Surrogate Endpoints as Predictors of Overall Survival in Metastatic Urothelial Cancer: A Trial-level Analysis

BACKGROUND: Surrogate endpoints (SEs), such as progression-free survival (PFS) and objective response rate (ORR), are frequently used in clinical trials. The relationship between SEs and overall survival (OS) has not been well described in metastatic urothelial cancer (MUC). OBJECTIVE: We evaluated trial-level data to assess the relationship between SEs and OS. We hypothesize a moderate surrogacy relationship between both PFS and ORR with OS. DESIGN, SETTING, AND PARTICIPANTS: We systematically reviewed phase 2/3 trials in MUC with two or more treatment arms, and report PFS and/or ORR, and OS. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Linear regression was performed, and the coefficient of determination (R(2)) and surrogate threshold effect (STE) estimate were determined between PFS/ORR and OS. RESULTS AND LIMITATIONS: Of 3791 search results, 59 trials and 62 comparisons met the inclusion criteria. Of the 53 trials that reported PFS, 31 (58%) reported proportional hazard regression for PFS and OS. Linear regression across trials demonstrated an R(2) of 0.60 between hazard ratio (HR) for PFS (HR(PFS)) and HR for OS (HR(OS)), and an STE of 0.41. Linear regression of ΔPFS (median PFS in months of the treatment arm – that of the control arm) and ΔOS demonstrated an R(2) of 0.12 and an STE of 14.1 mo. Thirty trials reported ORRs. Linear regression for ORR(ratio) and HR(OS) among all trials found an R(2) of 0.08; an STE of 95% was not reached at any value and ΔORR and HR(OS) similarly demonstrated a poor correlation with an R(2) value of 0.03. CONCLUSIONS: PFS provides only a moderate level of surrogacy for OS; An HR(PFS) of ≤0.41 provides 95% confidence of OS improvement. ORR is weakly correlated with OS and should be de-emphasized in MUC clinical trials. When PFS is discussed, proportional hazard regression should be reported. PATIENT SUMMARY: We examined the relationship between surrogate endpoints, common outcomes in clinical trials, with survival in urothelial cancer trials. Progression-free survival is moderately correlated, while objective response rate had a poor correlation with survival and should be de-emphasized as a primary endpoint.