What is the optimal treatment strategy for metastatic bladder cancer, including first‑line cisplatin‑eligible versus cisplatin‑ineligible regimens, maintenance avelumab, second‑line checkpoint inhibitors, FGFR‑targeted therapy, and enfortumab vedotin?

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Last updated: February 25, 2026 • View editorial policy

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Treatment of Metastatic Bladder Cancer

First-Line Therapy: The New Standard

Pembrolizumab plus enfortumab vedotin (EV + P) is now the preferred first-line treatment for metastatic urothelial bladder cancer, regardless of cisplatin eligibility, based on dramatic survival improvements showing median overall survival of 31.5 months versus 16.1 months with chemotherapy. 1

Evidence Supporting EV + P as First-Line

  • The EV-302 phase III trial demonstrated overwhelming superiority with hazard ratios of 0.47 for overall survival and 0.45 for progression-free survival (12.5 vs 6.3 months) compared to platinum-based chemotherapy 1
  • Objective response rate reached 67.7% versus 44.4% with chemotherapy, including complete responses in 29.1% versus 12.5% 1
  • This represents a category 1 recommendation from NCCN, the highest level of evidence 1
  • Grade ≥3 adverse events occurred in 55.9% (versus 69.5% with chemotherapy), demonstrating a more favorable toxicity profile 1

Key Toxicities to Monitor with EV + P

  • Skin reactions (67.1% any grade, 17.1% grade ≥3) 2
  • Peripheral neuropathy (60.5% any grade, 6.8% grade ≥3) 3
  • Hyperglycemia (6.1% grade ≥3) 3
  • Fatigue (9.2% grade ≥3) 2

Alternative First-Line Regimens When EV + P Is Unavailable

For Cisplatin-Eligible Patients

If pembrolizumab plus enfortumab vedotin is not available, gemcitabine plus cisplatin (GC) remains the historical standard for cisplatin-eligible patients. 1

Cisplatin Eligibility Criteria

Patients must meet ALL of the following 3, 4:

  • ECOG performance status 0-1
  • Creatinine clearance ≥60 mL/min
  • No grade ≥2 hearing loss
  • No grade ≥2 neuropathy
  • No New York Heart Association Class III heart failure

Dosing for Gemcitabine-Cisplatin

  • Gemcitabine 1,000 mg/m² IV on days 1,8, and 15 4
  • Cisplatin 70 mg/m² IV on day 1 or 2 4
  • Repeat every 21-28 days 4
  • Expected median overall survival: 9-15 months 3, 1

Alternative Cisplatin-Based Option

  • Dose-dense MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) with growth factor support is an equivalent alternative 3, 1
  • At 7.3 years median follow-up, 24.6% of patients were alive with ddMVAC versus 13.2% with standard MVAC 3
  • ddMVAC showed improved toxicity and efficacy compared to standard 28-day MVAC, making standard MVAC obsolete 3

For Cisplatin-Ineligible Patients

Pembrolizumab plus enfortumab vedotin remains the preferred option (category 1) even for cisplatin-ineligible patients. 1

When EV + P Is Not Available

If EV + P cannot be used, the treatment algorithm depends on patient fitness and PD-L1 status 3:

Option 1: Carboplatin-Based Chemotherapy

  • Gemcitabine plus carboplatin for patients fit for carboplatin but not cisplatin 3, 1
  • Response rates: 26-42% (lower than cisplatin-based regimens) 3, 4
  • Increased toxicity in renally impaired patients 4
  • This is a category 2B recommendation 3

Option 2: Checkpoint Inhibitor Monotherapy (Restricted)

  • Atezolizumab or pembrolizumab monotherapy only for 3, 1:
    • Patients with positive PD-L1 expression who are cisplatin-ineligible, OR
    • Patients ineligible for any platinum-containing chemotherapy regardless of PD-L1 status
  • Critical caveat: A 2018 FDA safety alert restricted first-line immunotherapy after trials demonstrated decreased survival versus platinum chemotherapy in patients with low PD-L1 expression 4
  • Do not use checkpoint inhibitor monotherapy in cisplatin-eligible patients, even with high PD-L1 expression 4

Treatment Duration and Response Assessment

  • Re-evaluate after 2-3 cycles of chemotherapy 3
  • Continue treatment for 2 more cycles if disease responds or remains stable 3
  • Maximum of 6 cycles depending on response 3, 1
  • Change therapy if no response after 2 cycles or if significant morbidities occur 3, 1

Maintenance Therapy After First-Line Platinum-Based Chemotherapy

Avelumab maintenance should be initiated in patients with stable or improved disease after 4-6 cycles of first-line platinum-based chemotherapy. 1

  • This represents a practice-changing treatment with the highest survival rates among maintenance strategies 5
  • Extrapolated from urothelial carcinoma trials showing improved outcomes 4
  • Only applicable if patient did not receive EV + P as first-line 3

