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Bladder / urothelial → Metastatic urothelial carcinoma

Last reviewed: 2026-09-22 · Next review: 2026-12-21

clinic-ready — EV+pembro is the 1L OS-proven default for many; FGFR/HER2 as labeled

Who this applies to

Unresectable locally advanced or metastatic urothelial carcinoma¹⁰¹¹.
Record cisplatin eligibility, prior perioperative/adjuvant IO or EV, sites (liver), neuropathy, glycemic status, FGFR3, HER2 IHC, PD-L1 (less central for EV+pembro)¹⁷⁸¹⁰.

Standard options

Clinical context	Option	Key inclusion	Typical course
Untreated la/mUC	EV plus pembrolizumab¹	Assess neuropathy, glucose, organ function, and prior perioperative exposure⁷.	EV days 1 and 8 plus pembrolizumab every 3 weeks in EV-302¹.
Cisplatin-eligible untreated la/mUC not using EV plus pembrolizumab	Nivolumab plus GC²	CheckMate 901-type cisplatin fitness².	GC induction then nivolumab maintenance per trial².
No progression after platinum	Avelumab maintenance³	JAVELIN Bladder 100 population³.	Continue until progression or unacceptable toxicity³.
Subsequent therapy	EV, biomarker-directed therapy, trial, or supportive care⁴⁵¹⁰	Match prior therapy and FGFR/HER2 status⁵⁸.	Regimen-specific⁷⁸.

1L most patients: EV 1.25 mg/kg d1,8 + pembrolizumab 200 mg d1 q3wk (EV-302)¹.
1L cisplatin-eligible if not using EV+pembro: nivo 360 mg + GC q3wk ×6 then nivo 480 mg q4wk (CheckMate 901)².
1L platinum then, if no PD: maintenance avelumab (JAVELIN)³. This pathway is largely displaced by EV+pembro but still applies if platinum was already given¹³.
Post platinum + PD-(L)1: EV monotherapy (EV-301)⁴.
FGFR3-altered after ≥1 line including PD-(L)1: erdafitinib (THOR cohort 1)⁵. Do not use erdafitinib in PD-(L)1-naive eligible patients (FDA limitation; THOR cohort 2 OS HR 1.18 vs pembro)⁸.
HER2-expressing: discuss T-DXd / other HER2 ADCs as trial or label-permitted tumor-agnostic options; RC48-C016 is not a verified US SOC in this pack¹⁰¹¹.
After platinum, pembrolizumab vs chemo (KEYNOTE-045) if no prior PD-1¹⁰¹¹.
Supportive care / trial¹⁰¹¹.

Therapy sequencing

Starting point or prior exposure	Next treatment order	Branch point / evidence boundary
Untreated la/mUC	EV plus pembrolizumab is the default sequence in this page for many patients¹.	Record baseline neuropathy, glycemic status, and prior perioperative EV or immune-checkpoint inhibitor before starting⁷.
Untreated cisplatin-eligible disease when EV plus pembrolizumab is not used	Nivolumab plus GC induction → nivolumab maintenance².	CheckMate 901 is a cisplatin-eligible regimen; it is not the platinum-induction → avelumab sequence²³.
Platinum induction without progression	Start avelumab maintenance rather than observation alone³.	Applies after 4–6 cycles of gemcitabine plus cisplatin or carboplatin in JAVELIN Bladder 100³.
Progression after platinum plus PD-(L)1 without prior EV	EV monotherapy⁴.	EV-301 directly studied this post-platinum, post-PD-(L)1 setting⁴.
Progression after EV plus pembrolizumab	Reassess FGFR3/HER2 and trial eligibility; use a biomarker-matched or non-cross-resistant option when its own label criteria are met⁵⁸¹⁰.	A preferred post-EV plus pembrolizumab sequence is not established by a randomized phase 3 trial in this source set; do not assume EV monotherapy is evidence-based after EV-containing first line¹¹⁰.
FGFR3/2-altered disease after PD-(L)1	Erdafitinib⁵.	THOR cohort 1 supports this after prior PD-(L)1; it does not support substituting erdafitinib for an eligible first PD-1 pathway⁵⁸.

