BRCA突变乳腺癌术后奥拉帕利有效
乳腺癌易感基因BRCA1和BRCA2是重要的抑癌基因，主要负责基因核糖核酸（DNA）双链同源重组修复，一旦发生致病突变，容易引起三阴性乳腺癌等恶性肿瘤，复发、进展或死亡风险也显著增加。多腺苷二磷酸核糖聚合酶基因PARP主要负责DNA单链修复，利用PARP抑制剂奥拉帕利，通过合成致死作用（两个非致死基因同时失活）可造成BRCA突变癌细胞死亡。OlympiAD研究已经证实，奥拉帕利可显著减少BRCA突变晚期乳腺癌患者疾病进展或死亡风险。那么，奥拉帕利能否进一步减少BRCA突变早期乳腺癌患者术后复发或死亡风险？
2021年6月3日，国际四大医学期刊之首、美国麻省医学会《新英格兰医学杂志》以及美国临床肿瘤学会第五十七届年会同时发表英国阿斯利康、伦敦大学癌症研究院托比罗宾斯研究中心、伦敦大学国王学院盖伊医院癌症中心、苏格兰前沿科学基金会、美国阿斯利康、哈佛大学医学院达纳法伯癌症研究所、波士顿前沿科学基金会、哈佛大学陈曾熙公共卫生学院、NRG肿瘤学协作组、宾夕法尼亚大学阿伯拉姆森癌症中心、匹兹堡大学希尔曼癌症中心、NSABP基金会、国家癌症研究所、凯撒集团瓦列霍医疗中心、洛杉矶加利福尼亚大学菲尔丁公共卫生学院、大卫格芬医学院、琼森综合癌症中心、亚特兰大北区医院癌症研究所、默克、休斯顿卫理公会癌症中心、康奈尔大学威尔医学院、以色列特拉维夫大学海姆谢巴医疗中心、意大利米兰大学欧洲肿瘤研究院、国际乳腺癌协作组、比利时布鲁塞尔自由大学朱尔博代研究所、西班牙巴塞罗那大学医院肿瘤研究所、加拿大温哥华癌症中心、瑞典哥德堡大学萨尔格伦斯卡医院、波兰格但斯克医科大学、玛丽居里国家肿瘤研究所、波美拉尼亚医科大学国际遗传性癌症中心、德国乳腺癌协作组、法兰克福大学癌症中心、科隆大学医院、奥地利维也纳医科大学、澳大利亚昆士兰大学、中国复旦大学附属肿瘤医院邵志敏等学者联合起草的OlympiA研究报告，探讨了BRCA突变早期乳腺癌术后奥拉帕利辅助治疗的有效性和安全性。该研究由美国国家癌症研究所和阿斯利康资助。
OlympiA (NCT02032823): A Randomised, Double-blind, Parallel Group, Placebo-controlled Multi-centre Phase III Study to Assess the Efficacy and Safety of Olaparib Versus Placebo as Adjuvant Treatment in Patients With gBRCA1/2 Mutations and High Risk HER2 Negative Primary Breast Cancer Who Have Completed Definitive Local Treatment and Neoadjuvant or Adjuvant Chemotherapy
该国际多中心双盲随机对照三期临床研究于2014年6月～2019年5月从全球23个国家420家医院入组BRCA1或BRCA2可遗传致病或可能致病变异并有高风险临床病理因素的人类表皮生长因子受体HER2阴性早期乳腺癌完成局部治疗和术前新辅助或术后辅助化疗患者1836例，按1∶1的比例随机分为两组：
治疗组921例（三阴性乳腺癌占81.5%）口服1年奥拉帕利
对照组915例（三阴性乳腺癌占82.8%）口服1年安慰剂
主要终点为无浸润癌生存，定义：随机分组至首次发生同侧乳腺浸润癌、局部区域浸润癌、远处复发、对侧乳腺浸润癌、第二原发浸润癌、任何原因所致死亡的时间。次要终点包括：无远处癌生存、总生存、安全性。
结果，截至2020年3月27日，事件数量达到预设中期分析条件，中位随访2.5年，奥拉帕利与安慰剂相比：
3年无浸润癌生存率：85.9%比77.1%（相差8.8个百分点，95%置信区间：4.5～13.0）
3年浸润癌或死亡率：低42%（风险比：0.58，99.5%置信区间：0.41～0.82，P<0.001）
3年无远处癌生存率：87.5%比80.4%（相差7.1个百分点，95%置信区间：3.0～11.1）
3年远处癌或死亡率：低43%（风险比，0.57，99.5%置信区间：0.39～0.83，P<0.001）
3年总生存率：92.0%比88.3%（相差3.7个百分点，95%置信区间：0.3～7.1）
3年总死亡率：低32%（风险比：0.68，99%置信区间：0.44～1.05，P>0.01）
安全性数据与奥拉帕利已知副作用一致，未见额外严重不良事件或特别关注不良事件。奥拉帕利对患者报告的整体生活质量影响不大。
因此，该研究结果表明，对于可遗传BRCA1或BRCA2致病或可能致病变异的高风险HER2阴性早期乳腺癌完成局部治疗和术前新辅助或术后辅助化疗患者，奥拉帕利单药辅助治疗与安慰剂相比，无浸润癌生存率、无远处癌生存率显著较高。奥拉帕利对患者报告的整体生活质量影响不大。
据悉，奥拉帕利已于2018年获得国家药品监督管理局批准进入中国内陆，商品名：利普卓，并于2019年获得国家医疗保障局批准进入医保目录，目前主要获准用于治疗卵巢癌、输卵管癌、腹膜癌。
相关链接
N Engl J Med. 2021 Jun 3. Online ahead of print.
Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer.
