Second-line chemotherapy is widely used in metastatic urothelial carcinoma after progression on first-line platinum-based therapy, but its independent contribution to survival, as opposed to selection of healthier patients, remains unclear. In this multicenter retrospective cohort of 142 patients treated with first-line platinum-based chemotherapy across seven Turkish centers, overall survival (OS) from first-line progression was compared between patients who received second-line chemotherapy (
n = 80) and those who did not (
n = 62), using multivariable Cox regression, inverse probability of treatment weighting (IPTW), propensity-score matching, landmark analysis, and a time-dependent Cox model. Median OS was 7.4 versus 4.7 months (log-rank
p = 0.064). Second-line chemotherapy was independently associated with improved OS on multivariable analysis (adjusted hazard ratio [aHR] 0.620; 95% confidence interval [CI] 0.423–0.907;
p = 0.014); Eastern Cooperative Oncology Group (ECOG) performance status ≥ 2 (aHR 3.881;
p = 0.001) and lower albumin (aHR 0.671;
p = 0.018) were also independent predictors. The association remained significant after IPTW (HR 0.648;
p = 0.025) and after a time-dependent Cox model (HR 0.632;
p = 0.019), and was unchanged in ECOG-restricted and Bellmunt-adjusted analyses (
p = 0.008,
p = 0.029); it narrowly missed significance after propensity-score matching (HR 0.645;
p = 0.051) and did not reach significance in the 3-month landmark analysis (HR 0.743;
p = 0.180). Power was limited (~49%). In a time-dependent Cox model—the analysis least susceptible to immortal-time bias, as it retains the full cohort and classifies pre-treatment person-time as unexposed—second-line chemotherapy remained independently associated with improved OS (HR 0.632;
p = 0.019), closely consistent with the primary multivariable estimate. The conventional Cox, IPTW, and propensity-score-matched analyses, which treat second-line receipt as a baseline exposure, were directionally concordant but share a common time-related bias and are therefore not independent confirmations. ECOG performance status was a consistent predictor throughout.
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