Surveillance and treatment de-escalation

Phase	Imaging / labs	Stop, hold, or de-escalate	Re-escalation / next line
On first-line EV plus pembrolizumab or platinum–ICI⁷¹⁰¹¹	Cross-sectional imaging every 9–12 weeks during active treatment; CBC, CMP, glucose, and neuropathy assessment on EV; immune-symptom review each cycle⁷¹⁰¹¹.	Continue until RECIST progression or unacceptable toxicity; hold EV for neuropathy grade ≥2 or hyperglycemia; hold pembrolizumab for immune events⁷.	Progression → EV monotherapy if post-platinum/post-PD-(L)1 without prior EV; FGFR/HER2-directed therapy; trial; supportive care⁴⁵¹⁰.
Avelumab maintenance after platinum without progression (JAVELIN)³¹⁰	Imaging every 12 weeks while on avelumab maintenance³¹⁰.	Continue until progression or unacceptable toxicity; trial allowed up to 2 years of avelumab³.	Progression → second-line options per sequencing table⁴⁵¹⁰.

EAU/NCCN recommend cross-sectional imaging for metastatic urothelial carcinoma on treatment and at progression; cystoscopy is not central for metastatic disease but remains relevant for bladder-primary local symptoms¹⁰¹¹.

Landmark evidence

Trial	Population	Intervention arm	Control arm	Key outcomes (both arms)	Key HR	Evidence status
EV-302 / KEYNOTE-A39	Untreated la/mUC; N=886¹	EV 1.25 mg/kg d1,8 + pembro 200 mg q3wk¹	Gemcitabine + cisplatin or carboplatin¹	PFS 12.5 vs 6.3 mo; OS 31.5 vs 16.1 mo (primary); update OS 33.8 vs 15.9 mo; grade ≥3 TRAE 55.9% vs 69.5%¹	PFS HR 0.45 (0.38–0.54); OS HR 0.47 (0.38–0.58); update OS HR 0.51 (0.43–0.61)¹	Powles 2024 NEJM PMID 38446675¹
CheckMate 901	Cisplatin-eligible untreated unresectable/metastatic UC; N=608²	Nivo 360 mg + GC q3wk ×6 → nivo 480 mg q4wk ≤2 y²	GC ×6²	OS 21.7 vs 18.9 mo; PFS 7.9 vs 7.6 mo; 12-mo PFS 34.2% vs 21.8%; ORR 57.6% vs 43.1%²	OS HR 0.78 (0.63–0.96); PFS HR 0.72 (0.59–0.88)²	van der Heijden 2023 NEJM PMID 37870949²
JAVELIN Bladder 100	Unresectable la/mUC without PD after 4–6 cycles gemcitabine-platinum; N=700³	Avelumab + BSC³	BSC³	1-y OS 71.3% vs 58.4%; OS 21.4 vs 14.3 mo; PFS 3.7 vs 2.0 mo³	OS HR 0.69 (0.56–0.86)³	Powles 2023 JCO long-term follow-up PMID 37071838³
EV-301	After platinum + PD-(L)1; N=608⁴	EV 1.25 mg/kg d1,8,15 q28d⁴	Docetaxel, paclitaxel, or vinflunine⁴	OS 12.88 vs 8.97 mo; PFS 5.55 vs 3.71 mo⁴	OS HR 0.70 (0.56–0.89); PFS HR 0.62 (0.51–0.75)⁴	Powles 2023 Ann Oncol long-term PMID 37678672⁴
THOR cohort 1 NCT03390504	FGFR3/2-altered after PD-(L)1; N=266⁵	Erdafitinib⁵	Docetaxel or vinflunine⁵	OS 12.1 vs 7.8 mo; PFS 5.6 vs 2.7 mo⁵	OS HR 0.64 (0.47–0.88); PFS HR 0.58 (0.44–0.78)⁵	Loriot 2023 NEJM PMID 37870920⁵; FDA Balversa⁸
KEYNOTE-045	After platinum; N=542¹⁰	Pembro 200 mg q3wk¹⁰	Paclitaxel, docetaxel, or vinflunine¹⁰	OS 10.3 vs 7.4 mo; PFS not different¹⁰	OS HR 0.73 (0.59–0.91); PFS HR 0.98 (0.81–1.19)¹⁰	Practice option per guideline when PD-1–naive after platinum¹⁰¹¹
TROPiCS-04 NCT04527991	After platinum + CPI; N=711⁹	Sacituzumab govitecan⁹	Paclitaxel, docetaxel, or vinflunine⁹	OS 10.3 vs 9.0 mo; PFS 4.2 vs 3.6 mo; ORR 23% vs 14%; grade ≥3 TRAE 67% vs 35%⁹	OS HR 0.86 (0.73–1.02), P=0.087 — primary not met⁹	2025 Ann Oncol PMID 39934055⁹
RC48-C016	Untreated HER2 IHC 1+/2+/3+ la/mUC; N=484¹⁰¹¹	Disitamab vedotin + toripalimab q2wk¹⁰	Gemcitabine + cisplatin or carboplatin¹⁰	PFS 13.1 vs 6.5 mo; OS 31.5 vs 16.9 mo; ORR 76.1% vs 50.2%¹⁰	PFS HR 0.36 (0.28–0.46); OS HR 0.54 (0.41–0.73)¹⁰	US FDA not in sources¹⁰¹¹

