100% (DFCI: 12/12; MSK: 43/43) of MSI-H tumors were MMRd. However, 14% (2/14) and 9.1% (6/66) of MMRd tumors in the DFCI and MSK cohorts respectively were microsatellite stable (MSS), and 26% (17/66) were MSI-indeterminate in the MSK cohort. Among patients treated with pembrolizumab, those with MMRd ( = 5) versus MMRp ( = 14) mCRPC experienced markedly improved rPFS (HR = 0.088, 95% CI: 0.011-0.70; = .0064) and OS (HR = 0.11, 95% CI: 0.014-0.80; = .010) from start of treatment. Four patients with MMRd experienced remissions of >= 2.5 years. SigMA detects additional cases of MMRd as compared to MSI testing in PCa and identifies patients likely to experience durable response to pembrolizumab.

中文翻译：

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基于面板的错配修复缺陷突变特征与转移性去势抵抗性前列腺癌中帕博利珠单抗的持久反应相关

免疫检查点抑制剂（ICIs）对前列腺癌（PCa）的疗效有限。需要更好的生物标志物来预测 ICI 的反应。我们试图证明基于组的突变特征可识别错配修复（MMR）缺陷（MMRd）PCa，并且是对派姆单抗（pembrolizumab）反应的生物标志物。获得了在 Dana-Farber 癌症研究所 (DFCI) 和纪念斯隆凯特林 (MSK) 测序的 2664 名 PCa 患者的临床基因组数据。收集了在 DFCI 接受派姆单抗治疗的转移性去势抵抗性前列腺癌 (mCRPC) 患者的临床结果。 SigMA 用于将肿瘤描述为 MMRd 或 MMR 熟练 (MMRp)。评估了 MMRd 与微卫星不稳定性 (MSI-H) 之间的一致性。收集接受派姆单抗治疗的患者的放射学无进展生存期 (rPFS) 和总生存期 (OS)。使用 Kaplan-Meier 方法估计事件时间分布。在这两个队列中，100%（DFCI：12/12；MSK：43/43）的 MSI-H 肿瘤为 MMRd。然而，DFCI 和 MSK 队列中分别有 14% (2/14) 和 9.1% (6/66) 的 MMRd 肿瘤是微卫星稳定 (MSS) 的，而在 MSK 队列中 26% (17/66) 是 MSI 不确定的。在接受派姆单抗治疗的患者中，MMRd (= 5) 与 MMRp (= 14) mCRPC 患者的 rPFS（HR = 0.088，95% CI：0.011-0.70；= 0.0064）和 OS（HR = 0.11，95%）显着改善CI：0.014-0.80；= .010) 从治疗开始算起。 4 名 MMRd 患者的缓解时间≥2.5 年。与 PCa 中的 MSI 检测相比，SigMA 检测到更多的 MMRd 病例，并确定可能对派姆单抗产生持久反应的患者。