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

Geyer, C.E.; Garber, J.E.; Gelber, R.D.; Yothers, G.; Taboada, M.; Ross, L.; Rastogi, P.; Cui, K.; Arahmani, A.; Aktan, G.; Armstrong, A.C.; Arnedos, M.; Balmana, J.; Bergh, J.; Bliss, J.; Delaloge, S.; Domchek, S.M.; Eisen, A.; Elsafy, F.; Fein, L.E.; Fielding, A.; Ford, J.M.; Friedman, S.; Gelmon, K.A.; Gianni, L.; Gnant, M.; Hollingsworth, S.J.; Im, S.-A.; Jager, A.; Johannsson, O.Th.; Lakhani, S.R.; Janni, W.; Linderholm, B.; Liu, T.-W.; Loman, N.; Korde, L.; Loibl, S.; Lucas, P.C.; Marme, F.; Martínez de Dueñas, Eduardo; McConnell, R.; Phillips, K.-A.; Piccart, M.; Rossi, G.; Schmutzler, R.; Senkus, Elżbieta; Shao, Z.; Sharma, P.; Singer, C.F.; Spanic, T.; Stickeler, E.; Toi, M.; Traina, T.A.; Viale, G.; Zoppoli, G.; Park, Y.H.; Yerushalmi, R.; Yang, H.; Pang, D.; Jung, K.H.; Mailliez, A.; Fan, Z.; Tennevet, Isabelle; Zhang, J.; Nagy, T.; Sonke, G.S.; Sun, Q.; Parton, M.; Colleoni, M.A.; Schmidt, M.; Brufsky, A.M.; Razaq, Wajeeha; Kaufman, B.; Cameron, D.; Campbell, C.; Tutt, A.N.J.; the OlympiA Clinical Trial Steering Committee and Investigators; Im, Seock-Ah

doi:10.1016/j.annonc.2022.09.159

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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

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Authors: Geyer, C.E.; Garber, J.E.; Gelber, R.D.; Yothers, G.; Taboada, M.; Ross, L.; Rastogi, P.; Cui, K.; Arahmani, A.; Aktan, G.; Armstrong, A.C.; Arnedos, M.; Balmana, J.; Bergh, J.; Bliss, J.; Delaloge, S.; Domchek, S.M.; Eisen, A.; Elsafy, F.; Fein, L.E.; Fielding, A.; Ford, J.M.; Friedman, S.; Gelmon, K.A.; Gianni, L.; Gnant, M.; Hollingsworth, S.J.; Im, S.-A.; Jager, A.; Johannsson, O.Th.; Lakhani, S.R.; Janni, W.; Linderholm, B.; Liu, T.-W.; Loman, N.; Korde, L.; Loibl, S.; Lucas, P.C.; Marme, F.; Martínez de Dueñas, Eduardo; McConnell, R.; Phillips, K.-A.; Piccart, M.; Rossi, G.; Schmutzler, R.; Senkus, Elżbieta; Shao, Z.; Sharma, P.; Singer, C.F.; Spanic, T.; Stickeler, E.; Toi, M.; Traina, T.A.; Viale, G.; Zoppoli, G.; Park, Y.H.; Yerushalmi, R.; Yang, H.; Pang, D.; Jung, K.H.; Mailliez, A.; Fan, Z.; Tennevet, Isabelle; Zhang, J.; Nagy, T.; Sonke, G.S.; Sun, Q.; Parton, M.; Colleoni, M.A.; Schmidt, M.; Brufsky, A.M.; Razaq, Wajeeha; Kaufman, B.; Cameron, D.; Campbell, C.; Tutt, A.N.J.; the OlympiA Clinical Trial Steering Committee and Investigators; Im, Seock-Ah

Issue Date: 2022-12

Publisher: Oxford University Press

Citation: Annals of Oncology, Vol.33 No.12, pp.1250-1268

Abstract: © 2022 The AuthorsBackground: 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.