Efficacy of maintenance olaparib plus bevacizumab in patients with newly diagnosed advanced ovarian cancer according to BRCA mutation genotype in the phase III PAOLA-1/ENGOT-ov25 trial

5571 Background: In the Phase III PAOLA-1/ENGOT-ov25 trial, the addition of maintenance olaparib (ola) to bevacizumab (bev) in patients (pts) with newly diagnosed advanced high-grade ovarian cancer (HGOC) resulted in prolonged progression-free survival (PFS), particularly for pts with HRD-positive tumors including a BRCA1/ BRCA2 mutation (BRCAm; Ray-Coquard et al. NEJM 2019). Preclinical data suggest that pts with mutations (mut) in the RING domain of BRCA1 are less sensitive to ola. The magnitude of benefit from ola + bev, according to the location of mut in the functional domains (FD) of BRCA , remains to be explored. Methods: Pts with newly diagnosed advanced HGOC in response after platinum-based chemotherapy + bev received maintenance bev (15 mg/kg q3w for 15 months [mo]) + either ola (300 mg bid for 24 mo) or placebo (pbo). In this post hoc exploratory analysis, PFS was analyzed in pts with BRCAm according to mut location in the FDs of BRCA1 (RING, DNA-binding domain [DNA-BD], or BRCA1 C terminus [BRCT]) and BRCA2 (RAD51-BD; DNA-BD). Results: Among the 806 randomized pts, 235 (29.2%) harbored a BRCAm: 160 (19.9%) with a BRCA1 mut and 76 (9.4%) with a BRCA2 mut. BRCA1 mut in FDs of RING, DNA-BD and BRCT were detected in 19 (11.8%), 41 (25.6%) and 34 (21.2%) pts, respectively. BRCA2 mut were detected in FDs of RAD51-BD and DNA-BD in 37 (48.7%) and 14 (18.4%) pts, respectively. With a median follow-up of 25.5 mo, 24-mo PFS rates and hazard ratios (HRs) according to mut locations are reported in the Table. In pts with a BRCA1 DNA-BD mut, 24-mo PFS was 89% and 14% (ola + bev vs pbo + bev; HR 0.08, 95% confidence interval [CI] 0.02–0.26) compared with 64% and 24% for pts with mut in RING + BRCT + other domains (HR 0.33, 95% CI 0.19–0.57). In pts with BRCA2 mut, 24-mo PFS for pts with mut in the DNA-BD was 91% vs 100% (ola + bev vs pbo + bev) compared with 82% and 44% for pts with mut in RAD51-BD + other domains (HR 0.21, 95% CI 0.08–0.54). Conclusions: In this exploratory analysis, pts with newly diagnosed advanced HGOC and a BRCAm had a PFS benefit from maintenance ola + bev regardless of mut locations in BRCA1/BRCA2. Sensitivity to ola + bev maintenance was particularly high for pts with mut in the DNA-BD of BRCA1. Pts with a mut in the DNA-BD of BRCA2 commonly had excellent outcomes. Clinical trial information: NCT02477644. [Table: see text]