Early versus deferred immunotherapy in urothelial carcinoma: a review of evidence and post-progression survival.

[OBJECTIVE] Metastatic urothelial carcinoma has undergone a major therapeutic transition, with first-line immune checkpoint inhibitor-based combinations now established as standard care. In this context, the key clinical question is no longer whether early immunotherapy should be used, but how evidence from historical deferred approaches, switch-maintenance, and contemporary upfront regimens can be interpreted through the lens of post-progression survival (PPS), a major determinant of overall survival (OS).

[METHODS] A narrative synthesis of randomized phase II-III trials (2016-2025), PubMed-indexed studies, and real-world datasets was performed. Data on efficacy (OS, progression-free survival [PFS], PPS), safety, and rates of access to second-line therapy were extracted from JAVELIN Bladder 100, KEYNOTE-045, EV-302/KEYNOTE-A39, CheckMate-901, KEYNOTE-361, IMvigor130, and DANUBE.

[RESULTS] Avelumab maintenance improved OS (23.8 vs 15.0 months) despite >50% crossover to ICIs. Pembrolizumab after progression prolonged OS (10.3 vs 7.4 months) without PFS benefit, highlighting PPS as a major survival determinant. Real-world evidence indicates that only a minority of patients initiating first-line therapy ultimately receive second-line treatment, supporting therapeutic strategies that ensure earlier exposure to immunotherapy. Frontline combinations, such as enfortumab vedotin plus pembrolizumab and nivolumab plus cisplatin/gemcitabine, have, therefore, redefined the treatment paradigm and are now preferred standards or validated frontline options, whereas pembrolizumab-chemotherapy, atezolizumab-based combinations, and dual-checkpoint approaches have not demonstrated comparable survival benefit.

[CONCLUSIONS] Early integration of immunotherapy remains the key principle underlying survival improvement in metastatic urothelial carcinoma, but this concept must now be interpreted within a modern therapeutic framework in which enfortumab vedotin plus pembrolizumab is the preferred first-line regimen for most patients. Avelumab maintenance and post-platinum pembrolizumab remain historically pivotal benchmark strategies and may still retain relevance where newer regimens are unavailable or unsuitable. Across treatment eras, PPS appears to be a major driver of OS and deserves more systematic reporting in future trials.