Baseline Sarcopenia is associated with Overall Survival but Not Toxicity in Patients Receiving Enfortumab Vedotin plus Pembrolizumab for Locally Advanced or Metastatic Urothelial Carcinoma

Background Enfortumab vedotin plus pembrolizumab (EV/P) is the first-line standard for locally advanced or metastatic urothelial carcinoma (la/mUC). Sarcopenia is common in this population and may affect outcomes, but its prognostic relevance in EV/P-treated patients is unclear. Systemic inflammation may further influence prognosis, yet combined muscle and inflammation assessment has not been evaluated. We examined the impact of baseline sarcopenia, inflammatory markers, and early skeletal muscle change on outcomes with EV/P. Methods This retrospective single-center study included consecutive la/mUC patients treated with first-line EV/P between October 2023 and July 2025. Sarcopenia was defined using sex-specific L3 skeletal muscle index thresholds. Skeletal muscle was quantified on baseline and early follow-up imaging. The modified Glasgow prognostic score (mGPS) was derived from baseline inflammatory markers and analyzed alone and in combination with sarcopenia. Associations with overall survival (OS), progression-free survival (PFS), radiographic response, and treatment-related toxicity were assessed using Kaplan–Meier and univariable and multivariable regression analyses. Results Thirty-seven patients were included; median age was 76 years, and 62% were sarcopenic at baseline. Baseline sarcopenia was associated with shorter OS in univariable analysis (median 10.7 months vs. not reached; p = 0.018) but not PFS. However, sarcopenia did not remain independently associated with OS after multivariable adjustment. mGPS alone was not prognostic, though combined sarcopenia and mGPS identified a high-risk subgroup with sarcopenia and mGPS 2. Sarcopenia and early skeletal muscle change were not associated with response or toxicity. Conclusion Baseline sarcopenia is common and associated with inferior OS in univariable analyses of EV/P-treated la/mUC, but it was not an independent predictor after multivariable adjustment. Combined sarcopenia and mGPS stratification improves prognostic discrimination and supports integrated muscle and inflammation assessment. Microabstract: Enfortumab vedotin plus pembrolizumab is the first-line standard for locally advanced or metastatic urothelial carcinoma, yet prognostic biomarkers remain limited. In this retrospective cohort of 37 patients, baseline sarcopenia was common and associated with shorter overall survival in univariable analyses, but not after multivariable adjustment. Combined sarcopenia and inflammatory status improved risk stratification, while sarcopenia was not associated with toxicity.