Molecular and clinical determinants of response and resistance to rucaparib for recurrent ovarian cancer treatment in ARIEL2 (Parts 1 and 2)

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 methyla...

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Bibliographic Details
Published in:Nature communications Vol. 12; no. 1; pp. 2487 - 13
Main Authors: Swisher, Elizabeth M., Kwan, Tanya T., Oza, Amit M., Tinker, Anna V., Ray-Coquard, Isabelle, Oaknin, Ana, Coleman, Robert L., Aghajanian, Carol, Konecny, Gottfried E., O’Malley, David M., Leary, Alexandra, Provencher, Diane, Welch, Stephen, Chen, Lee-may, Wahner Hendrickson, Andrea E., Ma, Ling, Ghatage, Prafull, Kristeleit, Rebecca S., Dorigo, Oliver, Musafer, Ashan, Kaufmann, Scott H., Elvin, Julia A., Lin, Douglas I., Chambers, Setsuko K., Dominy, Erin, Vo, Lan-Thanh, Goble, Sandra, Maloney, Lara, Giordano, Heidi, Harding, Thomas, Dobrovic, Alexander, Scott, Clare L., Lin, Kevin K., McNeish, Iain A.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 03.05.2021
Nature Publishing Group
Nature Portfolio
Subjects:
631/67/1517/1709
631/67/1857
Adult
Aged
Aged, 80 and over
AKT protein
Antineoplastic Agents - adverse effects
Antineoplastic Agents - therapeutic use
Biomarkers
BRCA1 protein
BRCA1 Protein - genetics
BRCA2 protein
BRCA2 Protein - genetics
Breast cancer
Cancer
Cancer therapies
Carcinoma, Ovarian Epithelial - drug therapy
Cell cycle
Cross-resistance
DNA methylation
DNA Methylation - genetics
DNA-Binding Proteins - genetics
Female
Health services
Homologous recombination
Homology
Humanities and Social Sciences
Humans
Indoles - adverse effects
Indoles - therapeutic use
Inhibitors
Methylation
Middle Aged
Modulators
multidisciplinary
Mutation
Neoplasm Recurrence, Local - drug therapy
Ovarian cancer
Ovarian carcinoma
Ovarian Neoplasms - drug therapy
Patients
Platinum
Platinum - therapeutic use
Poly(ADP-ribose) polymerase
Poly(ADP-ribose) Polymerase Inhibitors - adverse effects
Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use
Promoter Regions, Genetic - genetics
Scars
Science
Science (multidisciplinary)
ISSN:2041-1723, 2041-1723
Online Access:Get full text
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Summary: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. The identification of biomarkers of response to PARP inhibitors can enable selection of appropriate ovarian cancer patients for treatment. In this study, the authors report clinical results and exploratory biomarker analyses from the ARIEL2 phase 2 clinical trial on the safety and efficacy of the PARP inhibitor rucaparib in patients with recurrent ovarian cancers
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-021-22582-6