Tumor Gene Methylation May Predict Ovarian Cancer Response to Rucaparib

Elizabeth Swisher, MD

Hypermethylation of 2 wild-type tumor-associated genes increased ovarian cancer responsiveness to the PARP inhibitor rucaparib (Rubraca), according to a subgroup analysis of the randomized ARIEL2 trial presented at the 2017 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer.

Objective responses with rucaparib occurred in more than half of patients whose tumors exhibited BRCA1 promoter methylation and in 3 of 4 patients with RAD51C promoter methylation. Methylation of either gene was mutually exclusive of BRCA mutations or other homologous recombination genes. BRCA1 and RAD51C promoter methylation correlated strongly with loss of heterozygosity (LOH), which is associated with prolonged progression-free survival (PFS).

“BRCA1 and RAD51C methylation in ovarian carcinomas are associated with high loss of heterozygosity and sensitivity to rucaparib,” said senior study author Elizabeth Swisher, MD, a medical oncologist at the University of Washington. “Loss of BRCA1 methylation is common after exposure to platinum chemotherapy, even in platinum-sensitive patients. If methylation were to be used as a predictor of PARP inhibitor sensitivity, it would need to be assessed in a pretreatment, rather than archived specimen.”

“Routine sequencing of high-grade ovarian cancer would identify at least 10% to 15% of cases with somatic mutations and 20% with germline mutations that are likely to respond to PARP inhibition,” she added.

These findings stemmed from the subgroup analysis of the phase II ARIEL2 trial, which evaluated rucaparib in patients with relapsed, platinum-sensitive high-grade ovarian cancer. Swisher and colleagues sought to determine whether BRCA1 and RAD51C promoter hypermethylation might potentially correlate with markers of homologous recombination deficiency and response to rucaparib.

The analysis had its genesis in several lines of evidence. Promoter-region hypermethylation is associated with gene downregulation, and BRCA1 and RAD51C promoter hypermethylation has been associated with decreased gene expression in ovarian cancer. However, attenuated gene expression in ovarian cancer was not associated with improved survival, according to data from The Cancer Genome Atlas (TCGA).

Results of the ARIEL2 trial showed improved progression-free survival (PFS) in BRCA-mutant and BRCA wild-type/high LOH disease as compared with BRCA wild-type/low LOH. Additionally, patients with ovarian cancer with damaging mutations in other homologous recombination genes responded to rucaparib. However, some patients with mutated homologous recombination genes did not respond to the PARP inhibitor.

In the ARIEL2 analysis Swisher reported at the SGO meeting, there were 165 participants who had evaluable tumor samples. The results showed that 12.7% of tumors had BRCA1 promoter methylation and 2.4% had RAD51C promoter methylation, and the promoter methylation was mutually exclusive of BRCA1 mutation and other homologous recombination genes (P = .015). All 4 tumors with methylated RAD51C promoter and 16 of 20 evaluable specimens with methylated BRCA1 promoter had high LOH (80% association overall).

BRCA1 and RAD51C methylation was assessed in 90 and 99 paired archival and pretreatment biopsy specimens, respectively. Of 77 cases without BRCA1 methylation in archival tissue, one exhibited methylation in a pretreatment biopsy specimen. Of 13 cases with BRCA1 methylation in archival specimens, 4 were unmethylated in pretreatment biopsy specimens. RAD51C methylation was concordant between archival and pretreatment biopsy, but the sample included only 2 RAD51C methylated cancers.

Response data showed investigator-assessed responses to rucaparib in 11 of 21 (52.4%) of the BRCA-methylated cases, 3 of 4 (75%) RAD51C-methylated cases, and 29% of BRCA wild type/LOH-high cases. The median duration of response was 6.1 months for BRCA1 methylated cases and 9.5 months for RAD51C methylated cases.

Additionally, 2 patients with CDK12-mutated tumors had prolonged responses to rucaparib. CDK12 is involved in regulation of RNA splicing, and its loss leads to downregulation of many DNA repair genes and possibly homologous repair deficiency, said Swisher.

The ARIEL2 trial had a cutoff for high LOH of 14%, which was associated with a 42% reduction in the hazard for progression or death among patients with BRCA wild-type tumors treated with rucaparib (P = .0027). An analysis of PFS curves suggested an optimal cutoff of ≤6%, which will be evaluated in the phase III trial.

In December 2016, the FDA granted an accelerated approval to rucaparib as a treatment for patients with BRCA-positive advanced ovarian cancer who have received at least 2 prior lines of chemotherapy.

Swisher EM, Harrell MI, Lin K, et al. BRCA1 and RAD51C promoter hypermethylation confer sensitivity to the PARP inhibitor rucaparib in patients with relapsed, platinum-sensitive ovarian carcinoma in ARIEL2 Part 1. In: Proceedings from the Society for Gynecologic Oncology Annual Meeting on Women’s Cancer; March 12-14, 2017; National Harbor, MD.

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CDK12 mutations occur in approximately 3% of cases of high-grade serous ovarian cancers, according to data from TCGA. Approximately 56% of high-grade serous ovarian cancers are not associated with homologous repair deficiency, suggesting that a number of other genetic/molecular alterations could result in homologous repair deficiency in the disease, said Swisher.