Benefit from maintenance with PARP inhibitor in newly diagnosed ovarian cancer according to BRCA1/2 mutation type and site: a multicenter real-world study

Background: Knowledge about the association between the BRCA1/2 mutation type and location and response to poly (ADP-ribose) polymerase inhibitors (PARPis) as single agent in ovarian cancer is limited. This study aimed to investigate the effectiveness of PARPi based on functional domains (FD) [RING, BRCT, DNA-binding (BD), RAD51-BD] and types (frameshift, missense, nonsense, splicing) of BRCA1/2 gene mutations in ovarian cancer. Materials and methods: This multicenter real-world study retrospectively enrolled BRCA1/2-mutated ovarian cancer patients receiving olaparib maintenance between January 2010 and December 2022. Data were compared with historical series of patients who did not receive olaparib and analyzed based on the FD involved in BRCA1/2 mutations. Progression-free survival was calculated from the date of the last platinum-based treatment until recurrence or last follow-up. Results: After a median follow-up of 46 months (range 32-60 months), 140 patients who underwent olaparib maintenance were compared with 128 who did not. PARPi showed efficacy in the overall population. The no-exon 11 patients benefitted more from olaparib than exon 11 patients [hazard ratio (HR) 0.48, 95% confidence interval (CI) 0.25-0.93]. In the BRCA1 group, patients with mutations in RING and BRCT domains had significant benefits from PARPi (HR 0.08, 95% CI 0.01-0.75; HR 0.10, 95% CI 0.02-0.38, respectively). Among BRCA2-mutated patients, RAD51-BD mutations were associated with higher response to olaparib (HR 0.23, 95% CI 0.10-0.52). According to the mutation type, the major effect of PARPi was in the missense group (HR 0.04, 95% CI 0.01-0.31). No patients with p.(Ala1708Glu) in the BRCT domain (BRCA1) receiving PARPi experienced recurring disease in the study period. Conclusions: BRCA1/2-mutated patients benefit from olaparib, but with variations according to the mutation type and FDs. BRCA1-mutated patients in the RING or BRCT and BRCA2-mutated in the RAD51-BD have the greatest benefit. Patients with missense mutations, especially those with p.(Ala1708Glu), have the most significant advantage from maintenance with PARPi.