BLADDER cancer (BC) ranks as the ninth most common cancer globally, with men affected around four times more often than women. In 2022, there were approximately 614,000 new cases and over 220,000 deaths worldwide. BC primarily originates in the urothelium, accounting for about 90% of urothelial cancers, and develops through distinct stages.
Non-muscle invasive bladder cancer (NMIBC), representing roughly 75% of cases, remains confined to the bladder lining and submucosa, often recurring but rarely advancing. Muscle-invasive bladder cancer (MIBC), however, penetrates the bladder muscle and carries a higher risk of spreading through lymphatic and vascular systems.
The disease’s progression is driven by several genetic alterations and pathways. FGFR3 mutations promote tumour growth in NMIBC, while TP53 and RB1 gene losses contribute to genomic instability in MIBC. Other factors such as KDM6A mutations, activation of the PI3K-AKT-mTOR pathway, and PD-L1 overexpression aid tumour survival and immune system evasion. New targeted therapies, like Enfortumab Vedotin and Sacituzumab Govitecan, act on overexpressed proteins such as Nectin-4 and Trop-2 to combat tumour invasion and progression.
Cystoscopy remains the gold standard for diagnosing BC, often supplemented by urine cytology and imaging techniques like MRI, ultrasound, or CT scans to stage the tumour. Prognosis largely depends on tumour stage, grade, subtype, and metastasis, with metastatic MIBC patients facing poor survival rates, around 8% five-year survival when cancer has spread.
Recent clinical trials have transformed advanced urothelial carcinoma treatment, introducing antibody-drug conjugates (ADCs) and immune checkpoint inhibitors (ICIs). Notably, the EV-302 trial established the combination of Enfortumab Vedotin plus Pembrolizumab as a first-line therapy, regardless of cisplatin eligibility. Meanwhile, CheckMate-901 showed benefits in combining Nivolumab with standard chemotherapy.
Despite promising advances, challenges remain, including identifying which patients will benefit most, managing treatment resistance, and high drug costs. Ongoing trials, such as EV-303 and EV-304, continue to explore these new treatments, aiming to improve outcomes for bladder cancer patients.
Reference
Karam EA et al. Optimizing enfortumab vedotin plus pembrolizumab therapy. Oncotarget. 2025;16:481-94.
