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
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 tho...
| Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | article |
| Status: | Published version |
| Publication Date: | 2023 |
| Country: | España |
| Institution: | Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau) |
| Repository: | r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau |
| OAI Identifier: | oai:iibsantpau.fundanetsuite.com:p15662 |
| Online Access: | https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=15662 https://www.scopus.com/inward/record.uri?eid=2-s2.0-85144784154&doi=10.1016%2fj.annonc.2022.11.003&partnerID=40&md5=053359e51411958e1f3922d15aeb6f05 |
| Access Level: | Open access |
| Keyword: | bevacizumab BRCA1 protein DNA binding protein olaparib placebo Rad51 protein antineoplastic agent BRCA1 protein, human BRCA2 protein BRCA2 protein, human phthalazine derivative adult advanced cancer aged Article cancer chemotherapy cancer grading cancer patient cancer staging carboxy terminal sequence clinical outcome cohort analysis controlled study drug response exon exploratory research female follow up gene mutation genetic association genotype hazard ratio human human tissue maintenance therapy major clinical study middle aged oncogene ovary cancer post hoc analysis predictive value progression free survival protein domain retrospective study tumor suppressor gene genetics maintenance chemotherapy mutation ovary tumor pathology Antineoplastic Agents Bevacizumab BRCA1 Protein BRCA2 Protein Female Humans Maintenance Chemotherapy Mutation Ovarian Neoplasms Phthalazines |
| Summary: | 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. © 2022 The Author(s) |
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