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 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 Show all
NATURE COMMUNICATIONS | NATURE RESEARCH | Published : 2021
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..View full abstract
Awarded by Department of Defense Ovarian Cancer Research Program
Awarded by Stand Up To Cancer-Ovarian Cancer Research Fund Alliance-National Ovarian Cancer Coalition Dream Team Translational Cancer Research Grant
Funding from the National Breast Cancer Foundation of Australia (to A.D.) and the Department of Defense Ovarian Cancer Research Program (OC12056, to E.M.S. and S.H.K.) and a Stand Up To Cancer-Ovarian Cancer Research Fund Alliance-National Ovarian Cancer Coalition Dream Team Translational Cancer Research Grant (SU2C-AACR-DT16-15, to E.M.S. and S.H.K.). Stand Up To Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. We thank Elaina Mann, Jennifer Borrow, Jen Lenore, Jeff Isaacson, and Lindsey Rolfe for clinical development, statistical guidance, and operational support of the ARIEL2 study. In addition, we thank Vivian Chen and Mary Joyce for assistance in manuscript preparation. ARIEL2 was designed by the funder and a subgroup of investigators. Data presented and herein were collected by the funder; the funder and all authors interpreted and analyzed the data. This article was written by the authors, with medical writing and copy editing support paid for by the funder and provided by Nathan Yardley and Frederique H. Evans of Ashfield MedComms, an Ashfield Health company. All authors had full access to all trial data and had final responsibility for the decision to submit for publication.