Homologous Recombination Repair Gene Mutations to Predict Olaparib Plus Bevacizumab Efficacy in the First-Line Ovarian Cancer PAOLA-1/ENGOT-ov25 Trial
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Homologous Recombination Repair Gene Mutations to Predict Olaparib Plus Bevacizumab Efficacy in the First-Line Ovarian Cancer PAOLA-1/ENGOT-ov25 Trial. / Pujade-Lauraine, Eric; Brown, Jessica; Barnicle, Alan; Wessen, Jonathan; Lao-Sirieix, Pierre; Criscione, Steven W; du Bois, Andreas; Lorusso, Domenica; Romero, Ignacio; Petru, Edgar; Yoshida, Hiroyuki; Vergote, Ignace; Colombo, Nicoletta; Hietanen, Sakari; Provansal, Magali; Schmalfeldt, Barbara; Pignata, Sandro; Martín Lorente, Cristina; Berton, Dominique; Runnebaum, Ingo B; Ray-Coquard, Isabelle.
in: JCO PRECIS ONCOL, Jahrgang 7, Nr. 7, 01.2023, S. e2200258.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Homologous Recombination Repair Gene Mutations to Predict Olaparib Plus Bevacizumab Efficacy in the First-Line Ovarian Cancer PAOLA-1/ENGOT-ov25 Trial
AU - Pujade-Lauraine, Eric
AU - Brown, Jessica
AU - Barnicle, Alan
AU - Wessen, Jonathan
AU - Lao-Sirieix, Pierre
AU - Criscione, Steven W
AU - du Bois, Andreas
AU - Lorusso, Domenica
AU - Romero, Ignacio
AU - Petru, Edgar
AU - Yoshida, Hiroyuki
AU - Vergote, Ignace
AU - Colombo, Nicoletta
AU - Hietanen, Sakari
AU - Provansal, Magali
AU - Schmalfeldt, Barbara
AU - Pignata, Sandro
AU - Martín Lorente, Cristina
AU - Berton, Dominique
AU - Runnebaum, Ingo B
AU - Ray-Coquard, Isabelle
PY - 2023/1
Y1 - 2023/1
N2 - PURPOSE: 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.METHODS: 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.RESULTS: 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 > 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).CONCLUSION: 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.
AB - PURPOSE: 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.METHODS: 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.RESULTS: 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 > 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).CONCLUSION: 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.
KW - Humans
KW - Female
KW - Bevacizumab/therapeutic use
KW - Recombinational DNA Repair/genetics
KW - Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use
KW - Ovarian Neoplasms/drug therapy
KW - Mutation
KW - Genomic Instability
U2 - 10.1200/PO.22.00258
DO - 10.1200/PO.22.00258
M3 - SCORING: Journal article
C2 - 36716415
VL - 7
SP - e2200258
JO - JCO PRECIS ONCOL
JF - JCO PRECIS ONCOL
SN - 2473-4284
IS - 7
ER -
