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

TY - JOUR

T1 - 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

AU - Geyer, C E

AU - Garber, J E

AU - Gelber, R D

AU - Yothers, G

AU - Taboada, M

AU - Ross, L

AU - Rastogi, P

AU - Cui, K

AU - Arahmani, A

AU - Aktan, G

AU - Armstrong, A C

AU - Arnedos, M

AU - Balmaña, J

AU - Bergh, J

AU - Bliss, J

AU - Delaloge, S

AU - Domchek, S M

AU - Eisen, A

AU - Elsafy, F

AU - Fein, L E

AU - Fielding, A

AU - Ford, J M

AU - Friedman, S

AU - Gelmon, K A

AU - Gianni, L

AU - Gnant, M

AU - Hollingsworth, S J

AU - Im, S-A

AU - Jager, A

AU - Jóhannsson, Ó Þ

AU - Lakhani, S R

AU - Janni, W

AU - Linderholm, B

AU - Liu, T-W

AU - Loman, N

AU - Korde, L

AU - Loibl, S

AU - Lucas, P C

AU - Marmé, F

AU - Martinez de Dueñas, E

AU - McConnell, R

AU - Phillips, K-A

AU - Piccart, M

AU - Rossi, G

AU - Schmutzler, R

AU - Senkus, E

AU - Shao, Z

AU - Sharma, P

AU - Singer, C F

AU - Španić, T

AU - Stickeler, E

AU - Toi, M

AU - Traina, T A

AU - Viale, G

AU - Zoppoli, G

AU - Park, Y H

AU - Yerushalmi, R

AU - Yang, H

AU - Pang, D

AU - Jung, K H

AU - Mailliez, A

AU - Fan, Z

AU - Tennevet, I

AU - Zhang, J

AU - Nagy, T

AU - Sonke, G S

AU - Sun, Q

AU - Parton, M

AU - Colleoni, M A

AU - Schmidt, M

AU - Brufsky, A M

AU - Razaq, W

AU - Kaufman, B

AU - Cameron, D

AU - Campbell, C

AU - Tutt, A N J

AU - OlympiA Clinical Trial Steering Committee and Investigators

AU - Muller , Volkmar

N1 - Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

KW - Humans

KW - Female

KW - Breast Neoplasms/drug therapy

KW - Phthalazines/adverse effects

KW - Germ Cells/pathology

KW - BRCA1 Protein/genetics

U2 - 10.1016/j.annonc.2022.09.159

DO - 10.1016/j.annonc.2022.09.159

M3 - SCORING: Journal article

C2 - 36228963

VL - 33

SP - 1250

EP - 1268

JO - ANN ONCOL

JF - ANN ONCOL

SN - 0923-7534

IS - 12

ER -