Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer.

P Sharma, R Yerushalmi, Y H Park, G Zoppoli, G Viale, T A Traina, M Toi, E Stickeler, T Španić, C F Singer, H Yang, Z Shao, E Senkus, R Schmutzler, G Rossi, M Piccart, K-A Phillips, R McConnell, E Martinez de Dueñas, Q Sun, A N J Tutt, C Campbell, D Cameron, B Kaufman, W Razaq, A M Brufsky, M Schmidt, M A Colleoni, M Parton, F Marmé, G S Sonke, T Nagy, J Zhang, I Tennevet, Z Fan, A Mailliez, K H Jung, D Pang, G Aktan, F Elsafy, A Eisen, S M Domchek, S Delaloge, J Bliss, J Bergh, J Balmaña, M Arnedos, A C Armstrong, L E Fein, A Arahmani, K Cui, P Rastogi, L Ross, M Taboada, G Yothers, R D Gelber, J E Garber, A Jager, P C Lucas, S Loibl, L Korde, N Loman, T-W Liu, B Linderholm, W Janni, S R Lakhani, Ó Þ Jóhannsson, C E Geyer, S-A Im, S J Hollingsworth, M Gnant, L Gianni, K A Gelmon, S Friedman, J M Ford, A Fielding

Journal: Annals of oncology : official journal of the European Society for Medical Oncology 2022;33(12):1250-1268

PMID: 36228963

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Abstract

BACKGROUND

The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety.

PATIENTS AND METHODS

One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015.

RESULTS

With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI -0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome.

CONCLUSION

With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals.

