Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Feb;34(2):152-162.
doi: 10.1016/j.annonc.2022.11.003. Epub 2022 Nov 28.

Association of location of BRCA1 and BRCA2 mutations with benefit from olaparib and bevacizumab maintenance in high-grade ovarian cancer: phase III PAOLA-1/ENGOT-ov25 trial subgroup exploratory analysis

S I Labidi-Galy  1 , M Rodrigues  2 , J L Sandoval  3 , J E Kurtz  4 , F Heitz  5 , A M Mosconi  6 , I Romero  7 , U Denison  8 , S Nagao  9 , I Vergote  10 , G Parma  11 , T J Nøttrup  12 , E Rouleau  13 , G Garnier  14 , A El-Balat  15 , C Zamagni  16 , C Martín-Lorente  17 , E Pujade-Lauraine  4 , A Fiévet  13 , I L Ray-Coquard  18
Affiliations
Free article

Association of location of BRCA1 and BRCA2 mutations with benefit from olaparib and bevacizumab maintenance in high-grade ovarian cancer: phase III PAOLA-1/ENGOT-ov25 trial subgroup exploratory analysis

S I Labidi-Galy et al. Ann Oncol. 2023 Feb.
Free article

Abstract

Background: In the phase III PAOLA-1 study, the addition of maintenance olaparib to bevacizumab in patients with newly diagnosed high-grade ovarian cancer (HGOC) resulted in prolonged progression-free survival (PFS), particularly for homologous recombination deficiency-positive tumors, including those with a BRCA mutation (BRCAm). The magnitude of benefit from olaparib and bevacizumab according to the location of mutation in BRCA1/BRCA2 remains to be explored.

Patients and methods: Patients with advanced-stage HGOC responding after platinum-based chemotherapy + bevacizumab received maintenance therapy bevacizumab (15 mg/kg q3w for 15 months) + either olaparib (300 mg b.i.d. for 24 months) or placebo. PFS was analyzed in the subgroup of patients with BRCA1m/BRCA2m according to mutation location in the functional domains of BRCA1 [Really Interesting Gene (RING), DNA-binding domain (DBD), or C-terminal domain of BRCA1 (BRCT)] and BRCA2 [RAD51-binding domain (RAD51-BD); DBD].

Results: From 806 randomized patients, 159 harbored BRCA1m (19.7%) and 74 BRCA2m (9.2%). BRCA1m in RING, DBD, and BRCT domains was detected in 18, 40, and 33 patients, and BRCA2m in RAD51-BD and DBD in 36 and 13 patients, respectively. After a median follow-up of 25.5 months, benefit from maintenance olaparib + bevacizumab was observed irrespective of location of BRCAm. The benefit was particularly high for those with BRCA1m located in the DBD, with 24-month PFS estimated to be 89% and 15% [olaparib + bevacizumab versus placebo + bevacizumab hazard ratio = 0.08 (95% confidence interval 0.02-0.28); interaction P = 0.03]. In BRCA2m patients, 24-month PFS rates for those with mutations located in the DBD were 90% and 100% (olaparib + bevacizumab versus placebo + bevacizumab), respectively.

Conclusions: Advanced-stage BRCA-mutated HGOC patients reported PFS benefit from maintenance olaparib and bevacizumab regardless of mutation location. The benefit is particularly high for patients with mutations located in the DBD of BRCA1. Mutations located in the DBD of BRCA2 are also associated with excellent outcome.

Keywords: BRCA mutation; PARP inhibitor; genotype; location of mutation; olaparib; ovarian cancer; type of mutation.

PubMed Disclaimer

Conflict of interest statement

Disclosure SILG: consulting or advisory role (AstraZeneca). MR: consulting or advisory role (AstraZeneca, GlaxoSmithKline, Merck, Sharp & Dohme), research funding (Bristol Myers Squibb, Merck, Sharp & Dohme). JEK: consulting or advisory role (AstraZeneca, Bristol Myers Squibb, Clovis, Eisai, GlaxoSmithKline), travel, accommodations, expenses (Clovis, Eisai, GlaxoSmithKline). FH: honoraria (AstraZeneca, Clovis, GlaxoSmithKline, NovoCure, PharmaMar, Roche), consulting or advisory role (Amedes, AstraZeneca, Clovis, GlaxoSmithKline, NovoCure, PharmaMar, Roche), research funding (AstraZeneca, Roche). IR: consulting or advisory role (AstraZeneca, Clovis Oncology, GlaxoSmithKline), speakers’ bureau (AstraZeneca, GlaxoSmithKline, PharmaMar, Roche), travel, accommodations, expenses (AstraZeneca, Clovis, GlaxoSmithKline, PharmaMar, Roche), research funding (GlaxoSmithKline, Roche). SN: speakers’ bureau (AstraZeneca, Chugai, Merck, Sharp & Dohme, Mochida). IV: consulting or advisory role (Agenus, Aksebio, Amgen, AstraZeneca, Bristol Myers Squibb, Carrick Therapeutics, Clovis, Deciphera, Eisai, Elevar Therapeutics, Genmab, GlaxoSmithKline, Immunogen, Jazz Pharmaceuticals, Karyopharm Therapeutics, Merck, Sharp & Dohme, Mersana, Millennium, Novartis, Novocure, OCTIMET Oncology NV, Oncoinvent, Roche, Seattle Genetics, Sotio, Verastem, Zentalis), travel, accommodations, expenses (Amgen, AstraZeneca, Merck, Sharp & Dohme, Roche, Tesaro), research funding (Amgen, Genmab, Oncoinvent, Roche). ER: consulting or advisory role (AstraZeneca), travel, accommodations, expenses (AstraZeneca, Bristol Myers Squibb), honoraria (AstraZeneca, Bristol Myers Squibb, Clovis, GlaxoSmithKline). CZ: consulting or advisory role (Amgen, AstraZeneca, Celgene, Eisai, Lilly, Novartis, Pfizer, PharmaMar, Quintiles IMS, Roche, Tesaro), travel, accommodations, expenses (Celgene, Istituto Gentili, Novartis, Pfizer, PharmaMar, Pierre Fabre, Roche, Tesaro), honoraria (Istituto Gentili, Pierre Fabre, Takeda, Teva), research funding (AbbVie, Array BioPharma, AstraZeneca, Celgene, Daiichi Sankyo, Medivation, Morphotek, Novartis, Pfizer, Pierre Fabre, Roche/Genentech, Roche, Seattle Genetics, Synthon, Tesaro). All other authors have declared no conflicts of interest.

Publication types