High LOH is associated with response to the PARP inhibitor rucaparib in BRCA wild-type ovarian cancer.
Major finding: High LOH is associated with response to the PARP inhibitor rucaparib in BRCA wild-type ovarian cancer.
Approach: An open-label phase II trial tested rucaparib in patients with platinum-sensitive ovarian cancer.
Impact: Tumor LOH assessment may identify BRCA wild-type patients who may respond to PARP inhibition.
Mutations in BRCA1 or BRCA2 (BRCA) are common in patients with high-grade serous ovarian carcinomas, and, when the wild-type allele is lost, BRCA mutations can impair DNA-damage repair by homologous recombination, leading to deletion or duplication of chromosomal regions, which is termed genomic loss of heterozygosity (LOH). Homologous recombination–deficient tumors are sensitive to PARP inhibitors such as rucaparib, but although homologous recombination deficiencies can also occur in ovarian tumors without BRCA mutations, molecular predictors of rucaparib sensitivity in BRCA wild-type tumors have not been identified. Swisher, Lin, and colleagues hypothesized that genomic LOH might predict homologous recombination deficiency and rucaparib sensitivity and enrolled 206 patients in an open-label phase II trial of rucaparib in patients with relapsed, platinum-sensitive, high-grade ovarian carcinoma. In total, 192 patients could be classified into subgroups: 40 had BRCA mutations, 82 were BRCA wild-type with high LOH, and 70 were BRCA wild-type with low LOH. The primary endpoint was progression-free survival, and secondary endpoints included objective response rate, duration of response, and safety. The median progression-free survival was 12.8 months in patients with BRCA mutations, 5.7 months in LOH-high patients, and 5.2 months in LOH-low patients, but, on the whole, progression-free survival was significantly longer in the BRCA mutant and LOH high subgroups compared with the LOH low subgroup. Objective responses were observed in 80% of patients with BRCA mutations, 29% of LOH-high patients, and 10% of LOH-low patients. The median response duration was 9.2 months in the BRCA-mutant group, 10.8 months in the LOH-high group, and 5.6 months in the LOH-low group. Adverse events led to dose reductions in 39% of patients and withdrawal from the study in 9% of patients. These findings indicate that assessing genomic LOH in tumors may identify patients with high LOH who are more likely respond to rucaparib therapy, and further suggest that PARP inhibitors may be beneficial in a subset of BRCA wild-type tumors.