Poly ADP-ribose polymerase inhibitors (PARPi) have revolutionized the treatment of high grade serous ovarian carcinoma (HGSOC), especially those harbouring BRCA1/2 mutations. Emerging preclinical evidence suggest a potential relationship between BRCA specific-domain defects and sensitivity to PARPi. In particular, ring-less BRCA1 protein, characterized by a residual activity in RAD51 foci formation, has been associated with a reduced response to PARPi. On the contrary, mutations (mut) in the BRCA2 DNA binding domain (BD), that is essential for RAD51-induced architectural rearrangement of BRCA2, have been associated with an increased sensitivity to PARPi. Real world data regarding PARPi efficacy according to specific BRCA domain mut are missing.
The clinical data for pts with advanced HGSOC and BRCA1/2mut who received first-line platinum-based chemotherapy followed by PARPi from 2018-2021 at the University of Naples Federico II were retrospectively collected. BRCA1/2mut were classified according to location in BRCA1 protein (DNA-BD, BRCT, RING finger domain, others) and in BRCA2 protein (DNA-BD, RAD51-BD, others). The log-rank test was used to assess the difference in progression-free survival (PFS) distribution between the groups.
Among 41 pts, 25 harboured a BRCA1mut (61%) and 16 a BRCA2mut (39%). BRCA1 mut in the RING domain, DNA-BD and BRCT were detected in 3 (12%), 8 (32%), 7 (28%) pts, respectively; other mut in 7 pts (28%). BRCA2 mut in RAD51-BD and DNA-BD were detected in 8 (50%) and 6 (38%) pts, respectively; other mut in 2 pts (13%). No statistical differences in terms of PFS were observed according to the BRCA1mut (P = 0.87) or BRCA2mut (P = 0.18) domains. Interestingly, a numerically longer median PFS was observed in pts with BRCA2 BD mut compared to the other BRCA2 defects, (log-rank test for trend P = 0.05).
Pts diagnosed with advanced HGSOC derived similar PFS benefit from PARPi regardless the locations of BRCAmut. Although limited by a small cohort size our analysis suggests that DNA-BD BRCA2mut may predict increased sensitivity to PARPi.