Clinical trials that investigate treatment effectiveness in patients affected by high-risk non-muscle-invasive bladder cancer (HR-NMIBC) often use progression-free survival (PFS) as a surrogate end point. However, the efficacy of this surrogate end point and its association with overall survival (OS) are challenged by conflicting results that demonstrate lack of OS advantage, even when in the presence of PFS improvement.
A new study presented at the American Urological Association 2023 Annual Meeting sought to test the effect of time to progression on OS in a cohort of patients with HR-NMIBC treated with intravesical bacillus Calmette-Guérin therapy.
A total of 1510 patients at first diagnosis of T1 HR-NMIBC after transurethral resection of bladder tumor were included in the study. Procedures were performed across 18 different tertiary institutions between 2002 and 2012. Progression was defined as the time from HR-NMIBC diagnosis to development of muscle-invasive bladder cancer (MIBC). Covariates were ranked based on OS prediction, and classes were obtained based on time to progression. Cox regression models were then utilized.
At a median follow-up of 49 months, 483 patients had disease progression to MIBC, while 163 patients died. The median time to progression was 82 months. In relapse-free survival, time to progression and age were the most predictive components of OS. The C-index was 0.814 on the training set and 0.726 on the test set. The survival tree including these covariates defined 5 risk groups:
- PFS ≥62.5 months and age <77.5 years (reference)
- PFS ≥62.5 months and age ≥77.5 years (hazard ratio [HR], 9.0; P<.001)
- PFS between 10.5 and 62.5 months and age <79.5 years (HR, 14.3; P<.001)
- PFS <10.5 months and age <79.5 (HR, 44.9; P<.001)
- PFS <62.5 months and age ≥79.5 years (HR, 58.7; P<.001).
In multivariable Cox regression models accounting for progression status as a time-dependent covariate, longer PFS (as a continuous covariate) was associated with a longer OS (HR, 0.9; P<.001). Results were virtually the same after PFS stratification (PFS ≥10.5 months as reference) and included PFS between 10.5 and 62.5 months (HR, 0.4; P<.001) and PFS ≥62.5 months (HR, 0.2; P<.001).
PFS can be utilized as an efficient surrogate end point for OS due to its strong predictor status and high accuracy. Further studies evaluating the efficacy of HR-NMIBC treatments can benefit from using PFS as a surrogate for OS.