Biomarkers

Marker	Current clinic role	Emerging / investigational	How it changes decision now	Limits
FGFR3 (companion diagnostic)	Selects erdafitinib after prior PD-(L)1 in FGFR3/2-altered disease (THOR cohort 1)⁵⁸	Broader FGFR panels / earlier-line trials⁵¹⁰	Offers a labeled oral targeted option after PD-(L)1⁵⁸.	Do not substitute erdafitinib for an eligible first PD-1 pathway (FDA limitation; THOR cohort 2)⁸.
HER2 IHC	Informs discussion of HER2-directed ADC / trial options; RC48-C016 used IHC 1+/2+/3+¹⁰¹¹	Disitamab vedotin plus PD-1 programs (SGNDV-001; RC48-C016)¹⁰¹³¹⁸	Positive IHC prompts biomarker-matched or trial counseling after or instead of unlabeled sequencing¹⁰¹¹.	RC48-C016 is not a verified US first-line SOC in this pack; bladder-only T-DXd rates not in sources¹⁰¹¹.
PD-L1	Not the selector for EV plus pembrolizumab 1L in EV-302 as reported here¹	Historical platinum–avelumab and other ICI enrichment contexts³¹⁰	Does not gate first-line EV plus pembrolizumab on this page¹.	Less central once EV plus pembrolizumab is chosen¹¹⁰.
Nectin-4 context	Target of enfortumab vedotin; not used as a clinic assay to start EV plus pembrolizumab in EV-302¹⁷	Next-generation Nectin-4 ADCs after enfortumab exposure (e.g., NEXUS-01)¹⁶¹⁷	No pretreatment Nectin-4 assay required for labeled EV use on this page¹⁷.	Expression assays are not decision tools for SOC EV plus pembrolizumab here¹⁷.
NGS / TMB / MSI	NGS for FGFR and other trial targets when tissue/liquid testing is obtained⁵¹⁰	TMB/MSI-high tumor-agnostic ICI pathways when criteria are met¹⁰¹¹	Can open trial or labeled biomarker-matched options beyond FGFR⁵¹⁰.	TMB/MSI cutoffs and urothelial-specific rates are not detailed as practice selectors on this page¹⁰¹¹.

Upcoming research

Field direction after EV plus pembrolizumab as first-line Nectin-4 ADC plus PD-1 standard: competing HER2-directed vedotin ADCs with PD-1 in biomarker-selected untreated disease, next-generation Nectin-4 ADCs with non-MMAE payloads after enfortumab exposure, and still-unsettled post-EV plus pembrolizumab sequencing (FGFR, HER2, taxane, TROP2) without a randomized preferred line in this source set¹¹⁰¹³¹⁶.

