RESUMEN

ARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the PARP inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma. In this post hoc exploratory biomarker analysis of pre- and post-platinum ARIEL2 samples, RAD51C and RAD51D mutations and high-level BRCA1 promoter methylation predict response to rucaparib, similar to BRCA1/BRCA2 mutations. BRCA1 methylation loss may be a major cross-resistance mechanism to platinum and PARPi. Genomic scars associated with homologous recombination deficiency are irreversible, persisting even as platinum resistance develops, and therefore are predictive of rucaparib response only in platinum-sensitive disease. The RAS, AKT, and cell cycle pathways may be additional modulators of PARPi sensitivity.

Asunto(s)

Antineoplásicos/uso terapéutico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Indoles/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Proteína BRCA1/genética , Proteína BRCA2/genética , Metilación de ADN/genética , Proteínas de Unión al ADN/genética , Femenino , Humanos , Indoles/efectos adversos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Platino (Metal)/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Regiones Promotoras Genéticas/genética