Overview of Bladder Cancer Treatment
Urothelial carcinoma treatment has evolved rapidly with the introduction of enfortumab vedotin + pembrolizumab as a new first-line standard (EV-302/KEYNOTE-A39), checkpoint inhibitors for maintenance and second-line therapy, FGFR inhibitors for FGFR-altered tumors, and novel ADCs like sacituzumab govitecan. Non-muscle invasive disease options include intravesical BCG and nadofaragene firadenovec for BCG-unresponsive disease.
Treatment Paradigm by Stage
First-Line Advanced/Metastatic
- Enfortumab vedotin + Pembrolizumab (new standard, EV-302)
- Platinum-based chemotherapy (cisplatin-eligible patients)
Maintenance After Platinum
- Avelumab maintenance (JAVELIN Bladder 100)
Second-Line and Beyond
- Enfortumab vedotin (Padcev) - ADC
- Sacituzumab govitecan (Trodelvy) - Trop-2 ADC
- Erdafitinib (Balversa) for FGFR-altered tumors
- Pembrolizumab or atezolizumab
Non-Muscle Invasive (NMIBC)
- Nadofaragene firadenovec (Adstiladrin) for BCG-unresponsive
- Pembrolizumab for BCG-unresponsive CIS
Epidemiology & Impact
Bladder cancer is the sixth most common malignancy in the United States, with approximately 84,900 new cases and 18,200 deaths expected in 2025. The disease demonstrates a striking male predominance, affecting men approximately four times more often than women. Incidence rates are highest among White men and increase sharply with age, with a median age at diagnosis of 73 years. Cigarette smoking is the single most important risk factor, accounting for approximately 50% of cases. Occupational exposure to aromatic amines (particularly in dye, rubber, and chemical industries) accounts for another 10-20%. The majority of cases (approximately 75%) present as non-muscle-invasive bladder cancer (NMIBC), which is managed with transurethral resection and intravesical therapy. However, up to 50% of high-grade NMIBC will recur and 10-20% will progress to muscle-invasive disease, requiring lifelong surveillance that makes bladder cancer one of the most expensive cancers to treat per patient over a lifetime.
Molecular Biology & Biomarkers
Bladder cancer demonstrates distinct molecular subtypes that correlate with clinical behavior. The TCGA identified five expression subtypes: luminal-papillary, luminal-infiltrated, luminal, basal-squamous, and neuronal. Basal-squamous tumors are generally more aggressive but may be more responsive to platinum-based chemotherapy, while luminal-infiltrated tumors show evidence of immune cell infiltration and may respond to checkpoint immunotherapy. FGFR3 mutations and fusions are found in approximately 15-20% of muscle-invasive bladder cancers and up to 70% of low-grade non-muscle-invasive tumors, serving as the target for erdafitinib. HER2 alterations (mutation or amplification) occur in approximately 10-15% of cases and are under investigation as therapeutic targets. PD-L1 expression varies by assay and subtype but is used as a biomarker for first-line pembrolizumab eligibility in cisplatin-ineligible patients. The high tumor mutational burden of bladder cancer (second only to melanoma and lung cancer among solid tumors) likely explains its general responsiveness to immune checkpoint blockade.
Evolving Treatment Landscape
The treatment of advanced bladder cancer has been revolutionized since 2016, ending a two-decade drought in new approvals. Cisplatin-based combination chemotherapy (gemcitabine-cisplatin or MVAC) remains the first-line standard for cisplatin-eligible patients, but the EV-302/KEYNOTE-A39 trial demonstrated that enfortumab vedotin plus pembrolizumab significantly outperformed platinum-based chemotherapy, establishing this antibody-drug conjugate/immunotherapy combination as a new first-line option. Enfortumab vedotin targets Nectin-4, expressed on over 97% of bladder cancers, providing near-universal applicability. For FGFR-altered tumors, erdafitinib offers a targeted oral option. Avelumab maintenance therapy after first-line chemotherapy (based on the JAVELIN Bladder 100 trial) extends survival in patients who have not progressed on chemotherapy. Sacituzumab govitecan has shown activity in the post-immunotherapy setting, and the antibody-drug conjugate pipeline continues to expand rapidly for this disease.
Approved Therapies
Treatment Strategies
First-line: Enfortumab vedotin + pembrolizumab (EV-302/KEYNOTE-A39) is the new preferred first-line regimen; platinum-based chemotherapy (gemcitabine/cisplatin or gemcitabine/carboplatin) followed by avelumab maintenance for non-progressors remains an option. Second-line: Checkpoint inhibitors (pembrolizumab). Later lines: Antibody-drug conjugates (enfortumab vedotin, sacituzumab govitecan) or erdafitinib for FGFR-altered disease. Adjuvant: Nivolumab for high-risk resected urothelial carcinoma. NMIBC: BCG, nadofaragene firadenovec (BCG-unresponsive), or pembrolizumab (BCG-unresponsive CIS).