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

## TL;DR

This study finds that combining chemotherapy and immunotherapy improves survival for patients with aggressive metastatic urothelial cancer with variant histologies.

## Contribution

The study provides evidence supporting combination chemoimmunotherapy over monotherapies for de novo metastatic urothelial carcinoma with histologic subtypes.

## Key findings

- Combined chemoimmunotherapy was associated with better survival than chemotherapy alone.
- Immunotherapy alone had the poorest survival outcomes compared to other treatments.
- Prospective studies are needed to confirm these findings in high-risk patients.

## Abstract

Urothelial carcinoma can contain different histologic subtypes, often referred to as variant histologies, which are associated with aggressive behavior and poor outcomes. Patients with these tumors are frequently excluded from clinical trials, leaving limited evidence to guide first-line treatment decisions when the metastatic disease is present at diagnosis. Using a large national cancer database, we examined survival outcomes among patients with de novo metastatic urothelial carcinoma with histologic subtypes treated with chemotherapy, immunotherapy, or a combination chemoimmunotherapy. We found that patients who received combined chemoimmunotherapy had the best survival compared with chemotherapy alone, whereas immunotherapy alone was associated with the poorest outcomes. These findings suggest that immunotherapy by itself may not be sufficient for many patients with histologic subtypes and support the early use of combination-based treatment strategies. Prospective studies focused on this high-risk population are needed to confirm these observations.

Background: 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. Method: 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. Result: 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 p = 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. Conclusions: 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.