Abstract
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.
Publication types
-
Clinical Trial, Phase II
-
Multicenter Study
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
-
Adult
-
Aged
-
Aged, 80 and over
-
Antineoplastic Agents / adverse effects
-
Antineoplastic Agents / therapeutic use*
-
BRCA1 Protein / genetics
-
BRCA2 Protein / genetics
-
Carcinoma, Ovarian Epithelial / drug therapy*
-
DNA Methylation / genetics
-
DNA-Binding Proteins / genetics
-
Female
-
Humans
-
Indoles / adverse effects
-
Indoles / therapeutic use*
-
Middle Aged
-
Neoplasm Recurrence, Local / drug therapy
-
Ovarian Neoplasms / drug therapy*
-
Platinum / therapeutic use
-
Poly(ADP-ribose) Polymerase Inhibitors / adverse effects
-
Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use*
-
Promoter Regions, Genetic / genetics
Substances
-
Antineoplastic Agents
-
BRCA1 Protein
-
BRCA1 protein, human
-
BRCA2 Protein
-
BRCA2 protein, human
-
DNA-Binding Proteins
-
Indoles
-
Poly(ADP-ribose) Polymerase Inhibitors
-
RAD51C protein, human
-
RAD51D protein, human
-
Platinum
-
rucaparib
Associated data
-
ClinicalTrials.gov/NCT01891344