Teaching pack: Muscle-invasive and advanced bladder cancer

Muscle-invasive urothelial carcinoma is treated with cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy and urinary diversion, or by trimodality bladder preservation (maximal resection plus chemoradiation) in suitable patients. Perioperative immunotherapy has entered practice: adjuvant nivolumab after cystectomy (CheckMate 274) and durvalumab with neoadjuvant chemotherapy and after surgery (NIAGARA), which improved overall survival. For metastatic disease, enfortumab vedotin with pembrolizumab nearly doubled survival compared with platinum chemotherapy (EV-302) and became the standard first-line treatment in 2023; erdafitinib is used for FGFR3-altered tumours, and platinum chemotherapy followed by avelumab maintenance remains an option. Molecular subtypes (luminal, basal) and circulating tumour DNA are being used to select who needs adjuvant treatment.

• EV-302 was the first trial in forty years to beat platinum chemotherapy first line, and it did so by a wide margin.
• Perioperative immunotherapy now improves survival around cystectomy, and circulating tumour DNA promises to select who needs it.
• Bladder preservation with chemoradiation gives survival similar to cystectomy in selected patients and is under-used.

1. 1985MVAC chemotherapy established for advanced disease
2. 2003Neoadjuvant MVAC improves survival before cystectomy (SWOG 8710)
3. 2016Atezolizumab: first immunotherapy approval in bladder cancer
4. 2019Erdafitinib: first targeted drug for FGFR3-altered urothelial cancer
5. 2021Adjuvant nivolumab (CheckMate 274)
6. 2023EV-302: enfortumab vedotin plus pembrolizumab replaces platinum first line
7. 2024NIAGARA: perioperative durvalumab improves survival

• Durvalumab (treatment)
• Erdafitinib (treatment)
• Enfortumab vedotin (treatment)

• 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
• CheckMate 274 (phase 3, n=709): Disease-free survival: 22 months vs 10.9 months, HR 0.7
• Study of Nivolumab in Combination With Ipilimumab or Standard of Care Chemotherapy Compared to the Standard of Care Chemotherapy Alone in Treatment of Participants With Untreated Inoperable or Metastatic Urothelial Cancer (phase 3, n=1,314): Overall Survival (OS) in Cisplatin-ineligible Randomized Participants for Primary Study: 19.06 months vs 13.21 months, HR 0.79
• Study of MEDI4736 (Durvalumab) With or Without Tremelimumab Versus Standard of Care Chemotherapy in Urothelial Cancer (phase 3, n=1,126): To Assess the Efficacy of Durvalumab + Tremelimumab Combination Therapy Versus SoC in Terms of OS in Full Analysis Set: 15.1 months vs 12.1 months, HR 0.85
• An Open-label Study to Investigate the Efficacy and Safety of Dato-DXd + Rilvegostomig vs SoC in Adult Participants With High-risk MIUC (phase 3, n=915): result not yet recorded

• Cisplatin-ineligible patients still have fewer options.
• Choosing between cystectomy and bladder preservation lacks randomised evidence.
• Variant histologies are excluded from most trials.
• Cost and access to antibody-drug conjugates.

1. 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.
2. 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.
3. What fraction of advanced melanoma patients on nivolumab plus ipilimumab are alive at ten years?
   Answer

   About 43% overall survival (CheckMate 067), with melanoma-specific survival around 52%.
4. Which cooperative group ran the trial that put nivolumab into first-line Hodgkin lymphoma?
   Answer

   SWOG (S1826, nivolumab-AVD vs BV-AVD), leading to FDA approval in March 2026 for ages 12 and over.
5. What is the rationale for combining an ADC with a checkpoint inhibitor, and where is it proven?
   Answer

   ADC payloads cause immunogenic cell death and STING activation, releasing antigens and depleting suppressive myeloid cells; PD-1 blockade converts that priming into durable control. Proven in urothelial cancer (EV-302) and TNBC (ASCENT-04).

• Wikipedia: https://en.wikipedia.org/wiki/Bladder_cancer
• Wikipedia: https://en.wikipedia.org/wiki/Bladder_cancer