{"doi":"10.1200/po.22.00258","title":"Homologous Recombination Repair Gene Mutations to Predict Olaparib Plus Bevacizumab Efficacy in the First-Line Ovarian Cancer PAOLA-1/ENGOT-ov25 Trial","abstract":"<jats:sec><jats:title>PURPOSE</jats:title><jats:p> The PAOLA-1/ENGOT-ov25 trial of maintenance olaparib plus bevacizumab for newly diagnosed advanced high-grade ovarian cancer demonstrated a significant progression-free survival (PFS) benefit over placebo plus bevacizumab, particularly in patients with homologous recombination deficiency (HRD)–positive tumors. We explored whether mutations in non- BRCA1 or BRCA2 homologous recombination repair (non–BRCA HRRm) genes predicted benefit from olaparib plus bevacizumab in PAOLA-1. </jats:p></jats:sec><jats:sec><jats:title>METHODS</jats:title><jats:p> Eight hundred and six patients were randomly assigned (2:1). Tumors were analyzed using the Myriad MyChoice HRD Plus assay to assess non–BRCA HRRm and HRD status; HRD was based on a genomic instability score (GIS) of ≥ 42. In this exploratory analysis, PFS was assessed in patients harboring deleterious mutations using six non–BRCA HRR gene panels, three devised for this analysis and three previously published. </jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p> The non–BRCA HRRm prevalence ranged from 30 of 806 (3.7%) to 79 of 806 (9.8%) depending on the gene panel used, whereas 152 of 806 (18.9%) had non‐ BRCA1 or BRCA2 mutation HRD-positive tumors. The majority of tumors harboring non–BRCA HRRm had a low median GIS; however, a GIS of &gt; 42 was observed for tumors with mutations in five HRR genes ( BLM, BRIP1, RAD51C, PALB2, and RAD51D). Rates of gene-specific biallelic loss were variable (0% to 100%) in non–BRCA HRRm tumors relative to BRCA1-mutated (99%) or BRCA2-mutated (86%) tumors. Across all gene panels tested, hazard ratios for PFS (95% CI) ranged from 0.92 (0.51 to 1.73) to 1.83 (0.76 to 5.43). </jats:p></jats:sec><jats:sec><jats:title>CONCLUSION</jats:title><jats:p> Acknowledging limitations of small subgroup sizes, non–BRCA HRRm gene panels were not predictive of PFS benefit with maintenance olaparib plus bevacizumab versus placebo plus bevacizumab in PAOLA-1, irrespective of the gene panel tested. Current gene panels exploring HRRm should not be considered a substitute for HRD determined by BRCA mutation status and genomic instability testing in first-line high-grade ovarian cancer. </jats:p></jats:sec>","journal":"JCO Precision Oncology","year":2023,"id":600070,"datarank":0.611630616585858,"base_score":4.07753744390572,"endowment":4.07753744390572,"self_citation_contribution":0.611630616585858,"citation_network_contribution":0.0,"self_endowment_contribution":0.611630616585858,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":58,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":325481,"name":"Jessica Brown","orcid":"0000-0001-6806-8499","position":1,"is_corresponding":false},{"id":277346,"name":"Alan Barnicle","orcid":"0000-0002-1475-7587","position":2,"is_corresponding":false},{"id":1538203,"name":"Jonathan Wessen","orcid":null,"position":3,"is_corresponding":false},{"id":1538204,"name":"Pierre Lao-Sirieix","orcid":null,"position":4,"is_corresponding":false},{"id":1230378,"name":"Steven W. Criscione","orcid":"0000-0002-6550-5769","position":5,"is_corresponding":false},{"id":559346,"name":"Andreas du Bois","orcid":"0000-0002-8477-506X","position":6,"is_corresponding":false},{"id":406831,"name":"Domenica Lorusso","orcid":"0000-0003-0981-0598","position":7,"is_corresponding":false},{"id":1155877,"name":"Ignacio Romero","orcid":"0000-0003-0364-6969","position":8,"is_corresponding":false},{"id":1538205,"name":"Edgar Petru","orcid":null,"position":9,"is_corresponding":false},{"id":383187,"name":"Hiroyuki Yoshida","orcid":"0000-0001-8998-5050","position":10,"is_corresponding":false},{"id":258152,"name":"Ignace Vergote","orcid":"0000-0002-7589-8981","position":11,"is_corresponding":false},{"id":50716,"name":"Nicoletta Colombo","orcid":"0000-0003-2225-715X","position":12,"is_corresponding":false},{"id":883587,"name":"Sakari Hietanen","orcid":"0000-0003-4734-4743","position":13,"is_corresponding":false},{"id":1538206,"name":"Magali Provansal","orcid":null,"position":14,"is_corresponding":false},{"id":1282604,"name":"Barbara Schmalfeldt","orcid":"0000-0001-8142-2915","position":15,"is_corresponding":false},{"id":258141,"name":"Sandro Pignata","orcid":"0000-0002-8836-2633","position":16,"is_corresponding":false},{"id":1538207,"name":"Cristina Martín Lorente","orcid":"0000-0002-9827-0521","position":17,"is_corresponding":false},{"id":1538208,"name":"Dominique Berton","orcid":"0000-0001-6182-6998","position":18,"is_corresponding":false},{"id":305548,"name":"Ingo B. Runnebaum","orcid":"0000-0002-6702-4651","position":19,"is_corresponding":false},{"id":33577,"name":"Isabelle Ray‐Coquard","orcid":"0000-0003-2472-8306","position":20,"is_corresponding":false},{"id":1538202,"name":"Eric Pujade-Lauraine","orcid":"0000-0002-0759-7263","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Homologous Recombination Repair Gene Mutations to Predict Olaparib Plus Bevacizumab Efficacy in the First-Line