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

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.