Immune Checkpoint Inhibitors and Antibody-Drug Conjugates in Urothelial Carcinoma: Current Landscape and Future Directions.

Abstract

Background/objectives: Urothelial carcinoma (UC) treatment has been transformed by immunotherapy and antibody-drug conjugates (ADCs). This review evaluates the current evidence for these approaches and identifies future directions.

Methods: We conducted a structured review of clinical trials, meta-analyses, and guidelines published until early 2025.

Results: Immune checkpoint inhibitors have established benefits across multiple settings: post-platinum therapy (pembrolizumab, nivolumab), maintenance therapy (avelumab), adjuvant settings for high-risk muscle-invasive disease (nivolumab), and BCG-unresponsive non-muscle-invasive disease (pembrolizumab). Enfortumab vedotin (targeting Nectin-4) has proven effective in post-platinum/post-immunotherapy. Most significantly, enfortumab vedotin plus pembrolizumab has redefined first-line treatment with unprecedented survival benefits (median OS 31.5 months vs. 16.1 months with chemotherapy; HR 0.47), and nivolumab plus gemcitabine-cisplatin improved outcomes in cisplatin-eligible patients. Key challenges include managing unique toxicity profiles, optimizing treatment sequencing, and developing reliable biomarkers.

Conclusions: Combination approaches offer the most promising path forward, with future research needed on resistance mechanisms, biomarker development, and expanding these therapies to earlier disease stages.