Background: Data suggest synthetic lethality when TP53-deficient cells are exposed to genotoxic drugs plus the Wee1 inhibitor AZD1775 (MK-1775). AZD1775 plus C was well tolerated in patients (pts) with advanced solid tumors (NCT00648648). This current two-part study (NCT01357161) evaluated the efficacy of AZD1775 plus P/C compared with P/C alone in women with TP53-mutant OC. Methods: After confirming a dose of AZD1775 (225 mg bid; capsules) in 15 pts in part 1, pts in part 2 received AZD1775 or placebo bid for 2.5 days plus P (175 mg/m²; IV) and C (AUC5; IV) on day 1 per 21-day treatment cycle, until progression or the completion of six cycles. Primary objectives: PFS (enhanced [volumetric] RECIST v1.1, criterion for superiority = P< 0.1), safety and tolerability (CTCAE v4.0). Secondary objectives: PFS (RECIST v1.1), ORR (enhanced RECIST v1.1, CA-125 levels) and OS. Results: 121 pts with confirmed TP53 mutations were randomized, 59 and 62 to AZD1775/P/C and P/C, respectively. PFS by independent central review (~57% maturity) was greater with AZD1775/P/C compared with P/C alone (enhanced RECIST: HR 0.63, 80% CI 0.45, 0.89, 95% CI 0.38, 1.06, P= 0.080, median 34.14 vs 31.86 weeks; RECIST: HR 0.55, 80% CI 0.39, 0.79, 95% CI 0.32, 0.95, P= 0.030, median 42.86 vs 34.86 weeks). ORRs were 81.4% vs 75.8% (difference 5.6%, 95% CI for difference –9.4, 20.2, P= 0.459) with AZD1775/P/C vs P/C, respectively. Best response rates based on CA-125 criteria were 81.35% vs 74.19% with AZD1775/P/C vs P/C, respectively. OS data are immature. Most common adverse events (AEs) were nausea (78.0% vs 60.0% for AZD1775/P/C vs P/C, respectively), diarrhea (74.6% vs 36.7%), alopecia (54.2% vs 66.7%) and fatigue (54.2% vs 55.0%). 85 pts had grade ≥ 3 AEs (78.0% vs 65.0% for AZD1775/P/C vs P/C, respectively), 36 pts had serious AEs (40.7% vs 20.0%) and 25 pts had AEs resulting in discontinuation (20.3% vs 21.7%). Conclusions: AZD1775/P/C was associated with a significant increase in PFS when compared with P/C alone, met the preset primary and secondary PFS efficacy bar for clinical importance, and showed acceptable tolerability in women with TP53-mutant OC. Clinical trial information: NCT01357161