57P Prognostic impact of functional domain of BRCA1/2 mutation in platinum-sensitive recurrent epithelial ovarian cancer patients receiving PARP inhibitors

PARP inhibitors (PARPi) have revolutionized the management of epithelial ovarian cancer (EOC). In this context, BRCA1/2 mutations represent the main predictor of benefit from PARPi. However, little is known regarding the impact of the type of BRCA mutation on benefit derived from PARPi and on prognosis. This retrospective observational study included patients treated with PARPi for platinum-sensitive recurrent EOC at our Institution between 2015-2023. Progression-free survival (PFS) and overall survival (OS) from start of PARPi were evaluated according to the involved BRCA functional domain (DNA-binding domain DBD, really interesting new gene RING, RAD51-binding domain RAD51-BD, BRCA1 C Terminus BRCT) and the type of alteration (missense, nonsense, large rearrangements, frameshift, in-frame, splicing, synonymous). Of 113 patients identified, 33.6% (n=38) presented a BRCA mutated tumour (germline=34, somatic=4; BRCA1=22, BRCA2=16). Mutations were more frequently located in the DBD for BRCA1 (n=6) and in the RAD51-BD for BRCA2 (n=4); most mutations were non-sense (n=14) and frameshift (n=13). At a median follow-up of 56.7 months, BRCA functional domains were significantly associated with OS, with a median OS not reached for DBD (95%CI NR-NR), 8.5 months (95%CI NE-NE) for RING, 21.6 months (95%CI 5.2-38.1) for RAD51-BD, 23.4 months (95%CI 20.6-26.3) for BRCT and 51.7 months (95%CI 20.1-83.3) for other domains (p=0.01). Mutations in DBD or other domains were also associated with a numerically longer PFS from start of PARPi as compared to RING, RAD51-BD, and BRCT (median PFS 66.7, 30.8, 7.4, 5.2, 13.3 months, respectively; p=0.22). On the contrary, the type of alteration observed in BRCA1/2 genes was not significantly associated with PFS and OS from start of PARPi (p=0.60 and p=0.64, respectively). In platinum-sensitive recurrent EOC treated with PARPi, BRCA1/2 mutations carry a different prognostic impact in terms of PFS and OS from start of PARPi according to the functional domain of the gene involved. If confirmed, this might be used in clinical practice to further optimize prognostic assessment of these patients.