Address: NRG Oncology/NSABP Foundation, Pittsburgh; Department of Medicine, UPMC Hillman Cancer Center, Pittsburgh.; Dana-Farber Cancer Institute, Harvard Medical School, Boston.; Dana-Farber Cancer Institute, Harvard Medical School, Boston; Harvard T.H. Chan School of Public Health, Boston; Frontier Science Foundation, Boston.; NRG Oncology/NSABP Foundation, Pittsburgh; Department of Biostatistics, University of Pittsburgh, Pittsburgh, USA.; Oncology Biometrics Department, AstraZeneca, Macclesfield.; Department of Data Management, Frontier Science (Scotland), Kincraig, Scotland, UK.; Department of Oncology R&D, AstraZeneca, Gaithersburg, USA.; Research Operations Department, Breast International Group, Brussels, Belgium.; Global Oncology Clinical Development, Merck and Co. Inc., Rahway, USA.; Department of Medical Oncology, The Christie Hospital NHS Foundation Trust Manchester, UK.; European Organisation for Research and Treatment (EORTC), Brussels, Belgium; The Department of Medical Oncology, Institut Bergonie, Bordeaux, France.; Medical Oncology Department, Vall d'Hebron Institute of Oncology and Vall d'Hebron University Hospital, Barcelona, Spain.; Department of Oncology-Pathology, Swedish Breast Cancer Group, Karolinska Institute and Breast Cancer Center, Karolinska University Hospital and Karolinska Comprehensive Cancer Center, Stockholm, Sweden.; Department of Clinical Trials and Statistics Unit (ICR-CTSU), The Institute of Cancer Research, London, UK.; Department of Cancer Medicine, Institute Gustave Roussy and Unicancer Breast Group, Paris, France.; Department of Medicine, Basser Center for BRCA at the Abramson Cancer Center, University of Pennsylvania, Philadelphia, USA.; Odette Cancer Centre, Department of Medicine, University of Toronto, Toronto, Canada.; Department of Clinical Research, Instituto de Oncologia De Rosario, Santa Fe, Argentina.; Department of Medicine/Oncology, Stanford University School of Medicine, Stanford.; Facing Our Risk of Cancer Empowered, Tampa, USA.; Department of Medical Oncology, BC Cancer, Vancouver, Canada.; Department of Oncology, International Breast Cancer Study Group, Bern, Switzerland; Department of Medical Oncology, Ospedale Infermi AUSL della Romagna, Rimini, Italy.; Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.; Department of Late Development Oncology, AstraZeneca, Cambridge, UK.; Department of Internal Medicine, Cancer Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.; Department of Medical Oncology, Dutch Breast Cancer Research Group, Utrecht, the Netherlands.; Department of Medical Oncology, Landspítali University Hospital of Iceland, Icelandic Breast Cancer Group, Reykjavik, Iceland.; Department of Anatomical Pathology, The University of Queensland Centre for Clinical Research and Pathology Queensland, Brisbane, Australia.; Department for Obstetrics and Gynecology, Universitaetsklinikum, University of Ulm, Ulm, Germany.; Department of Oncology, Sahlgrenska University Hospital, Gothenburg; Department of Oncology, The Institute of Clinical Sciences, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.; Division of Cancer Research, National Health Research Institutes, Taiwan Cooperative Oncology Group, Taipei City, Taiwan.; Department of Hematology, Oncology, and Radiation Physics, Swedish Association of Breast Oncologists, Skåne University Hospital, Lund, Sweden.; Clinical Investigations Branch, Division of Cancer Treatment and Diagnosis, The National Cancer Institute, Rockville, USA.; Medicine and Research, German Breast Group, Neu-Isenburg; Medicine and Research, The Center for Hematology and Oncology Bethanien and Goethe University, Frankfurt, Germany.; NRG Oncology/NSABP Foundation, Pittsburgh; Department of Pathology, UPMC Hillman Cancer Center, Pittsburgh, USA.; Medical Faculty Mannheim, Heidelberg University, Mannheim Germany and the German Breast Group, Neu-Isenburg, Germany.; Médica Consorcio Hospitalario Provincial de Castellón, Servicio de Oncología, Castellón, Spain.; Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne; Breast Cancer Trials, Australia and New Zealand, Newcastle, Australia.; Department of Scientific Direction, Institut Jules Bordet, l'Université Libre de Bruxelles, Brussels.; Department of Research and Development, Breast International Group, Brussels, Belgium.; The Center for Familial Breast and Ovarian Cancer and the Center for Integrated Oncology, Faculty of Medicine, University Hospital Cologne, Cologne, Germany.; Department of Oncology and Radiotherapy, Medical University of Gdańsk, Gdańsk, Poland.; Fudan University Shanghai Cancer Center, Shanghai, China.; Department of Internal Medicine, Division of Medical Oncology, University of Kansas Medical Center, Westwood, USA.; Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.; Department of Patient Advocacy, Europa Donna-The European Breast Cancer Coalition, Milan, Italy; Europa Donna Slovenia, Ljubljana, Slovenia.; Department of Obstetrics and Gynecology, University Hospital Aachen, Aachen, Germany.; Department of Breast Surgery Kyoto University Hospital, Kyoto, Japan.; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA.; Department of Pathology, University of Milan, European Institute of Oncology IRCCS, Milan.; Internal Medicine Oncology Unit, Gruppo Oncologico Italiano di Ricerca Clinica, Parma; Università degli Studi di Genova and IRCCS Ospedale Policlinico San Martino, Genoa, Italy.; Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.; Department of Oncology, Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Beilinson Hospital, Petach Tikva; Faculty of Medicine, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.; Department of Breast Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou.; Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China.; Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.; Department of Medical Oncology, Breast Cancer Unit, Oscar Lambret Center, Lillie, France.; Department of Breast Surgery, First Hospital of Jilin University, Jilin, China.; Department of Medical Oncology, Centre Henri Becquerel, Rouen, France.; Breast Cancer Center, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China.; Chemotherapy Department B, Országos Onkológiai Intézet, National Institute of Oncology, Budapest, Hungary.; Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands.; Department of Breast Surgery, Peking Union Medical College Hospital, Peking, China.; Breast Unit, Royal Marsden Hospital, London, UK.; Division of Medical Senology, European Institute of Oncology (IEO), IRCCS, Milan.; Department of Obstetrics and Gynecology, University Medical Center Mainz, Mainz, Germany.; Department of Internal Medicine, Section of Hematology/Oncology, Oklahoma University Health, Oklahoma City, USA.; The Breast Oncology Institute, Chaim Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel.; Edinburgh Cancer Research Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh.; Department of Statistics and Programming, Frontier Science (Scotland), Kincraig, Scotland.; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London; The Breast Cancer Now Unit, Guy's Hospital Cancer Centre, King's College London, London, UK. Electronic address: [email protected].

DOI: 10.1016/j.annonc.2022.09.159