Ovarian Cancer PAOLA-1/ENGOT-ov25 Trial","abstract":"<jats:sec><jats:title>PURPOSE</jats:title><jats:p> The PAOLA-1/ENGOT-ov25 trial of maintenance olaparib plus bevacizumab for newly diagnosed advanced high-grade ovarian cancer demonstrated a significant progression-free survival (PFS) benefit over placebo plus bevacizumab, particularly in patients with homologous recombination deficiency (HRD)–positive tumors. We explored whether mutations in non- BRCA1 or BRCA2 homologous recombination repair (non–BRCA HRRm) genes predicted benefit from olaparib plus bevacizumab in PAOLA-1. </jats:p></jats:sec><jats:sec><jats:title>METHODS</jats:title><jats:p> Eight hundred and six patients were randomly assigned (2:1). Tumors were analyzed using the Myriad MyChoice HRD Plus assay to assess non–BRCA HRRm and HRD status; HRD was based on a genomic instability score (GIS) of ≥ 42. In this exploratory analysis, PFS was assessed in patients harboring deleterious mutations using six non–BRCA HRR gene panels, three devised for this analysis and three previously published. </jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p> The non–BRCA HRRm prevalence ranged from 30 of 806 (3.7%) to 79 of 806 (9.8%) depending on the gene panel used, whereas 152 of 806 (18.9%) had non‐ BRCA1 or BRCA2 mutation HRD-positive tumors. The majority of tumors harboring non–BRCA HRRm had a low median GIS; however, a GIS of &gt; 42 was observed for tumors with mutations in five HRR genes ( BLM, BRIP1, RAD51C, PALB2, and RAD51D). Rates of gene-specific biallelic loss were variable (0% to 100%) in non–BRCA HRRm tumors relative to BRCA1-mutated (99%) or BRCA2-mutated (86%) tumors. Across all gene panels tested, hazard ratios for PFS (95% CI) ranged from 0.92 (0.51 to 1.73) to 1.83 (0.76 to 5.43). </jats:p></jats:sec><jats:sec><jats:title>CONCLUSION</jats:title><jats:p> Acknowledging limitations of small subgroup sizes, non–BRCA HRRm gene panels were not predictive of PFS benefit with maintenance olaparib plus bevacizumab versus placebo plus bevacizumab in PAOLA-1, irrespective of the gene panel tested. Current gene panels exploring HRRm should not be considered a substitute for HRD determined by BRCA mutation status and genomic instability testing in first-line high-grade ovarian cancer. </jats:p></jats:sec>","is_dataset_classified":null,"base_score":4.07753744390572,"endowment":4.07753744390572,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"36716415","pmcid":"PMC9928987","openalex_id":"https://openalex.org/W4318575269","authors":[],"funders":[],"total_grants":0,"fwci":6.7694,"citation_percentile":0.97874796,"influential_citations":0,"citation_trend":[{"year":2023,"count":16},{"year":2024,"count":17},{"year":2025,"count":20},{"year":2026,"count":5}],"oa_status":"hybrid","license":"cc-by-nc-nd","oa_locations":[{"url":"https://ascopubs.org/doi/pdfdirect/10.1200/PO.22.00258?role=tab","host_type":"journal"},{"url":"https://ascopubs.org/doi/pdfdirect/10.1200/PO.22.00258?role=tab","host_type":"publisher"},{"url":"https://ascopubs.org/doi/pdfdirect/10.1200/PO.22.00258","host_type":"publisher"},{"url":"https://doi.org/10.1200/po.22.00258","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/36716415","host_type":"repository"},{"url":"https://hdl.handle.net/10281/403218","host_type":"repository"},{"url":"https://ddd.uab.cat/record/303903","host_type":"repository"},{"url":"https://lirias.kuleuven.be/handle/20.500.12942/714631","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/9928987","host_type":"repository"},{"url":"https://www.utupub.fi/handle/10024/183491","host_type":"repository"},{"url":"https://boa.unimib.it/bitstream/10281/403218/2/10281-403218_VoR.pdf","host_type":"repository"},{"url":"https://ddd.uab.cat/pub/artpub/2023/303903/303903.pdf","host_type":"repository"},{"url":"https://lirias.kuleuven.be/retrieve/1fd80c4c-d160-4640-9174-56a9a54994de","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC9928987/pdf/po-7-e2200258.pdf","host_type":"repository"},{"url":"https://www.utupub.fi/bitstream/10024/183491/1/pujade-lauraine-et-al-2023-homologous-recombination-repair-gene-mutations-to-predict-olaparib-plus-bevacizumab-efficacy.pdf","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC9928987","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC9928987?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["PARP inhibition in cancer therapy","Ovarian cancer diagnosis and treatment","BRCA gene mutations in cancer"],"mesh_terms":["Poly(ADP-ribose) Polymerase Inhibitors","Bevacizumab","Female","Humans","Mutation","Ovarian Neoplasms","Phthalazines","Piperazines","Genomic Instability","Recombinational DNA Repair"],"keywords":["Olaparib","Ovarian cancer","Bevacizumab","Homologous recombination","Medicine","Oncology","PALB2","PARP inhibitor","Internal medicine","BRCA mutation","Cancer research","Hazard ratio","Cancer","Mutation","Gene","Germline mutation","Biology","Genetics","Chemotherapy","Poly ADP ribose polymerase","Confidence interval","Polymerase"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"nct"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-29T12:08:58.798183Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}