1. Molecular and clinical determinants of response and resistance to rucaparib for recurrent ovarian cancer treatment in ARIEL2 (Parts 1 and 2).
- Author
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Swisher EM, Kwan TT, Oza AM, Tinker AV, Ray-Coquard I, Oaknin A, Coleman RL, Aghajanian C, Konecny GE, O'Malley DM, Leary A, Provencher D, Welch S, Chen LM, Wahner Hendrickson AE, Ma L, Ghatage P, Kristeleit RS, Dorigo O, Musafer A, Kaufmann SH, Elvin JA, Lin DI, Chambers SK, Dominy E, Vo LT, Goble S, Maloney L, Giordano H, Harding T, Dobrovic A, Scott CL, Lin KK, and McNeish IA
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Agents adverse effects, BRCA1 Protein genetics, BRCA2 Protein genetics, DNA Methylation genetics, DNA-Binding Proteins genetics, Female, Humans, Indoles adverse effects, Middle Aged, Neoplasm Recurrence, Local drug therapy, Platinum therapeutic use, Poly(ADP-ribose) Polymerase Inhibitors adverse effects, Promoter Regions, Genetic genetics, Antineoplastic Agents therapeutic use, Carcinoma, Ovarian Epithelial drug therapy, Indoles therapeutic use, Ovarian Neoplasms drug therapy, Poly(ADP-ribose) Polymerase Inhibitors therapeutic use
- 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.
- Published
- 2021
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