Program	Why it may change care	Evidence status
SGNDV-001 / DV-001 (NCT05911295)	Phase 3 disitamab vedotin (HER2 ADC) plus pembrolizumab versus gemcitabine–platinum in untreated HER2 IHC ≥1+ la/mUC; dual primary BICR PFS and OS¹³¹⁴¹⁵.	Ongoing (active, not recruiting); design manuscript peer-reviewed; efficacy results pending¹³¹⁴.
RC48-C016 (NCT05302284)	Phase 3 disitamab vedotin plus toripalimab versus chemotherapy in untreated HER2 IHC 1+/2+/3+ la/mUC; peer-reviewed PFS/OS benefit versus chemotherapy¹⁸.	Peer-reviewed (NEJM); US regulatory status as a first-line standard is not established in this pack¹⁰¹¹¹⁸.
NEXUS-01 (NCT06465069)	Phase 1 next-generation Nectin-4 ADC LY4052031 (camptothecin/topo-I payload) in advanced UC, including post-enfortumab cohorts¹⁶¹⁷.	Ongoing phase 1 (recruiting); early activity congress-reported (ASCO 2026 / UroToday); not practice-changing yet¹⁶¹⁷.
Post–EV plus pembrolizumab sequencing	Preferred order among FGFR-directed therapy, HER2 options, taxane, and TROP2 ADC after first-line EV plus pembrolizumab¹⁵⁹¹⁰.	No randomized phase 3 preferred sequence in this source set; treat as an evidence gap¹¹⁰.

Toxicity

Regimen and comparator	Trial-level safety outcomes	Counseling focus
EV plus pembrolizumab versus platinum chemotherapy, EV-302	Grade ≥3 treatment-related AEs 55.9% vs 69.5%¹.	Report progressive neuropathy, rash, visual symptoms, hyperglycemia symptoms, cough/dyspnea, diarrhea, or endocrine symptoms promptly¹⁷.
Nivolumab plus GC versus GC, CheckMate 901	Grade ≥3 treatment-related AEs 61.8% vs 51.7%; discontinuation 21.1% vs 17.4%².	Review cytopenias, infection, renal function, neuropathy, and immune toxicity².
Avelumab maintenance plus BSC, JAVELIN Bladder 100	Long-term treatment-related-AE discontinuation 10.2%; no new safety signal with ≥2 years of follow-up³.	Report new diarrhea, abdominal pain, cough/dyspnea, rash, jaundice, or endocrine symptoms promptly³.
EV monotherapy versus chemotherapy, EV-301	Grade ≥3 treatment-related AEs 52.4% vs 50.5%⁴.	Report progressive neuropathy, rash, visual symptoms, or hyperglycemia symptoms promptly⁴⁷.
Erdafitinib versus chemotherapy, THOR cohort 1	Grade 3–4 treatment-related AEs 45.9% vs 46.4%⁵.	Review hyperphosphatemia, nail/skin, and ocular symptoms; prompt ophthalmology assessment for visual change⁵⁶.
Sacituzumab govitecan versus chemotherapy, TROPiCS-04	Grade ≥3 treatment-related AEs 67% vs 35%; primary OS endpoint not met⁹.	Urgent contact for fever/infection, severe diarrhea, dehydration, or marked fatigue⁹.
Pembrolizumab or a tumor-agnostic HER2-directed agent, when an individual indication applies	This page does not contain a comparable urothelial trial safety table for each later-line use¹⁰¹¹.	Follow the selected agent's label and trial protocol; report immune-toxicity symptoms or new cough/dyspnea promptly¹⁰¹¹.

