Lessons from the NOVA trial: an editorial on results, biomarkers, and patient selection for PARP inhibition in recurrent ovarian cancer

BRCA1 and BRCA2 are key proteins in the repair of double-strand DNA breaks via homologous recombination (HR) repair. Ovarian carcinomas (OC) with BRCA1 and BRCA2 (BRCA) mutations have HR deficiency (HRD) and are characterized by increased platinum sensitivity and response to poly [adenosine diphosphate (ADP)-ribose] polymerase (PARP) inhibitors, resulting in improved overall survival (1-5). PARP inhibitors generate synthetic lethality in BRCA-mutated carcinomas (6-9), but OC without BRCA mutations can also respond to PARP inhibitors, likely secondary to other sources of HRD (10-13). While up to half of high-grade serous ovarian carcinomas may have a defect in HR, we have found that most histologic subtypes of OC also have a proportion of cases with HRD (1,14). The most common cause of HRD in OC is germline and somatic BRCA mutations, found in approximately 15% and 6%, but mutations or epigenetic silencing of other HR repair genes also contribute (10,14,15). Because cancers with defective HR rely on more error-prone DNA repair such as non-homologous end-joining (NHEJ) or alternative end-joining (alt-EJ), HRD can result in characteristic DNA errors and structural alterations. Thus, a BRCA-like genomic signature may serve as a downstream marker of HRD (16-19). However, finding the best means to identify women without BRCA mutations who are most likely to benefit from PARP inhibitor therapy remains a diagnostic challenge and therapeutic need.