Progression-free survival as an endpoint for clinical trials in first-line metastatic urothelial cancer.

Abstract

251 Background: Advances in the first-line treatment of metastatic urothelial cancer (UC) have proven elusive. The lack of appropriate intermediate endpoints to screen the activity of novel regimens may be a barrier to progress, particularly in this disease state characterized by relatively high response rates but short response durations. Progression-free-survival (PFS) at fixed time points may overcome several of the limitations of response rate-based endpoints, but would be further supported by establishing benchmarks and demonstrating a correlation between PFS and overall survival (OS). Methods: Data were pooled from eight phase II and III trials evaluating first-line cisplatin-based chemotherapy in metastatic UC. Landmark analyses for progression at 3, 6, and 9 months after treatment initiation were performed to minimize lead-time bias. A proportional hazards model was used to assess the utility of PFS for predicting OS. Results: 545 patients were included in the analysis. The median PFS was 7.75 months (95% CI, 7.06, 8.18) and the median OS was 12.35 months (95% CI, 10.97, 13.44). The results of the landmark analysis, adjusted for performance status ≥ 1 and presence of visceral metastases, is shown in the Table. By using the Fleischer model, the estimated correlation between PFS and OS was 0.86 (bootstrap standard error 0.001, 95% CI 0.83, 0.89). Conclusions: PFS at 3, 6, and 9 months predicted OS in this analysis of patients with metastatic UC treated with first-line cisplatin-based chemotherapy. This analysis provides benchmarks, and support, for the use of PFS as an endpoint for phase II trials screening the activity of novel regimens as first-line treatment for metastatic UC. [Table: see text]