Oncology and Supportive Care Department, Hôpital Foch, Suresnes, France.
Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.
Prostate Cancer Prostatic Dis. 2020 Dec;23(4):549-560. doi: 10.1038/s41391-020-0233-3. Epub 2020 May 4.
A great number of DNA-damage repair (DDR) pathways have been recognized to be frequently dysregulated in advanced stages of prostate cancer. DNA-repair defects in prostate cancer represents a clinically relevant disease subset. Tumors whose ability to repair double-strand DNA breaks by homologous recombination is compromised, are highly sensitive to blockade of the repair of DNA single-strand breaks via the inhibition of the enzyme poly(ADP) ribose polymerase (PARP).
A systematic review of the literature has been conducted in January 2020 using PubMed Medline database in line with the recommendations from the PRISMA guidelines. The following string terms were used for searching clinical trial articles: castration resistant OR castrate resistance OR castration refractory AND prostate cancer AND PARP OR poly(ADP-ribose) polymerase inhibitor OR DNA-repair OR homologous recombination repair. On-going clinical trials with olaparib, niraparib, talazoparib, veliparib, and rucaparib in mCRPC were searched on the clinicalTrials.gov website.
From this research 176 articles were identified. After title screening and abstract reading, five papers and four abstract were considered for the systematic review. Thirty-two clinical trials were also identified: from these 16 trials which did not include mCRPC patients or only prostate cancer patients, trials not yet recruiting and trials including radio-metabolic treatments were excluded. Sixteen trials were included and discussed in the paper.
Olaparib has been the first agent showing a benefit in terms of rPFS and ORR alone or in combination with abiraterone plus prednisone in patients with DDR deficiency prostate cancer. Also rucaparib showed a benefit in terms of PSA response rate and ORR in patients with BRCA2 and BRCA1 mutation in a phase-II study. Other phase-III clinical trials are evaluating niraparib and talazoparib, alone or in combination with AR signaling inhibitors.
大量的 DNA 损伤修复（DDR）途径已被认为在前列腺癌的晚期频繁失调。前列腺癌中的 DNA 修复缺陷代表了具有临床相关性的疾病亚群。那些通过同源重组修复双链 DNA 断裂能力受损的肿瘤，对通过抑制聚（ADP-核糖）聚合酶（PARP）来阻断 DNA 单链断裂的修复非常敏感。
我们在 2020 年 1 月按照 PRISMA 指南的建议，使用 PubMed Medline 数据库对文献进行了系统回顾。用于搜索临床试验文章的以下字符串术语是：去势抵抗或去势抵抗或去势难治性和前列腺癌和 PARP 或聚（ADP-核糖）聚合酶抑制剂或 DNA 修复或同源重组修复。在 clinicalTrials.gov 网站上搜索奥拉帕利、尼拉帕利、他拉唑帕利、维利帕利和鲁卡帕利在 mCRPC 中的正在进行的临床试验。
从这项研究中确定了 176 篇文章。经过标题筛选和摘要阅读，有 5 篇论文和 4 篇摘要被认为是系统综述的一部分。还确定了 32 项临床试验：其中 16 项试验不包括 mCRPC 患者或仅包括前列腺癌患者，未招募的试验和包括放射代谢治疗的试验被排除在外。有 16 项试验被纳入并在论文中讨论。
奥拉帕利是第一个在 DDR 缺陷型前列腺癌患者中单独或联合阿比特龙加泼尼松治疗时显示出在 rPFS 和 ORR 方面获益的药物。在一项 II 期研究中，鲁卡帕利在 BRCA2 和 BRCA1 突变的患者中也显示出 PSA 反应率和 ORR 的获益。其他 III 期临床试验正在评估尼拉帕利和他拉唑帕利，单独或联合 AR 信号抑制剂使用。
