Survival Outcomes of First-Line Therapy in De Novo Metastatic Urothelial Carcinoma with Histologic Subtypes: A National Cancer Database Analysis

<b>Background</b>: Urothelial carcinoma with histologic subtypes represent an aggressive and understudied population frequently excluded from prospective clinical trials. Evidence guiding optimal first-line systemic therapy in de novo metastatic disease with histologic subtypes remains limited. <b>Method</b>: Patients with de novo stage IV urothelial carcinoma with histologic subtypes diagnosed between 2016 and 2021 were identified from the National Cancer Database (NCDB). Eligible patients received first-line chemotherapy, immunotherapy, or concurrent chemoimmunotherapy (both modalities initiated within 30 days). Overall survival (OS) was compared across groups using Kaplan-Meier methods and compared using log-rank tests and multivariable Cox regression. <b>Result</b>: Among 800 patients, 596 (74.5%) received chemotherapy, 106 (13%) received immunotherapy, and 98 (12%) received concurrent chemoimmunotherapy. Survival differed significantly across treatment groups (log-rank <i>p</i> = 0.005). Concurrent chemoimmunotherapy was associated with longer OS compared with chemotherapy alone (HR 0.73, 95% CI 0.55-0.93) and immunotherapy monotherapy. Immunotherapy alone was associated with inferior survival compared with chemotherapy. <b>Conclusions</b>: In de novo metastatic urothelial carcinoma with histologic subtypes, concurrent chemoimmunotherapy and chemotherapy were associated with superior survival compared with immunotherapy monotherapy. These findings support the consideration of early combination-based strategies and highlight the need for prospective studies dedicated to this high-risk population.