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

Elizabeth M. Swisher (), Tanya T. Kwan, Amit M. Oza, Anna V. Tinker, Isabelle Ray-Coquard, Ana Oaknin, Robert L. Coleman, Carol Aghajanian, Gottfried E. Konecny, David M. O’Malley, Alexandra Leary, Diane Provencher, Stephen Welch, Lee-may Chen, Andrea E. Wahner Hendrickson, Ling Ma, Prafull Ghatage, Rebecca S. Kristeleit, Oliver Dorigo, Ashan Musafer, Scott H. Kaufmann, Julia A. Elvin, Douglas I. Lin, Setsuko K. Chambers, Erin Dominy, Lan-Thanh Vo, Sandra Goble, Lara Maloney, Heidi Giordano, Thomas Harding, Alexander Dobrovic, Clare L. Scott, Kevin K. Lin and Iain A. McNeish
Additional contact information
Elizabeth M. Swisher: University of Washington
Tanya T. Kwan: Clovis Oncology, Inc.
Amit M. Oza: University Health Network
Anna V. Tinker: BC Cancer—Vancouver
Isabelle Ray-Coquard: GINECO, Centre Léon Bérard and University Claude Bernard
Ana Oaknin: Vall d’Hebron Institute of Oncology (VHIO)
Robert L. Coleman: MD Anderson Cancer Center
Carol Aghajanian: Memorial Sloan Kettering Cancer Center
Gottfried E. Konecny: University of California Los Angeles
David M. O’Malley: James Cancer Center
Alexandra Leary: Gustave Roussy Cancer Center and INSERM U981
Diane Provencher: l’Université de Montréal (CHUM)
Stephen Welch: Lawson Health Research Institute
Lee-may Chen: University of California San Francisco Helen Diller Family Comprehensive Cancer Center
Andrea E. Wahner Hendrickson: Mayo Clinic
Ling Ma: Rocky Mountain Cancer Centers
Prafull Ghatage: Tom Baker Cancer Center
Rebecca S. Kristeleit: Guy’s and St. Thomas NHS Foundation Trust
Oliver Dorigo: Stanford University Cancer Center and Stanford Cancer Institute
Ashan Musafer: Austin Hospital
Scott H. Kaufmann: Mayo Clinic
Julia A. Elvin: Foundation Medicine, Inc.
Douglas I. Lin: Foundation Medicine, Inc.
Setsuko K. Chambers: University of Arizona Cancer Center
Erin Dominy: Clovis Oncology, Inc.
Lan-Thanh Vo: Clovis Oncology, Inc.
Sandra Goble: Clovis Oncology, Inc.
Lara Maloney: Clovis Oncology, Inc.
Heidi Giordano: Clovis Oncology, Inc.
Thomas Harding: Clovis Oncology, Inc.
Alexander Dobrovic: Austin Hospital
Clare L. Scott: Royal Melbourne Hospital and Walter and Eliza Hall Institute of Medical Research
Kevin K. Lin: Clovis Oncology, Inc.
Iain A. McNeish: Imperial College London

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-22582-6

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