On-treatment monitoring

SOC/option regimen	Hallmark monitoring toxicity and published rate	Patient action / clinic response
EV plus pembrolizumab	EV-302 FDA label treatment-arm rates (single-arm label rates; no paired comparator % in the retained label table): peripheral neuropathy 67%, grade 3–4 8%; rash 68%, grade 3–4 15%; increased glucose 66%, grade 3–4 14%; dry eye 24%, no grade 3–4 event⁷. Trial-level grade ≥3 TRAEs 55.9% vs 69.5% with platinum chemotherapy¹.	Check sensory and motor symptoms, skin, glucose, and visual symptoms at each treatment review. New or worsening numbness/weakness, thirst/polyuria, rash, or vision change should prompt contact before the next dose⁷.
Nivolumab plus GC	CheckMate 901: anemia 57.2%, grade ≥3 22.0%; neutropenia 30.6%, grade ≥3 18.8%; decreased neutrophils 24.7%, grade ≥3 14.5%; one treatment-related grade-5 sepsis².	Check CBC and renal function and review fever, neuropathy, hearing change, and immune-mediated diarrhea, dyspnea, hepatitis, or endocrinopathy; fever, dyspnea, or severe diarrhea needs urgent assessment².
Avelumab maintenance	JAVELIN Bladder 100: infusion reaction 10.2%, grade ≥3 0.9%; long-term treatment-related-AE discontinuation 10.2%³.	Premedicate during the first four infusions per label and review thyroid, hepatic, renal, pulmonary, and bowel symptoms during and after treatment; new cough/dyspnea, persistent diarrhea/abdominal pain, jaundice, or marked fatigue should prompt urgent contact³.
EV monotherapy	EV-301: peripheral neuropathy 48.0%, grade ≥3 7.4%; hyperglycemia 6.8%, grade ≥3 4.4%; skin reactions 47.3%, grade ≥3 14.9%⁴.	Monitor sensory symptoms, glucose, and skin from the first cycles; hold and assess for progressive neuropathy, severe rash/blistering, or symptomatic hyperglycemia⁴⁷.
Erdafitinib	THOR cohort 1: hyperphosphatemia 80.0%, grade 3–4 5.2%; central serous retinopathy 17.0%, grade 3–4 2.2%⁵.	Check phosphate on days 14–21 then monthly; arrange scheduled ophthalmic monitoring and hold treatment for visual change⁵⁶.
Sacituzumab govitecan	TROPiCS-04 reported grade ≥3 treatment-related AEs 67%; this page's retrieved primary source did not provide a named rate for neutropenia or diarrhea⁹.	Check CBC and review bowel symptoms; fever, infection symptoms, severe diarrhea, or dehydration needs urgent contact⁹.
Pembrolizumab after platinum if PD-1–naive	KEYNOTE-045: pruritus 19.5%, grade 3–5 3.1%; hypothyroidism 7.1%, no grade 3–5 event; grade 3–5 pneumonitis 2.3% and colitis 1.1%¹⁰¹¹.	Check liver enzymes, creatinine, and thyroid function; report diarrhea/abdominal pain, cough/dyspnea, jaundice, rash, or endocrine symptoms promptly¹⁰¹¹.
Tumor-agnostic HER2-directed agent, when an individual indication applies	No urothelial-specific safety rate was retrieved for every tumor-agnostic option listed here¹⁰¹¹.	Use the selected agent's label-specific monitoring and report its designated serious symptoms promptly¹⁰¹¹.