Second-Line Therapy

After Progression on Platinum-Based Chemotherapy (Without Prior Immunotherapy)

Pembrolizumab monotherapy is the category 1 recommendation, demonstrating overall survival of 10.3 versus 7.4 months compared to chemotherapy (p=0.002). 1

  • Only 15% grade 3-4 adverse events versus 49.4% with chemotherapy 1
  • Other approved checkpoint inhibitors include atezolizumab, nivolumab, durvalumab, and avelumab, all approved regardless of PD-L1 expression 3, 1

After Progression on Immunotherapy

Enfortumab vedotin is strongly recommended for patients previously treated with platinum-containing chemotherapy who had disease progression during or after treatment with a PD-1 or PD-L1 inhibitor. 3

Subsequent-Line Therapy (Third-Line and Beyond)

For Patients Who Have Exhausted Standard Options

The treatment algorithm depends on prior platinum response and FGFR mutation status 6:

Option 1: Platinum Rechallenge (Preferred if Applicable)

  • If platinum-free interval ≥6-12 months after initial therapy and patient remains platinum-eligible, rechallenge with platinum-based chemotherapy is preferred 6
  • Retrospective analysis showed higher disease control rate and longer overall survival compared to non-platinum chemotherapy in platinum-sensitive patients 6

Option 2: Erdafitinib for FGFR-Altered Tumors

  • Strong alternative if patient has FGFR2/3 mutations or FGFR3 fusions confirmed by FDA-approved testing 3, 6
  • Specifically indicated for patients previously treated with platinum-containing chemotherapy who had disease progression during or after PD-1/PD-L1 inhibitor treatment 3, 6

Option 3: Single-Agent Chemotherapy

  • Paclitaxel, docetaxel, or vinflunine if platinum rechallenge not feasible 3, 6
  • Gemcitabine/paclitaxel combination if patient has not recently received gemcitabine 6
  • Expected response rates: 8-30% depending on agent 6
  • Median overall survival: 5-7 months 3, 6

Molecular Testing Requirements

Molecular/genomic testing should be performed early, ideally at diagnosis, to facilitate therapeutic decisions and avoid delays in subsequent lines. 1

Essential Testing

  • FGFR3/FGFR2 genetic alterations: Required for eligibility to erdafitinib in later lines 1, 6
  • PD-L1 expression: Required if considering monotherapy immunotherapy as first-line 1

Role of Surgery and Radiation in Metastatic Disease

Metastasectomy for Oligometastatic Disease

Metastasectomy may be beneficial for highly selected patients meeting ALL of the following criteria 1:

  • No evidence of rapid progression
  • Favorable response to preoperative systemic therapy
  • Solitary metastatic lesions

Critical pitfall: Do not perform metastasectomy in patients with rapidly progressive disease or multiple metastatic sites 1

Palliative Radiotherapy

  • Useful for selected patients with symptomatic metastatic sites 1, 6
  • Consider for control of local symptoms, particularly bone metastases or sites causing pain or obstruction 6
  • Nephroureterectomy may be offered as palliative treatment to symptomatic patients with resectable locally advanced tumors 3

Special Populations

Poor-Risk Patients

Poor-risk patients are defined as those with 3:

  • Poor performance status (ECOG ≥2)
  • Visceral disease (liver, lung) or bone metastases
  • Abnormal alkaline phosphatase or lactic dehydrogenase levels

These patients show very poor tolerance to multi-agent combination programs and few complete remissions 3. Regimens with lower toxicity profiles are recommended 3.

Squamous Cell Carcinoma of the Bladder

  • Gemcitabine plus cisplatin is recommended despite limited histology-specific data 4
  • Expected median overall survival: 9-13 months (markedly lower than 13-15 months for urothelial carcinoma) 4
  • Five-year overall survival: less than 5% 4
  • Do not postpone platinum-based chemotherapy to use immunotherapy as first-line in cisplatin-eligible patients 4

Clinical Trial Enrollment

Clinical trial enrollment is strongly recommended for all patients, particularly for second-line and subsequent therapies, as data for later-line therapy are highly variable and limited. 3, 6

This recommendation is especially critical for patients with squamous histology given the paucity of histology-specific trials 4.

References

1
Guideline

Treatment of Metastatic Urothelial Bladder Cancer

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2026

2
Research

Enfortumab Vedotin With or Without Pembrolizumab in Cisplatin-Ineligible Patients With Previously Untreated Locally Advanced or Metastatic Urothelial Cancer.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2023

3
Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

4
Guideline

First‑Line Platinum‑Based Chemotherapy for Metastatic Squamous Cell Carcinoma of the Bladder

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2026

6
Guideline

Treatment for Metastatic Urothelial Cancer After Multiple Failed Lines

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2026

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Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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