BACKGROUND Multiple loss-of-function alterations in genes that are involved in DNA repair, including homologous recombination repair, are associated with response to poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition in patients with prostate and other cancers. METHODS We conducted a randomized, open-label, phase 3 trial evaluating the PARP inhibitor olaparib in men with metastatic castration-resistant prostate cancer who had disease progression while receiving a new hormonal agent (e.g., enzalutamide or abiraterone). All the men had a qualifying alteration in prespecified genes with a direct or indirect role in homologous recombination repair. Cohort A (245 patients) had at least one alteration in BRCA1, BRCA2, or ATM; cohort B (142 patients) had alterations in any of 12 other prespecified genes, prospectively and centrally determined from tumor tissue. Patients were randomly assigned (in a 2:1 ratio) to receive olaparib or the physician's choice of enzalutamide or abiraterone (control). The primary end point was imaging-based progression-free survival in cohort A according to blinded independent central review. RESULTS In cohort A, imaging-based progression-free survival was significantly longer in the olaparib group than in the control group (median, 7.4 months vs. 3.6 months; hazard ratio for progression or death, 0.34; 95% confidence interval, 0.25 to 0.47; P<0.001); a significant benefit was also observed with respect to the confirmed objective response rate and the time to pain progression. The median overall survival in cohort A was 18.5 months in the olaparib group and 15.1 months in the control group; 81% of the patients in the control group who had progression crossed over to receive olaparib. A significant benefit for olaparib was also seen for imaging-based progression-free survival in the overall population (cohorts A and B). Anemia and nausea were the main toxic effects in patients who received olaparib. CONCLUSIONS In men with metastatic castration-resistant prostate cancer who had disease progression while receiving enzalutamide or abiraterone and who had alterations in genes with a role in homologous recombination repair, olaparib was associated with longer progression-free survival and better measures of response and patient-reported end points than either enzalutamide or abiraterone. (Funded by AstraZeneca and Merck Sharp & Dohme; PROfound ClinicalTrials.gov number, NCT02987543.).

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。

背景技术涉及DNA修复(包括同源重组修复)的基因的多种功能丧失改变与前列腺癌和其他癌症患者对聚(二磷酸腺苷-核糖)聚合酶(PARP)抑制的反应有关。方法 我们进行了一项随机、开放标签、3 期试验，评估 PARP 抑制剂奥拉帕尼在接受新激素药物（如恩杂鲁胺或阿比特龙）后疾病进展的转移性去势抵抗性前列腺癌男性中的疗效。所有男性在同源重组修复中具有直接或间接作用的预先指定基因的合格改变。队列 A（245 名患者）的 BRCA1、BRCA2 或 ATM 至少有一处改变；队列 B（142 名患者）有 12 个其他预先指定的基因中的任何一个发生改变，从肿瘤组织中前瞻性地和集中地确定。患者被随机分配（以 2:1 的比例）接受奥拉帕尼或医生选择的恩杂鲁胺或阿比特龙（对照）。根据盲法独立中央审查，主要终点是队列 A 中基于影像学的无进展生存期。结果 在队列 A 中，奥拉帕尼组基于影像学的无进展生存期显着长于对照组（中位数，7.4 个月 vs. 3.6 个月；进展或死亡的风险比，0.34；95% 置信区间，0.25 至0.47；P<0.001)；在确认的客观反应率和疼痛进展时间方面也观察到了显着的益处。队列 A 的中位总生存期在奥拉帕尼组为 18.5 个月，在对照组为 15.1 个月；对照组中有 81% 出现进展的患者交叉接受奥拉帕尼治疗。在总体人群（队列 A 和 B）中，基于影像学的无进展生存期也观察到了奥拉帕尼的显着益处。贫血和恶心是接受奥拉帕尼的患者的主要毒性作用。结论：在接受恩杂鲁胺或阿比特龙时疾病进展且基因改变与同源重组修复有关的转移性去势抵抗性前列腺癌男性中，奥拉帕尼与更长的无进展生存期和更好的反应测量和患者-报告的终点比恩杂鲁胺或阿比特龙。（由 AstraZeneca 和 Merck Sharp & Dohme 资助；PROfound ClinicalTrials.gov 编号为 NCT02987543。）。