Overall survival in the OlympiA phase Ill trial of adjuvant olaparib in patients with germime 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.; ... ; OlympiA Clinical Trial Steering Committee and Investigators (2022)

Article / Letter to editor

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 (Delta 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% (Delta 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Delta 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 35 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 IDES and DDFS with no new safety signals.

• breast cancer
• BRCA1/2
• PARP inhibition
• olaparib
• adjuvant therapy

• All 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.; S.A. im; Jager, A.; Lakhani, S.R.; Janni, W.; Linderholm, B.; Liu, T.W.; Loman, N.; Korde, L.; Loibl, S.; Lucas, P.C.; Marme, F.; Duenas, E.M. de; McConnell, R.; Phillips, K.A.; Piccart, M.; Rossi, G.; Schmutzler, R.; Senkus, E.; 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, I.; Zhang, J.; Nagy, T.; Sonke, G.S.; Sun, Q.; Parton, M.; Colleoni, M.A.; Schmidt, M.; Brufsky, A.M.; Razaq, W.; Kaufman, B.; Cameron, D.; Campbell, C.; Tutt, A.N.J.; Johannsson, O.T.; OlympiA Clinical Trial Steering Committee and Investigators
• Date: 2022-11-28
• Journal: Annals of Oncology
• Volume: 33
• Issue: 12
• Pages: 1250 - 1268
• DOI: doi:10.1016/j.annonc.2022.09.159