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 MusaferScott 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, Iain A. McNeish

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number2487
JournalNature communications
Volume12
Issue number1
DOIs
StatePublished - Dec 2021

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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