Prognostic effect of neoadjuvant chemotherapy in gBRCA-mutated compared to gBRCA wild-type patients with advanced HGSOC treated with first-line PARP inhibitor maintenance: A large series propensity score–matching analysis.

Abstract

5602 Background: Recent results from the TRUST trial (ENGOTov33/AGO-OVAR OP.7) have renewed interest in the prognostic role of primary debulking surgery (PDS) versus interval debulking surgery (IDS) in advanced high-grade serous ovarian cancer (HGSOC). This study evaluated the prognostic impact of neoadjuvant chemotherapy (NACT) according to germline BRCA (gBRCA) status in advanced HGSOC patients receiving first-line PARP inhibitor (PARPi) maintenance, and its influence on outcomes at recurrence. Methods: We retrospectively identified patients with advanced HGSOC, treated between 2019 and 2024 at our gynecologic oncology referral center, who underwent upfront surgery and platinum-based chemotherapy followed by PARPi monotherapy. gBRCA status, surgical approach(PDS vs NACT+IDS), and survival outcomes, were collected. Patients were stratified by gBRCA status (gBRCAmut vs gBRCAwt). Propensity score matching (PSM) was performed based on age, ECOG-PS, FIGO stage, tumor histotype, surgical approach, and residual disease after first cytoreduction. Progression-free survival (PFS), overall survival(OS), post-recurrence PFS(PFS2), and post-recurrence OS(OS2) were analyzed. Results: After PSM, 406 patients were included (203 gBRCAmut and 203 gBRCAwt). In the gBRCAmut cohort, 58.6% underwent PDS and 41.4% received NACT+IDS, while 42.9% and 57.1% of gBRCAwt underwent PDS and NACT+IDS, respectively. All gBRCAmut patients received olaparib maintenance; among gBRCAwt, those with somatic BRCA mutations received olaparib (45/203) and the remainder niraparib (158/203). Complete cytoreduction was achieved in 92.1% of cases, with no differences between groups. Among gBRCAwt patients, median PFS was 43 months with PDS versus 19 months with NACT+IDS (p=0.008). Among gBRCAmut, median PFS was not reached with PDS and was 28 months with NACT+IDS (p<0.001). Median OS was not reached in either surgical group for gBRCAwt patients, whereas in gBRCAmut patients median OS was not reached with PDS and was 60 months following NACT+IDS (p<0.001). At recurrence, PFS2 did not differ by upfront treatment. However, NACT+IDS was associated with inferior OS2 in both gBRCAwt (p=0.019) and gBRCAmut (p=0.048) patients, with shorter median OS2 observed in gBRCAmut (15 vs 18 months). Conclusions: NACT was associated with inferior survival outcomes in advanced HGSOC patients receiving first-line PARPi, with a more pronounced detrimental effect observed in gBRCAmut patients. This suggests that BRCA-mutated tumors, despite their intrinsic sensitivity to PARP inhibition, may be particularly vulnerable to the negative consequences of delayed cytoreduction, with potential implications for treatment sequencing and surgical decision-making.