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.
Highlights
ARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the poly(ADP-ribose) polymerase (PARP) inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma
PARP inhibitor (PARPi) response[7,37], we examined the relationship between rucaparib response and homologous recombination repair (HRR) gene mutation status
To examine whether a decrease in methylation correlates with resistance to prior therapies and poor response to rucaparib, we focused on patients with BRCA wild-type (BRCAwt) high-grade ovarian carcinoma (HGOC) whose archival samples showed high methylation and who had a matched screening biopsy prior to rucaparib treatment (n = 17) (Fig. 3c)
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. Homologous recombination deficiency (HRD) sensitizes neoplasms to rucaparib and other DNA-damaging agents (e.g., platinum-based chemotherapy)[2,3], and platinum sensitivity in high-grade ovarian carcinoma (HGOC) is a strong clinical predictor of benefit from PARP inhibitors (PARPi)[4,5,6,7]. We present clinical results from Part 2 and post hoc exploratory biomarker analyses using the rich dataset of archival tissue samples and screening biopsies required from patients in both Parts 1 and 2
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