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
Por:
Labidi-Galy S.I., Rodrigues M., Sandoval J.L., Kurtz J.E., Heitz F., Mosconi A.M., Romero I., Denison U., Nagao S., Vergote I., Parma G., Nøttrup T.J., Rouleau E., Garnier G., El-Balat A., Zamagni C., Martín-Lorente C., Pujade-Lauraine E., Fiévet A., Ray-Coquard I.L.
Publicada:
1 ene 2023
Ahead of Print:
1 feb 2023
Resumen:
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)
Filiaciones:
Labidi-Galy S.I.:
Department of Oncology, Hôpitaux Universitaires de Genève, Geneva, Switzerland
Department of Medicine, Division of Oncology, Faculty of Medicine, University of Geneva, Swiss Cancer Center Leman, Geneva, Switzerland
Rodrigues M.:
INSERM U830, Institut Curie, PSL Research University, Paris, Paris, France
Department of Medical Oncology, Institut Curie, PSL Research University, Paris, France
ARCAGY-GINECO, Paris, France
Sandoval J.L.:
Department of Oncology, Hôpitaux Universitaires de Genève, Geneva, Switzerland
Department of Medicine, Division of Oncology, Faculty of Medicine, University of Geneva, Swiss Cancer Center Leman, Geneva, Switzerland
Kurtz J.E.:
ARCAGY-GINECO, Paris, France
ICANS (Institut de Cancérologie Strasbourg Europe), Strasbourg, France
Heitz F.:
Department of Gynecology & Gynecologic Oncology, Ev. Kliniken Essen-Mitte, Essen, Germany
AGO, Berlin, Germany
Charité—Universitätsmedizin Berlin, Campus Virchow, Berlin, Germany
Mosconi A.M.:
S.C. di Oncologia Medica Osp., S. Maria della Misericordia—AO di Perugia, Perugia, Italy
MITO, Italy
Romero I.:
Instituto Valenciano de Oncología, Valencia, Spain
GEICO, Spain
Denison U.:
Institute for Gynaecological Oncology und Senology—Karl Landsteiner, Klinik Hietzing, Vienna, Austria
AGO, Austria
Nagao S.:
Hyogo Cancer Center, Hyogo, Japan
Okayama University Hospital, Okayama, Japan
Vergote I.:
University Hospital Leuven, Leuven Cancer Institute, Leuven, Belgium
BGOG, Belgium
Parma G.:
Istituto Europeo Oncologia, Milan, Italy
MANGO, Italy
Nøttrup T.J.:
Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
NSGO, Denmark
Rouleau E.:
Department of Medical Biology and Pathology, Cancer Genetics Laboratory, Gustave Roussy, Villejuif, France
Garnier G.:
Centre Hospitalier Princesse Grace, Monaco
GINECO, Monaco
El-Balat A.:
Charité—Universitätsmedizin Berlin, Campus Virchow, Berlin, Germany
Spital Uster, Frauenklinik, Uster, Switzerland
Klinikum der Johann Wolfgang Goethe-Universität Frankfurt, Klinik für Frauenheilkunde und Geburtshilfe, Frankfurt, Germany
Zamagni C.:
IRCCS Azienda Ospedaliero-universitaria di Bologna, Bologna, Italy
Martín-Lorente C.:
GEICO, Spain
Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Pujade-Lauraine E.:
ARCAGY-GINECO, Paris, France
ICANS (Institut de Cancérologie Strasbourg Europe), Strasbourg, France
Fiévet A.:
Department of Medical Biology and Pathology, Cancer Genetics Laboratory, Gustave Roussy, Villejuif, France
Ray-Coquard I.L.:
ARCAGY-GINECO, Paris, France
ICANS (Institut de Cancérologie Strasbourg Europe), Strasbourg, France
Centre Léon Bérard, Lyon, France
Health Services and Performance Research Lab (EA 7425 HESPER), University Claude Bernard Lyon, Lyon, France
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