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

2021-05-03

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

Journal Article

0000-0003-2331-0434

0000-0002-8109-4023

0000-0003-2472-8306

0000-0003-1902-3256

0000-0002-2371-0844

0000-0003-3825-1326

0000-0002-1976-5201

0000-0002-4900-7145

0000-0003-0105-9760

0000-0002-3689-5956

0000-0002-9387-7586

10.1038/s41467-021-22582-6

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.

link

Nature Communications 2021; 12(1): 2487

Nature Communications