Abstract: Metastatic castration-resistant prostate cancer (mCRPC) is an aggressive and fatal disease with a median survival of 36 months. With the advent of genetic sequencing to identify individual genomic profiles and acquired tumor-specific pathways, targeted therapies have revolutionized cancer treatment, including the treatment strategy in mCRPC. Poly(adenosine 5ʹ-diphosphate) ribose polymerase inhibitors (PARPi) are oral drugs that target mutations in the homologous recombination repair (HRR) pathway, which are found in approximately 27% of prostate cancer patients. In May 2020, the first PARP inhibitor, olaparib, was approved by the US Food and Drug Administration for men with mCRPC with HHR gene mutations based on the findings of the Phase III PROfound trial that showed improved overall survival in men with mCRPC who received olaparib and whose disease had progressed on a novel hormonal agent. This review summarizes the current evidence and clinical utility of olaparib as treatment in men with mCRPC. We describe the mechanism of action of PARPi, key clinical trials of olaparib in men with mCRPC, and ongoing Phase II and III clinical trials investigating olaparib in combination therapy and as front-line therapy in mCRPC.

Keywords: olaparib, PARP inhibitors, prostate cancer, DNA damage repair, homologous recombination repair


中文翻译：

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奥拉帕尼治疗转移性去势抵抗性前列腺癌的临床效用：当前证据和患者选择的回顾

摘要：转移性去势抵抗性前列腺癌 (mCRPC) 是一种侵袭性和致命的疾病，中位生存期为 36 个月。随着用于识别个体基因组图谱和获得性肿瘤特异性通路的基因测序的出现，靶向治疗彻底改变了癌症治疗，包括 mCRPC 的治疗策略。聚（腺苷 5'-二磷酸腺苷）核糖聚合酶抑制剂 (PARPi) 是一种口服药物，其靶向同源重组修复 (HRR) 途径中的突变，在大约 27% 的前列腺癌患者中发现了这种突变。2020 年 5 月，第一个 PARP 抑制剂奥拉帕尼，根据 III 期 PROfound 试验的结果，美国食品和药物管理局批准了具有 HHR 基因突变的 mCRPC 男性患者，该研究表明，接受 olaparib 且其疾病因新型激素药物而进展的 mCRPC 男性患者的总生存期有所改善。本综述总结了奥拉帕尼治疗 mCRPC 男性的当前证据和临床效用。我们描述了 PARPi 的作用机制、奥拉帕尼在 mCRPC 男性中的关键临床试验，以及正在进行的研究奥拉帕尼联合治疗和作为 mCRPC 一线治疗的 II 期和 III 期临床试验。

关键词：奥拉帕尼，PARP抑制剂，前列腺癌，DNA损伤修复，同源重组修复