Poly (ADP-ribose) polymerase (PARP) inhibitors have antitumor activity in advanced prostate cancer associated with loss of homologous recombination repair (HRR) function. About 20% of all patients with advanced prostate cancer present germline or tumor mutations in HRR-related genes, the most common being BRCA2, mutated in approximately 10% of all advanced prostate cancers. Challenges related to sample availability, tumor heterogeneity and access to NGS technology need to be addressed for a successful implementation of genomic stratification in routine clinical practice. The recent regulatory approvals of PARP inhibitors olaparib and rucaparib represent the first molecular biomarker-guided drugs for men with prostate cancer. While these findings represent a significant advance in the field of precision medicine and prostate cancer, there are still many unsolved questions on the optimal use of PARP inhibitors in this disease. Several clinical trials have shown that different mutations in various genes are associated with distinct magnitudes of sensitivity to PARP inhibitors, with BRCA2 mutations associating with more frequent and durable responses, questioning the benefit for subset of patients with mutations in other HRR-associated genes. In this review, we scrutinize the clinical development of different PARP inhibitors for the treatment of advanced prostate cancer, and we discuss how the study of additional biomarkers and the design of rational drug combinations can maximize patient benefit from this drug class.

中文翻译：

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晚期前列腺癌中的 PARP 抑制剂：何时使用？

聚 (ADP-核糖) 聚合酶 (PARP) 抑制剂在与同源重组修复 (HRR) 功能丧失相关的晚期前列腺癌中具有抗肿瘤活性。大约 20% 的晚期前列腺癌患者在 HRR 相关基因中存在种系或肿瘤突变，最常见的是 BRCA2，在大约 10% 的晚期前列腺癌中发生突变。为了在常规临床实践中成功实施基因组分层，需要解决与样本可用性、肿瘤异质性和获得 NGS 技术相关的挑战。PARP 抑制剂 olaparib 和 rucaparib 最近获得的监管批准代表了首个针对男性前列腺癌的分子生物标志物指导药物​​。虽然这些发现代表了精准医学和前列腺癌领域的重大进步，PARP抑制剂在该病中的最佳使用仍有许多悬而未决的问题。几项临床试验表明，各种基因的不同突变与对 PARP 抑制剂的不同敏感性程度相关，BRCA2 突变与更频繁和持久的反应相关，质疑其他 HRR 相关基因突变患者亚群的益处。在这篇综述中，我们仔细研究了不同 PARP 抑制剂治疗晚期前列腺癌的临床开发，并讨论了其他生物标志物的研究和合理药物组合的设计如何使患者从该药物类别中获益最大化。几项临床试验表明，不同基因的不同突变与对 PARP 抑制剂的不同程度的敏感性有关，BRCA2 突变与更频繁和持久的反应相关，质疑其他 HRR 相关基因突变患者子集的益处。在这篇综述中，我们仔细研究了不同 PARP 抑制剂治疗晚期前列腺癌的临床开发，并讨论了其他生物标志物的研究和合理药物组合的设计如何使患者从该药物类别中获益最大化。几项临床试验表明，不同基因的不同突变与对 PARP 抑制剂的不同程度的敏感性有关，BRCA2 突变与更频繁和持久的反应相关，质疑其他 HRR 相关基因突变患者子集的益处。在这篇综述中，我们仔细研究了不同 PARP 抑制剂治疗晚期前列腺癌的临床开发，并讨论了其他生物标志物的研究和合理药物组合的设计如何使患者从该药物类别中获益最大化。