The Association Between Location of BRCA Mutation and Efficacy of PARP Inhibitor as a Frontline Maintenance Therapy in Advanced Epithelial Ovarian Cancer.

BACKGROUND

The location of BRCA mutations within functional domains may affect sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapy. This study aimed to evaluate the progression-free survival (PFS) benefit from the PARP inhibitor in relation to the location of mutations in / in newly diagnosed ovarian cancer.

MATERIALS AND METHODS

Patients with advanced stage III-IV epithelial ovarian cancer who had deleterious or were analyzed. PFS and clinical and molecular data were compared between patients who received olaparib or niraparib as frontline maintenance therapy and those who did not. Subgroup analyses were conducted based on the location of mutations within the functional domain or the ovarian cancer cluster region (OCCR).

RESULTS

Of the 380 patients, 242 (63.7%) harbored mutation, 137 (36.1%) harbored , and one (0.3%) harbored both and . With a median follow-up of 35.8 months, the DNA binding domain in (HR, 0.34; 95% CI, 0.15-0.79; = 0.01) and (HR, 0.25; 95% CI, 0.08-0.78; = 0.01) demonstrated particularly significant benefit. In patients who harbored mutation in the C-terminal domain (BRCT), no statistically significant PFS benefit from PARP inhibitor was observed (HR, 0.76; 95% CI, 0.39-1.52; = 0.44). PFS benefit from PARP inhibitor maintenance was observed in both OCCR (HR, 0.49; 95% CI, 0.32-0.74; < 0.01) and non-OCCR (HR, 0.51; 95% CI, 0.27-0.63; < 0.01).

CONCLUSIONS

Frontline PARP inhibitor maintenance therapy demonstrated a significant PFS benefit in patients with / mutations, with particularly pronounced benefits for those with mutations located in the DBD of and . However, the benefit was less evident for patients with mutations located in the BRCT domain.