Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer (SOC) and a BRCA mutation (BRCAm).

5505 Background: Previously, we reported that maintenance treatment with the oral PARP inhibitor olaparib (400 mg bid) led to a significant PFS improvement vs placebo in patients (pts) with platinum-sensitive relapsed SOC (Ledermann et al NEJM2012). A preplanned subgroup analysis from this randomized, double-blind Phase II trial (NCT00753545) suggested that olaparib may lead to a greater PFS, and an OS, benefit in pts with a known germline BRCAm (gBRCAm). Since gBRCA wild-type (gBRCAwt) pts may develop somatic tumor (t)BRCAm, efficacy analyses were performed for all pts with BRCAm. Methods: gBRCAm status was determined retrospectively for all consenting pts (n = 166) using blood samples taken before randomization. tBRCAm status was determined from archival tumor samples of 196 pts. We analyzed PFS/OS by gBRCAm and total BRCAm status. Preliminary data are reported. Results: gBRCA status was known for 218/265 pts (gBRCAm, 96; gBRCAwt, 122). Including tBRCAm, 136 pts had a BRCAm (BRCAwt, 116). gBRCAm pts had the greatest PFS benefit with olaparib maintenance vs placebo (median: 11.2 vs 4.1 months [m]; HR, 0.17; 95% CI 0.09-0.32; P<0.001) and a significant QoL improvement, as measured with Trial Outcome Index (OR, 4.08; 95% CI 1.11-19.85; p = 0.03). The PFS benefit was consistent when tBRCAm pts were included (median: 11.2 vs 4.3 m; HR, 0.19; 95% CI 0.11-0.32; p <0.0001). In an interim analysis of OS (58% maturity), a comparison of olaparib vs placebo in the overall population led to a HR of 0.88 (95% CI 0.64-1.21) with medians of 29.8 vs 27.8 m, respectively. Although HRs from the gBRCAm and gBRCAwt subgroups were similar (0.85 and 0.84, respectively), 13/37 gBRCAm placebo pts received a subsequent PARP inhibitor, confounding the OS data in this subgroup. The analysis of all BRCAm pts was less confounded and resulted in an OS HR of 0.74 (95% CI 0.46-1.19; median: 34.9 vs 31.9 m). 19 pts have received olaparib for >3 years. Olaparib tolerability was similar in BRCAm pts and the overall population. Conclusions: Olaparib maintenance treatment led to the greatest clinical benefit in pts with a BRCAm. These compelling data warrant confirmation in phase III trials. Clinical trial information: NCT00753545.