Background

Germline DNA damage repair gene mutation (gDDRm) is found in >10% of metastatic prostate cancer (mPC). Their prognostic and predictive impact relating to standard therapies is unclear.

Objective

To determine whether gDDRm status impacts benefit from established therapies in mPC.

Design, setting, and participants

This is a retrospective, international, observational study. Medical records were reviewed for 390 mPC patients with known gDDRm status. All 372 patients from Royal Marsden (UK), Weill-Cornell (NY), and University of Washington (WA) were previously included in a prevalence study (Pritchard, NEJM 2016); the remaining 18 were gBRCA1/2m carriers, from the kConFab consortium, Australia.

Outcome measurements and statistical analysis

Response rate (RR), progression-free survival (PFS), and overall survival (OS) data were collected. To account for potential differences between cohorts, a mixed-effect model (Weibull distribution) with random intercept per cohort was used.

Results and limitations

The gDDRm status was known for all 390 patients (60 carriers of gDDRm [gDDRm+], including 37 gBRCA2m, and 330 cases not found to carry gDDRm [gDDRm–]); 74% and 69% were treated with docetaxel and abiraterone/enzalutamide, respectively, and 36% received PARP inhibitors (PARPi) and/or platinum. Median OS from castration resistance was similar among groups (3.2 vs 3.0 yr, p = 0.73). Median docetaxel PFS for gDDRm+ (6.8 mo) was not significantly different from that for gDDRm– (5.1 mo), and RRs were similar (gDDRm+ = 61%; gDDRm– = 54%). There were no significant differences in median PFS and RR on first-line abiraterone/enzalutamide (gDDRm+ = 8.3 mo, gDDRm– = 8.3 mo; gDDRm+ = 46%, gDDRm– = 56%). Interaction test for PARPi/platinum and gDDRm+ resulted in an OS adjusted hazard ratio of 0.59 (95% confidence interval 0.28–1.25; p = 0.17). Results are limited by the retrospective nature of the analysis.

Conclusions

mPC patients with gDDRm appeared to benefit from standard therapies similarly to the overall population; prospective studies are ongoing to investigate the impact of PARPi/platinum.

Patient summary

Patients with inherited DNA repair mutations benefit from standard therapies similarly to other metastatic prostate cancer patients.

中文翻译：

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具有种系 DNA 修复突变的前列腺癌患者的临床结果：一项国际研究的回顾性分析

背景

种系 DNA 损伤修复基因突变 (gDDRm) 存在于 >10% 的转移性前列腺癌 (mPC) 中。它们对标准疗法的预后和预测影响尚不清楚。

客观的

确定 gDDRm 状态影响是否受益于 mPC 的既定疗法。

设计、设置和参与者

这是一项回顾性、国际性、观察性研究。对 390 名已知 gDDRm 状态的 mPC 患者的医疗记录进行了审查。来自皇家马斯登（英国）、威尔-康奈尔大学（纽约）和华盛顿大学（华盛顿州）的所有 372 名患者此前均被纳入患病率研究中（Pritchard，NEJM 2016）；其余 18 个是 g BRCA1/2 m 携带者，来自澳大利亚 kConFab 联盟。

结果测量和统计分析

收集有效率（RR）、无进展生存期（PFS）和总生存期（OS）数据。为了解释队列之间的潜在差异，使用了每个队列随机截距的混合效应模型（威布尔分布）。

结果和局限性

所有 390 名患者的 gDDRm 状态均已知（60 名 gDDRm [gDDRm+] 携带者，包括 37 g BRCA2 m，以及 330 名未发现携带 gDDRm [gDDRm–] 的病例）；74% 和 69% 分别接受多西紫杉醇和阿比特龙/恩杂鲁胺治疗，36% 接受 PARP 抑制剂 (PARPi) 和/或铂类治疗。各组间去势抵抗的中位 OS 相似（3.2 年 vs 3.0 年，p  = 0.73）。gDDRm+ 的中位多西紫杉醇 PFS（6.8 个月）与 gDDRm– 的中位多西紫杉醇 PFS（5.1 个月）没有显着差异，RR 相似（gDDRm+ = 61%；gDDRm– = 54%）。一线阿比特龙/恩杂鲁胺的中位 PFS 和 RR 无显着差异（gDDRm+ = 8.3 个月，gDDRm– = 8.3 个月；gDDRm+ = 46%，gDDRm– = 56%）。PARPi/铂和 gDDRm+ 的相互作用测试得出 OS 调整后的风险比为 0.59（95% 置信区间 0.28–1.25；p  = 0.17）。结果受到分析的回顾性的限制。

结论

与总体人群类似，患有 gDDRm 的 mPC 患者似乎也能从标准治疗中受益；前瞻性研究正在进行中，以调查 PARPi/铂的影响。

患者总结

与其他转移性前列腺癌患者类似，具有遗传性 DNA 修复突变的患者也能从标准疗法中受益。