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Original ArticleFree Preview

Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer

List of authors.
  • Andrew N.J. Tutt, M.B., Ch.B., Ph.D.,
  • Judy E. Garber, M.D., M.P.H.,
  • Bella Kaufman, M.D.,
  • Giuseppe Viale, M.D.,
  • Debora Fumagalli, M.D., Ph.D.,
  • Priya Rastogi, M.D.,
  • Richard D. Gelber, Ph.D.,
  • Evandro de Azambuja, M.D., Ph.D.,
  • Anitra Fielding, M.B., Ch.B.,
  • Judith Balma?a, M.D., Ph.D.,
  • Susan M. Domchek, M.D.,
  • Karen A. Gelmon, M.D.,
  • Simon J. Hollingsworth, Ph.D.,
  • Larissa A. Korde, M.D., M.P.H.,
  • Barbro Linderholm, M.D., Ph.D.,
  • Hanna Bandos, Ph.D.,
  • El?bieta Senkus, M.D., Ph.D.,
  • Jennifer M. Suga, M.D.,
  • Zhimin Shao, M.D.,
  • Andrew W. Pippas, M.D.,
  • Zbigniew Nowecki, M.D., Ph.D.,
  • Tomasz Huzarski, M.D., Ph.D.,
  • Patricia A. Ganz, M.D.,
  • Peter C. Lucas, M.D., Ph.D.,
  • Nigel Baker, M.Sc.,
  • Sibylle Loibl, M.D., Ph.D.,
  • Robin McConnell, M.Sc.,
  • Martine Piccart, M.D., Ph.D.,
  • Rita Schmutzler, M.D., Dr.Med.Habil.,
  • Guenther G. Steger, M.D.,
  • Joseph P. Costantino, Dr.P.H.,
  • Amal Arahmani, Ph.D.,
  • Norman Wolmark, M.D.,
  • Eleanor McFadden, M.A.,
  • Vassiliki Karantza, M.D., Ph.D.,
  • Sunil R. Lakhani, M.D.,
  • Greg Yothers, Ph.D.,
  • Christine Campbell, M.Sc.,
  • and Charles E. Geyer, Jr., M.D.
  • for the OlympiA Clinical Trial Steering Committee and Investigators*

Abstract

Background

Poly(adenosine diphosphate每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每associated early breast cancer.

Methods

We conducted a phase 3, double-blind, randomized trial involving patients with human epidermal growth factor receptor 2 (HER2)每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每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每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每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. (Funded by the National Cancer Institute and AstraZeneca; OlympiA ClinicalTrials.gov number, NCT02032823.)

Funding and Disclosures

Supported by grants (U10CA180868, UG1CA189867, and U10CA180822) from the National Cancer Institute and funding and provision of olaparib and placebo by AstraZeneca as part of an alliance between AstraZeneca and Merck.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

This article was published on June 3, 2021, at NEJM.org.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

We thank the patients and their families, the staff members of the trial partners (the Breast International Group, NRG Oncology, Frontier Science, AstraZeneca, Merck Sharp & Dohme, and the National Cancer Institute), the current and former members of the trial committees and the investigators (listed in the Supplementary Appendix), and Aaron Borg, Ph.D., and Helen Stimpson, Ph.D., of Oxford PharmaGenesis for support with the collation of author comments on earlier versions of the manuscript.

Author Affiliations

From the Breast Cancer Now Toby Robins Research Centre, the Institute of Cancer Research (A.N.J.T.), and the Breast Cancer Now Unit, Guy*s Hospital Cancer Centre, King*s College London (A.N.J.T.), London, AstraZeneca, Cambridge (S.J.H., N.B.), and Frontier Science (Scotland), Kincraig (R.M.C., E.M.F., C.C.) 〞 all in the United Kingdom; Dana每Farber Cancer Institute, Harvard Medical School (J.E.G., R.D.G.), Frontier Science Foundation (R.D.G.), and Harvard T.H. Chan School of Public Health (R.D.G.) 〞 all in Boston; the Breast Oncology Institute, Chaim Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel (B.K.); the University of Milan, European Institute of Oncology IRCCS, Milan (G.V.); Breast International Group (D.F., A.A.) and Institut Jules Bordet, l*Universit谷 Libre de Bruxelles (E.A., M.P.), Brussels; NRG Oncology (P.R., H.B., P.C.L., N.W., G.Y., C.E.G.) and the Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania (S.M.D.), Philadelphia, and the UPMC Hillman Cancer Center (P.R., P.C.L., N.W.) and the Department of Biostatistics (H.B., J.P.C., G.Y.), University of Pittsburgh, and the NSABP Foundation (N.W.), Pittsburgh 〞 all in Pennsylvania; AstraZeneca, Gaithersburg (A.F.), and the National Cancer Institute, Rockville (L.A.K.) 〞 both in Maryland; Vall d*Hebron Institute of Oncology and Vall d*Hebron University Hospital (J.B.) 〞 both in Barcelona; BC Cancer, Vancouver, BC, Canada (K.A.G.); Sahlgrenska University Hospital (B.L.) and the Institute of Clinical Sciences, Department of Oncology, Sahlgrenska Academy, Gothenburg University (B.L.) 〞 both in Gothenburg, Sweden; the Department of Oncology and Radiotherapy, Medical University of Gda里sk, Gda里sk (E.S.), the Maria Sk?odowska-Curie National Research Institute of Oncology, Warsaw (Z.N.), the International Hereditary Cancer Center, Pomeranian Medical University, Szczecin (T.H.), and Read-Gene, Grzepnica (T.H.) 〞 all in Poland; Kaiser Permanente Vallejo Medical Center, Vallejo (J.M.S.), and the UCLA Fielding School of Public Health, David Geffen School of Medicine at UCLA (P.A.G.), and the UCLA Jonsson Comprehensive Cancer Center (P.A.G.), Los Angeles 〞 all in California; Fudan University Shanghai Cancer Center, Shanghai, China, (Z.S.); Georgia NCORP, Northside Hospital Cancer Institute (A.W.P.), and Piedmont Healthcare (A.W.P.) 〞 both in Atlanta; German Breast Group, Neu-Isenburg (S.L.), the Center for Hematology and Oncology Bethanien and Goethe University, Frankfurt (S.L.), and the Center for Familial Breast and Ovarian Cancer and the Center for Integrated Oncology, Faculty of Medicine, University Hospital Cologne, Cologne (R.S.) 〞 all in Germany; the Department of Internal Medicine I and Gaston H. Glock Research Center, Medical University of Vienna, Vienna (G.G.S.); Merck, Kenilworth, NJ (V.K.); the University of Queensland Centre for Clinical Research and Pathology Queensland (S.R.L.) 〞 both in Brisbane, QLD, Australia; and Houston Methodist Cancer Center (C.E.G.) and Weill Cornell Medical College (C.E.G.) 〞 both in Houston.

Address reprint requests to Dr. Tutt at the Breast Cancer Now Toby Robins Research Centre, the Institute of Cancer Research, 237 Fulham Rd., London SW3 6JB, United Kingdom, or at .

The members of the OlympiA Steering Committee and the trial investigators are listed in the Supplementary Appendix, available at NEJM.org.

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