Teaching pack: Bladder & urothelial cancer

Urothelial carcinoma of the bladder is the tenth most common cancer worldwide and the most expensive to manage per patient, because three quarters present as non-muscle-invasive disease that recurs for years and demands lifelong cystoscopy. Smoking causes about half of cases. Muscle-invasive disease (25%) has required radical cystectomy with neoadjuvant cisplatin since the 2000s, and metastatic disease relied on platinum chemotherapy for four decades.

Between 2019 and 2026 the field was rebuilt. In metastatic disease, enfortumab vedotin plus pembrolizumab nearly doubled survival over chemotherapy (EV-302, 2023). The same pair then moved around surgery: EV-303 in cisplatin-ineligible patients (EFS HR 0.40, approved November 2025) and EV-304 in cisplatin-eligible patients (positive December 2025), after NIAGARA had already established perioperative durvalumab (approved March 2025). Adjuvant nivolumab (CheckMate 274) and ctDNA-guided adjuvant atezolizumab (IMvigor011, the first ctDNA-based approval, 2026) cover the post-cystectomy space. In non-muscle-invasive disease, the BCG-unresponsive population gained four bladder-sparing options (pembrolizumab, nadofaragene firadenovec, N-803 + BCG, and the gemcitabine-eluting device TAR-200), with the oncolytic virus cretostimogene filing in 2026, and durvalumab + BCG became the first systemic immunotherapy in BCG-naive disease (POTOMAC, May 2026). Erdafitinib remains the only targeted drug, for FGFR3-altered tumours after immunotherapy.

• ADC + IO first line.
• First ctDNA-guided adjuvant approval.
• EV + pembrolizumab across metastatic, cisplatin-ineligible perioperative (approved 2025), and cisplatin-eligible perioperative (positive 2025) settings.
• Perioperative durvalumab (NIAGARA) and adjuvant nivolumab (CheckMate 274) with overall survival benefit.
• First ctDNA-guided drug approval in any cancer: adjuvant atezolizumab for ctDNA-positive MIBC (IMvigor011, 2026).
• Five bladder-sparing options for BCG-unresponsive disease, including a drug-eluting device and an oncolytic virus in registration.

1. 1976BCG immunotherapy for bladder cancer
2. 1976Morales reports intravesical BCG for bladder cancer
3. 1990BCG approved for carcinoma in situ; SWOG maintenance schedule follows (2000)
4. 2003SWOG 8710: neoadjuvant MVAC before cystectomy improves survival
5. 2012Global BCG shortage begins after Sanofi production halt
6. 2016Atezolizumab: first new bladder drug in 30 years
7. 2016Atezolizumab: first new bladder cancer drug in 30 years (later withdrawn)
8. 2017Pembrolizumab beats chemotherapy in second line (KEYNOTE-045)
9. 2019Erdafitinib (first targeted therapy) and enfortumab vedotin (first ADC) approved
10. 2020Avelumab maintenance (JAVELIN Bladder 100); pembrolizumab for BCG-unresponsive CIS

• Izalontamab brengitecan (product)
• AK146D1 (product)
• Disitamab vedotin (product)
• Intismeran autogene (product)
• EV-304 / KEYNOTE-B15 (trial)
• Cretostimogene grenadenorepvec (product)
• BOND-003 (trial)
• Gemcitabine intravesical system (TAR-200) (product)
• Bladder preservation for MIBC after perioperative EV + pembrolizumab complete response (idea)
• Urine tumour DNA to replace surveillance cystoscopy in NMIBC (idea)
• Sacituzumab tirumotecan (product)
• Zelenectide pevedotin (product)

• JAVELIN Bladder 100 (phase 3, n=700): Overall survival: 21.4 months vs 14.3 months, HR 0.69
• THOR (phase 3, n=266): Overall survival (cohort 1): 12.1 months vs 7.8 months, HR 0.64
• EV-302 / KEYNOTE-A39 (phase 3, n=886): Progression-free survival (BICR): 12.5 months vs 6.3 months, HR 0.45
• NIAGARA (phase 3, n=1,063): Event-free survival: 46.1 months, HR 0.68
• POTOMAC (phase 3, n=1,018): Disease-free survival: pending
• CheckMate 274 (phase 3, n=709): Disease-free survival: 22 months vs 10.9 months, HR 0.7

• BCG supply.
• Bladder preservation strategies.
• Nectin-4 ADC resistance.
• BCG supply remains inadequate a decade after shortages began; alternatives are unproven for BCG-naive high-risk disease.
• What to give after EV + pembrolizumab fails: platinum rechallenge, HER2 or TROP2 ADCs, and bispecific ADCs are untested in sequence.
• Whether perioperative therapy's high complete response rates permit bladder preservation in MIBC.

1. What regimen replaced platinum chemotherapy as first-line treatment for advanced bladder cancer, and how big was the effect?
   Answer

   Enfortumab vedotin plus pembrolizumab (EV-302): OS 31.5 vs 16.1 months, HR 0.47.
2. Which TROP2 ADCs are approved for first-line metastatic triple-negative breast cancer?
   Answer

   Sacituzumab govitecan (Trodelvy), as monotherapy for PD-1-ineligible patients (ASCENT-03) and with pembrolizumab for PD-L1 CPS ≥10 disease (ASCENT-04), and datopotamab deruxtecan (Datroway) for PD-1/PD-L1-ineligible patients (TROPION-Breast02), both approved in 2026.
3. What is the standard treatment for stage II-III triple-negative breast cancer today?
   Answer

   Neoadjuvant pembrolizumab with carboplatin/paclitaxel then anthracycline chemotherapy, surgery, and adjuvant pembrolizumab (KEYNOTE-522); adjuvant olaparib for germline BRCA carriers with residual disease (OlympiA); capecitabine for residual disease without BRCA.
4. What is the first bispecific ADC to succeed in a phase 3 trial, and in which cancer?
   Answer

   Izalontamab brengitecan (iza-bren, BL-B01D1), an EGFR×HER3 bispecific ADC from SystImmune/BMS, met PFS and OS in previously treated TNBC (BL-B01D1-307, February 2026) and also in oesophageal squamous cell carcinoma.
5. What was the first cancer drug approved on the basis of a blood test for leftover disease?
   Answer

   Atezolizumab for ctDNA-positive muscle-invasive bladder cancer after cystectomy (IMvigor011, using Signatera), approved Q2 2026; DFS HR 0.64, OS HR 0.59.
6. Can a blood test decide who needs chemotherapy after colon cancer surgery?
   Answer

   Yes in stage II: the DYNAMIC trial used ctDNA to guide adjuvant chemotherapy, halving its use (15% vs 28%) with non-inferior recurrence-free survival (93.5% vs 92.4% at two years).

• NCI PDQ: bladder cancer treatment: https://www.cancer.gov/types/bladder/hp/bladder-treatment-pdq
• FDA: durvalumab + BCG approval (May 2026): https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-combination-bacillus-calmette-guerin-high-risk-non-muscle-invasive-bladder
• Wikipedia: https://en.wikipedia.org/wiki/Bladder_cancer
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1417
• Guideline: https://pmc.ncbi.nlm.nih.gov/articles/PMC11163648/