Tutt ANJ, Garber JE, Kaufman B, Viale G, Fumagalli D, Rastogi P, Gelber RD, de Azambuja E, Fielding A, Balmana J, Domchek SM, Gelmon KA, Hollingsworth SJ, Korde LA, Linderholm B, Bandos H, Senkus E, Suga JM, Shao Z, Pippas AW, Nowecki Z, Huzarski T, Ganz PA, Lucas PC, Baker N, Loibl S, McConnell R, Piccart M, Schmutzler R, Steger GG, Costantino JP, Arahmani A, Wolmark N, McFadden E, Karantza V, Lakhani SR, Yothers G, Campbell C, Geyer CE Jr; OlympiA Clinical Trial Steering Committee and Investigators.
Toby Robins Research Centre, Institute of Cancer Research; Guy's Hospital Cancer Centre, King's College London, London; AstraZeneca, Cambridge; Frontier Science (Scotland), Kincraig, United Kingdom; Dana-Farber Cancer Institute, Harvard Medical School; Frontier Science Foundation; Harvard T.H. Chan School of Public Health, Boston; Chaim Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel; University of Milan, European Institute of Oncology IRCCS, Milan; Breast International Group; Institut Jules Bordet, l'Université Libre de Bruxelles, Brussels; NRG Oncology; Abramson Cancer Center, University of Pennsylvania, Philadelphia; UPMC Hillman Cancer Center, University of Pittsburgh; NSABP Foundation, Pittsburgh, Pennsylvania; AstraZeneca, Gaithersburg; National Cancer Institute, Rockville, Maryland; Vall d'Hebron Institute of Oncology and Vall d'Hebron University Hospital, Barcelona; BC Cancer, Vancouver, BC, Canada; Sahlgrenska University Hospital, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden; Medical University of Gdańsk, Gdańsk; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw; International Hereditary Cancer Center, Pomeranian Medical University, Szczecin; Read-Gene, Grzepnica, Poland; Kaiser Permanente Vallejo Medical Center, Vallejo; UCLA Fielding School of Public Health, David Geffen School of Medicine at UCLA, UCLA Jonsson Comprehensive Cancer Center, Los Angeles, California; Fudan University Shanghai Cancer Center, Shanghai, China; Georgia NCORP, Northside Hospital Cancer Institute, Piedmont Healthcare, Atlanta; German Breast Group, Neu-Isenburg; Center for Hematology and Oncology Bethanien; Goethe University, Frankfurt; University Hospital Cologne, Cologne, Germany; Medical University of Vienna, Vienna; Merck, Kenilworth, NJ; University of Queensland, Brisbane, QLD, Australia; Houston Methodist Cancer Center; Weill Cornell Medical College, Houston.
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
FUNDING: National Cancer Institute and AstraZeneca
OlympiA ClinicalTrials.gov number: NCT02032823
PMID: 34081848
DOI: 10.1056/NEJMoa2105215