Cappellaro, Anelise Poluboiarinov

Abstract Objective The validity of progression-free survival (PFS) as a surrogate for overall survival (OS) in the antibody-drug conjugate (ADCs) era remains uncertain. We evaluated the association between treatment effects on PFS and OS in randomized trials of ADCs for metastatic breast cancer (mBC) and explored the surrogate threshold effect (STE). Methods PubMed, Embase, Cochrane, and ClinicalTrials.gov were searched for published randomized controlled phase II–IV trials evaluating ADCs in mBC and reporting hazard ratios (HRs) for both PFS and OS. A meta-epidemiological approach was used. The primary metric was the ratio of hazard ratios (rHR = HR_PFS/ HR_OS), with rHR < 1 indicating a larger effect on PFS. Trial-level associations were assessed using weighted linear regression (R²) and Spearman’s correlation. Results Twenty-one trials (n = 21; 18 phase III) evaluating nine ADCs were included. The pooled rHR was 0.79 (95% CI, 0.73–0.86), indicating a larger relative effect on PFS than OS. Numerically, the largest discrepancies were observed in triple-negative disease (rHR 0.72) and trials allowing crossover (rHR 0.71). Concordant statistical significance between endpoints occurred in 76% of the trials, whereas 24% showed a significant PFS benefit without OS improvement. The trial-level association between PFS and OS was moderate (R² = 0.62; ρ = 0.67). Conclusion Treatment effects on PFS consistently exceeded those on OS, although effect directions were highly concordant between endpoints. These findings provide an exploratory framework to contextualize the relationship between PFS and OS in ADC trials, requiring further validation in diverse clinical settings.

e13076 Background: Progression-free survival (PFS) is frequently used as a primary endpoint in contemporary oncology trials, including antibody–drug conjugate (ADC) studies in metastatic breast cancer (MBC) settings, despite uncertainty regarding its validity as a surrogate for overall survival (OS). A meta-epidemiological analysis was performed to quantify the systematic differences between the treatment effects on PFS and OS in ADC randomized clinical trials (RCTs). Methods: Phase II–III ADC RCTs with MBC patients reporting hazard ratios (HRs) with 95% confidence intervals (CIs) for both progression-free survival (PFS) and overall survival (OS) were included. Differences in treatment effects within each trial were quantified using the ratio of hazard ratios (rHR = HR_PFS/HR_OS). Random-effects models were used to pool the rHRs across the trials. Prespecified subgroup and meta-regression analyses were used to evaluate the trial characteristics, clinical context, and regulatory status. Sensitivity analyses assessed the robustness across varying assumptions of the within-trial correlation between the endpoints. Results: Twenty-one RCTs evaluating nine ADCs in patients with MBC were included, comprising three phase II (14%) and 18 phase III (86%) studies. The pooled rHR demonstrated significantly larger treatment effects for PFS than for OS (rHR, 0.79; 95% CI, 0.73–0.86), with no between-trial heterogeneity (I² = 0%, τ² = 0). Sensitivity analyses assuming within-trial correlations between PFS and OS ranging from 0 to 0.95 yielded consistent results. Greater divergence between endpoints was observed in trials enrolling patients with triple-negative breast cancer (rHR, 0.72; 95% CI, 0.61–0.85) and HER2-low disease (rHR, 0.77; 95% CI, 0.62–0.96). Phase III trials showed larger differences than phase II trials (rHR, 0.79 vs. 0.89). When OS was a secondary endpoint, divergence was greater than when OS was primary (rHR, 0.77 vs. 0.87). Across trials, 16 of 21 studies (76%) demonstrated concordant effect directions between PFS and OS: 11 (52%) with a statistically significant benefit for both endpoints and 5 (24%) with neither endpoint significant. Discordance occurred in five trials (24%), all characterized by a statistically significant PFS benefit without a corresponding OS improvement. No trial demonstrated an OS benefit in the absence of a PFS benefit. Conclusions: Across ADC trials, PFS systematically overestimated OS treatment effects, underscoring the limitations of PFS as a standalone surrogate endpoint. These findings support the cautious interpretation of PFS-driven efficacy and reinforce the need for endpoint validation frameworks tailored to the mechanism, disease context, and trial design.