Background: Cortisol contributes to chemotherapy resistance by suppressing apoptotic pathways that cytotoxic agents utilize. Preclinical and clinical data indicate that glucocorticoid receptor (GR) modulation with relacorilant (RELA) reverses the anti-apoptotic effects of cortisol and restores the efficacy of cytotoxic agents. We report overall survival (OS) results from a randomized, controlled phase 2 study of RELA + nab-paclitaxel (NP) compared to NP only in patients with ovarian cancer (NCT03776812). The primary analysis showed improved progression-free survival (PFS) and a favorable safety profile with intermittent RELA + NP vs NP only, despite overrepresentation of primary platinum-refractory patients in the intermittent RELA + NP (n = 7) vs the NP-only arm (n = 1). Methods: A phase 2, open-label, randomized, 3-arm study of 2 RELA dosing schedules + NP compared with NP only was performed. 178 women with recurrent, platinum-resistant/refractory, high-grade serous or endometrioid epithelial ovarian, primary peritoneal, or fallopian tube cancer or ovarian carcinosarcoma with ≤4 prior chemotherapeutic regimens were enrolled. Patients were randomized 1:1:1 to: a) NP (80 mg/m²) + intermittent RELA (150 mg QD the day before, of, and after NP) (n = 60); b) NP (80 mg/m²) + continuous RELA (100 mg QD) (n = 58); or c) NP only (100 mg/m²) (n = 60). NP was administered on days 1, 8, and 15 of each 28-day cycle. The primary endpoint was PFS; OS was a secondary endpoint. OS data for the intermittent and continuous arms were compared to NP only using a 2-sided log-rank test, stratified by presence of ascites and relapse within 6 months on previous taxane, at a 0.05 level of significance without multiplicity adjustment. Results: At the pre-defined OS analysis (128 OS events), hazard ratios (HRs) were 0.67 (95% CI [0.43, 1.03], P= 0.066) and 0.85 (95% CI [0.56, 1.29], P= 0.447) for intermittent and continuous RELA + NP vs NP only. Median OS was 13.9 (95% CI [11.1, 18.4]), 11.3 (95% CI [7.5, 16.4]), and 12.2 (95% CI [7.7, 15.3]) months in the intermittent RELA + NP, continuous RELA + NP, and NP-only arms. In the subgroup of patients without primary platinum-refractory disease, a statistically significant improvement in OS was observed with HR 0.63 (95% CI [0.39, 0.99], P= 0.045) and median OS of 13.9 (95% CI [11.1, 18.4]) vs 12.2 (95% CI [7.7, 15.3]) months for intermittent RELA + NP vs NP only. Conclusions: In addition to the improved PFS and DOR observed at the primary analysis, the OS analysis confirmed the survival benefit of intermittent RELA + NP compared to NP only, particularly in patients who were not primary platinum refractory. A phase 3 trial evaluating intermittent RELA + NP vs investigator’s choice of chemotherapy in patients without primary platinum-refractory disease is ongoing (NCT05257408). Clinical trial information: NCT03776812.