Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer
Andrew N J Tutt, Judy E Garber, Bella Kaufman, Giuseppe Viale, Debora Fumagalli, Priya Rastogi, Richard D Gelber, Evandro de Azambuja, Anitra Fielding, Judith Balmaña, Susan M Domchek, Karen A Gelmon, Simon J Hollingsworth, Larissa A Korde, Barbro Linderholm, Hanna Bandos, Elżbieta Senkus, Jennifer M Suga, Zhimin Shao, Andrew W Pippas, Zbigniew Nowecki, Tomasz Huzarski, Patricia A Ganz, Peter C Lucas, Nigel Baker, Sibylle Loibl, Robin McConnell, Martine Piccart, Rita Schmutzler, Guenther G Steger, Joseph P Costantino, Amal Arahmani, Norman Wolmark, Eleanor McFadden, Vassiliki Karantza, Sunil R Lakhani, Greg Yothers, Christine Campbell, Charles E Geyer Jr, OlympiA Clinical Trial Steering Committee and Investigators
Abstract
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. (Funded by the National Cancer Institute and AstraZeneca; OlympiA ClinicalTrials.gov number, NCT02032823.).
Copyright © 2021 Massachusetts Medical Society.
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References
- Dorling L, Carvalho S, Allen J, et al. Breast cancer risk genes — association analysis in more than 113,000 women. N Engl J Med 2021; 384: 428–39.
- Hu C, Hart SN, Gnanaolivu R, et al. A population-based study of genes previously implicated in breast cancer. N Engl J Med 2021; 384: 440–51.
- Kuchenbaecker KB, Hopper JL, Barnes DR, et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA 2017; 317: 2402–16.
- Mavaddat N, Barrowdale D, Andrulis IL, et al. Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Cancer Epidemiol Biomarkers Prev 2012; 21:1 34–47.
- Atchley DP, Albarracin CT, Lopez A, et al. Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer. J Clin Oncol 2008; 26: 4282–8.
- Lakhani SR, Van De Vijver MJ, Jacquemier J, et al. The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol 2002; 20: 2310–8.
- NCCN genetic/familial high-risk assessment: breast and ovarian version 1. 2020. National Comprehensive Cancer Network, April 2021. ().
- Tutt A, Ashworth A. The relationship between the roles of BRCA genes in DNA repair and cancer predisposition. Trends Mol Med 2002; 8:5 71–6.
- Davies H, Glodzik D, Morganella S, et al. HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. Nat Med 2017; 23: 517–25.
- Staaf J, Glodzik D, Bosch A, et al. Whole-genome sequencing of triple-negative breast cancers in a population-based clinical study. Nat Med 2019; 25: 1526–33.
- Tutt AN, Lord CJ, McCabe N, et al. Exploiting the DNA repair defect in BRCA mutant cells in the design of new therapeutic strategies for cancer. Cold Spring Harb Symp Quant Biol 2005; 70: 139–48.
- Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005; 434:9 17–21.
- Bryant HE, Schultz N, Thomas HD, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 2005; 434: 913–7.
- Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009; 361: 123–34.
- Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 2010;3 76: 235–44.
- Audeh MW, Carmichael J, Penson RT, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet 2010;3 76: 245–51.
- Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015; 33: 244–50.
- Shah PD, Patil S, Dickler MN, Offit K, Hudis CA, Robson ME. Twenty-one-gene recurrence score assay in BRCA-associated versus sporadic breast cancers: differences based on germline mutation status. Cancer 2016; 122:1 178–84.
- Tryggvadottir L, Olafsdottir EJ, Olafs-dottir GH, et al. Tumour diploidy and survival in breast cancer patients with BRCA2 mutations. Breast Cancer Res Treat 2013; 140: 375–84.
- Mittendorf EA, Jeruss JS, Tucker SL, et al. Validation of a novel staging system for disease-specific survival in patients with breast cancer treated with neoadjuvant chemotherapy. J Clin Oncol 2011; 29: 1956–62.
- Hudis CA, Barlow WE, Costantino JP, et al. Proposal for standardized definitions for efficacy end points in adjuvant breast cancer trials: the STEEP system. J Clin Oncol 2007;2 5:2127–32.
- Stone A. The application of bespoke spending functions in group-sequential designs and the effect of delayed treatment switching in survival trials. Pharm Stat 2010; 9:1 51–61.
- Cuzick J. Forest plots and the inter-pretation of subgroups. Lancet 2005;3 65: 1308.
- Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med 2017; 377: 523–33.
- Litton JK, Rugo HS, Ettl J, et al. Tala-zoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med 2018; 379: 753–63.
- Fasching PA, Link T, Hauke J, et al. Neoadjuvant paclitaxel/olaparib in comparison to paclitaxel/carboplatinum in patients with HER2-negative breast cancer and homologous recombination deficiency (GeparOLA study). Ann Oncol 2021; 32: 4957.
- Burstein HJ, Curigliano G, Loibl S, et al. Estimating the benefits of therapy for early-stage breast cancer: the St. Gallen International Consensus Guidelines for the primary therapy of early breast cancer 2019. Ann Oncol 2019; 30: 1541–57.
- NCCN clinical practice guidelines in oncology — breast cancer version 5.2020. National Comprehensive Cancer Network, July 15, 2021. ().
- Tutt A, Tovey H, Cheang MCU, et al. Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT trial. Nat Med 2018; 24: 628–37.
- Zhang J, Lin Y, Sun XJ, et al. Biomarker assessment of the CBCSG006 trial: a randomized phase III trial of cisplatin plus gemcitabine compared with paclitaxel plus gemcitabine as first-line therapy for patients with metastatic triple-negative breast cancer. Ann Oncol 2018; 29: 1741–7.
- Murai J, Huang SY, Das BB, et al. Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res 2012;7 2: 5588–99.
- Morice PM, Leary A, Dolladille C, et al. Myelodysplastic syndrome and acute myeloid leukaemia in patients treated with PARP inhibitors: a safety meta-analysis of randomised controlled trials and a retrospective study of the WHO pharmacovigilance database. Lancet Haematol 2021;8 (2): e122–e134.
- Pohl-Rescigno E, Hauke J, Loibl S, et al. Association of germline variant status with therapy response in high-risk earlystage breast cancer: a secondary analysis of the GeparOcto randomized clinical trial. JAMA Oncol 2020; 6: 744–8.
- Masuda N, Lee SJ, Ohtani S, et al. Ad-juvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med 2017;3 76: 2147–59.
- Robson ME, Tung N, Conte P, et al. OlympiAD final overall survival and tolerability results: olaparib versus chemotherapy treatment of physician’s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. Ann Oncol 2019; 30: 558–66.
- Tutt A, Ashworth A. Can genetic test-ing guide treatment in breast cancer? Eur J Cancer 2008; 44: 2774–80.
Source: PubMed