Epic phrase

#Metastatic urothelial carcinoma

Counseling: First-line EV plus pembrolizumab (EV-302) improved median overall survival about 32 vs 16 months with platinum chemotherapy (OS HR 0.47 vs platinum). CheckMate 901 nivolumab plus GC median OS 21.7 vs 18.9 months with GC alone (HR 0.78 vs GC). Post-platinum maintenance avelumab median OS 21.4 vs 14.3 months with BSC alone (HR 0.69 vs BSC). After platinum plus PD-(L)1, EV monotherapy median OS 12.9 vs 9.0 months with chemotherapy (HR 0.70 vs chemo). FGFR-altered after PD-(L)1: erdafitinib median OS 12.1 vs 7.8 months with chemotherapy (HR 0.64 vs chemo).
Counseling: Reviewed surveillance and de-escalation: imaging every 9–12 weeks on active therapy; avelumab maintenance imaging every 12 weeks; cystoscopy not central for metastatic disease; hold EV for neuropathy ≥2 or hyperglycemia; continue avelumab until progression or 2-year cap; progression after EV+pembro → biomarker-directed or trial options.
Monitoring: EV plus pembrolizumab requires review of new or worsening numbness/weakness, rash, vision changes, and thirst/polyuria before each dose; the EV-302 label reports treatment-arm rates (single-arm label rates; no paired comparator % in the retained label table): peripheral neuropathy 67%, rash 68%, and increased glucose 66%. Trial-level grade ≥3 TRAEs were 55.9% vs 69.5% with platinum chemotherapy. EV monotherapy requires the same surveillance, with EV-301 treatment-arm rates: peripheral neuropathy 48.0%, hyperglycemia 6.8%, and skin reactions 47.3%. Erdafitinib requires phosphate and scheduled ocular monitoring; sacituzumab requires CBC and diarrhea review.
Counseling: Promptly contact oncology for progressive numbness/weakness, rash, visual symptoms, thirst/polyuria, cough/dyspnea, diarrhea, fever/infection, or other concerning treatment effects. *** after-hours/urgent-assessment instructions reviewed.
Discussed workup and extent of disease: * (sites). Histology: *. Prior therapy: *** (including perioperative EV/IO if any).
Biomarkers: PD-L1 *; FGFR3 *; HER2 *; NGS: *.
Discussed prognosis and goals (control, QoL).
Discussed treatment order: untreated disease → EV plus pembrolizumab for most patients; if platinum induction is used without progression → avelumab maintenance; after platinum plus PD-(L)1 without EV → EV monotherapy; after EV plus pembrolizumab → reassess FGFR3/HER2 and trial eligibility because a preferred randomized post-EV sequence is not established. ***
Discussed options: first-line enfortumab vedotin + pembrolizumab (EV-302) for most untreated la/mUC; nivolumab + gemcitabine-cisplatin if cisplatin-eligible and not using EV+pembro; maintenance avelumab if platinum already given without progression; EV monotherapy after platinum + PD-(L)1; erdafitinib if FGFR3-altered after PD-(L)1 (not instead of first PD-1 if eligible); sacituzumab — TROPiCS-04 did not meet OS; HER2-directed therapy / trial; supportive care.
He / she opts to proceed with *. Discussed key toxicities: * (EV: neuropathy, rash, hyperglycemia; IO irAEs; platinum; erdafitinib: phosphate, ocular).
Labs / staging: ***
Referrals: ***
Follow-up: ***

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Guideline references

Sources

Changelog

2026-09-22: Clarified on-treatment imaging every 9–12 weeks and avelumab maintenance imaging every 12 weeks; noted cystoscopy is not central for metastatic disease; expanded Biomarkers to five-column table.
2026-09-22: Renamed Upcoming trial results to Upcoming research; reframed for ongoing trials and field direction (SGNDV-001/DV-001, RC48-C016, NEXUS-01).
2026-09-22: Labeled EV-302 monitoring rates as single-arm label rates and restated grade ≥3 TRAEs vs platinum; mirrored comparator-named efficacy counseling in the paired dotphrase.
2026-09-22: Added line-level source superscripts ([^n]) linked to numbered Sources.
2026-09-22: Added Surveillance and treatment de-escalation section; strengthened quantified benefit counseling in dotphrase.
2026-09-21: Updated on-treatment monitoring with retrieved EV-302 label, CheckMate 901, JAVELIN, THOR, and KEYNOTE-045 named-event rates.
2026-09-21: Added therapy sequencing and regimen-level on-treatment monitoring, including trial-specific EV neuropathy, hyperglycemia, skin-reaction, and erdafitinib phosphate/ocular data.
2026-09-21: Renamed the prospective-evidence section to Upcoming trial results.
2026-09-21: Removed Bottom line; added a compact Guidelines table and disease → setting page framing. No treatment recommendations or trial statistics changed.
2026-09-21: Weekly skim — no practice-changing updates since last review.
2026-09-14: expanded from stub; EV-302 both-arm OS/PFS, CheckMate 901, JAVELIN, THOR/FDA limitation, TROPiCS-04 negative OS, RC48-C016 labeled non-US pending
2026-09-14: initial stub

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