Impact of metformin, statins, and beta blockers on survival in patients with primary ovarian cancer: Combined analysis of four prospective trials of AGO-OVAR and ENGOT/GCIG collaborators

Objective: The aim of this study was to investigate the association of co-medication with metformin, a statin, or beta blocker with survival in patients with primary ovarian cancer. Methods: Individual data from three phase III, randomized controlled trials (AGO-OVAR 11, AGO-OVAR 12, and AGO-OVAR 16) and one phase II trial (AGO-OVAR 15) were pooled and analyzed. Patients were classified as ever user if the specific co-medication was documented at least once during the trial, and were compared with never users as controls. Association of co-medications and outcomes were adjusted for potential confounders (age, International Federation of Gynecology and Obstetrics stage, histology, residual disease after surgery, Eastern Cooperative Oncology Group (ECOG) performance status, body mass index, Charlson Comorbidity Index, and assigned treatment within the trial) in multivariate Cox regression analyses. Results: Overall, n=2857 patients were included. Ever users were: 100 patients received metformin (3.5%), 226 patients received statins (7.9%), and 475 (16.6%) patients received beta blockers (n=391 selective beta blockers; 84 non-selective beta blockers) as co-medication. There were no significant differences regarding the baseline characteristics except that ever users were significantly older, more obese, and had more comorbidities, according to the Charlson Comorbidity Index, compared with controls. Multivariate analyses for progression free survival and overall survival revealed neither a significant impact of metformin on survival (progression free survival hazard ratio (HR) 0.94, 95% confidence interval CI 0.69 to 1.29, p=0.7; overall survival HR 0.82, 95% CI 0.58 to 1.17, p=0.28) nor for statins (progression free survival HR 0.98, 95% CI 0.82 to 1.18, p=0.87; overall survival HR 0.91, 95% CI 0.74 to 1.12, p=0.37). In contrast, ever users of selective beta blockers had a significantly higher risk for recurrence and death (progression free survival HR 1.22, 95% CI 1.05 to 1.41, p=0.009; overall survival HR 1.25 95% CI 1.06 to 1.47, p=0.009). Conclusions: In this analysis, co-medication with metformin or statins had no significant impact on survival in patients with primary ovarian cancer. In contrast, co-medication with a beta blocker was associated with worse survival. However, whether this observation is related to the underlying condition rather than a direct negative impact on tumor biology remains unclear.