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.
BRCA mutation
PARP inhibitor
genotype
location of mutation
olaparib
ovarian cancer
type of mutation
Journal
Annals of oncology : official journal of the European Society for Medical Oncology
ISSN: 1569-8041
Titre abrégé: Ann Oncol
Pays: England
ID NLM: 9007735
Informations de publication
Date de publication:
02 2023
02 2023
Historique:
received:
19
04
2022
revised:
15
09
2022
accepted:
08
11
2022
pubmed:
24
12
2022
medline:
8
2
2023
entrez:
23
12
2022
Statut:
ppublish
Résumé
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 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]. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 36564284
pii: S0923-7534(22)04733-0
doi: 10.1016/j.annonc.2022.11.003
pii:
doi:
Substances chimiques
Bevacizumab
2S9ZZM9Q9V
Antineoplastic Agents
0
olaparib
WOH1JD9AR8
BRCA1 Protein
0
Phthalazines
0
BRCA1 protein, human
0
BRCA2 protein, human
0
BRCA2 Protein
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
152-162Informations de copyright
Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.
Déclaration de conflit d'intérêts
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.