Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer.
Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer.
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辅助奥拉帕尼用于BRCA1或BRCA2突变乳腺癌患者。
DOI：
10.1056/nejmoa2105215
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发表时间：
2021-06-24
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聚（二磷酸腺苷-核糖）聚合酶抑制剂通过合成致死作用靶向同源重组修复缺陷的癌症。需要新的治疗方法来减少BRCA 1或BRCA 2生殖细胞突变相关的早期乳腺癌患者的复发。我们进行了一项III期、双盲、随机试验，纳入了接受局部治疗和新辅助或辅助化疗的人表皮生长因子受体2（HER 2）阴性早期乳腺癌患者，这些患者伴有BRCA 1或BRCA 2生殖系致病性或可能致病性变异和高风险临床病理因素。患者被随机分配（以1：1的比例）接受1年的口服奥拉帕尼或安慰剂治疗。主要终点是无侵袭性疾病生存期。共有1836例患者接受了随机化。在预先指定的事件驱动中期分析（中位随访时间为2.5年）中，奥拉帕尼组的3年无侵袭性疾病生存率为85.9%，安慰剂组为77.1%（差异，8.8个百分点; 95%置信区间[CI]，4.5至13.0;侵袭性疾病或死亡的风险比，0.58; 99.5% CI，0.41至0.82; P<0.001）。奥拉帕尼组的3年无远处转移生存率为87.5%，安慰剂组为80.4%（差异为7.1个百分点; 95% CI为3.0 - 11.1;远处转移疾病或死亡的风险比为0.57; 99.5% CI为0.39 - 0.83; P<0.001）。奥拉帕尼与安慰剂相比，死亡率更低（分别为59和86）（风险比，0.68; 99%CI，0.44 - 1.05; P = 0.02）;然而，在P值小于0.01的统计学分析边界处，组间差异不显著。安全性数据与奥拉帕尼的已知副作用一致，没有过多的严重不良事件或特别关注的不良事件。在高危、HER 2阴性早期乳腺癌和生殖系BRCA 1或BRCA 2致病性或可能致病性变异的患者中，与安慰剂相比，完成局部治疗和新辅助或辅助化疗后的辅助奥拉帕尼与无侵袭性或远处疾病的生存期显著延长相关。奥拉帕尼对全球患者报告的生活质量影响有限。（由美国国家癌症研究所和阿斯利康资助; OlympiA ClinicalTrials.gov编号，NCT 02032823。
Poly(adenosine diphosphate–ribose) polymerase inhibitors target cancers with defects in homologous recombination repair by synthetic lethality. New therapies are needed to reduce recurrence in patients with BRCA1 or BRCA2 germline mutation–associated early breast cancer. We conducted a phase 3, double-blind, randomized trial involving patients with human epidermal growth factor receptor 2 (HER2)–negative early breast cancer with BRCA1 or BRCA2 germline pathogenic or likely pathogenic variants and high-risk clinicopathological factors who had received local treatment and neoadjuvant or adjuvant chemotherapy. Patients were randomly assigned (in a 1:1 ratio) to 1 year of oral olaparib or placebo. The primary end point was invasive disease–free survival. A total of 1836 patients underwent randomization. At a prespecified event-driven interim analysis with a median follow-up of 2.5 years, the 3-year invasive disease– free survival was 85.9% in the olaparib group and 77.1% in the placebo group (difference, 8.8 percentage points; 95% confidence interval [CI], 4.5 to 13.0; hazard ratio for invasive disease or death, 0.58; 99.5% CI, 0.41 to 0.82; P<0.001). The 3-year distant disease–free survival was 87.5% in the olaparib group and 80.4% in the placebo group (difference, 7.1 percentage points; 95% CI, 3.0 to 11.1; hazard ratio for distant disease or death, 0.57; 99.5% CI, 0.39 to 0.83; P<0.001). Olaparib was associated with fewer deaths than placebo (59 and 86, respectively) (hazard ratio, 0.68; 99% CI, 0.44 to 1.05; P = 0.02); however, the between-group difference was not significant at an interim-analysis boundary of a P value of less than 0.01. Safety data were consistent with known side effects of olaparib, with no excess serious adverse events or adverse events of special interest. Among patients with high-risk, HER2-negative early breast cancer and germline BRCA1 or BRCA2 pathogenic or likely pathogenic variants, adjuvant olaparib after completion of local treatment and neoadjuvant or adjuvant chemotherapy was associated with significantly longer survival free of invasive or distant disease than was placebo. Olaparib had limited effects on global patient-reported quality of life. (Funded by the National Cancer Institute and AstraZeneca; OlympiA ClinicalTrials.gov number, NCT02032823.)