Key points
- When bladder cancer has spread, the main treatment is drugs, and this treatment has improved greatly in recent years [1].
- Today chemotherapy is combined with immunotherapy, and the newer combination of enfortumab vedotin with pembrolizumab made patients live almost twice as long as chemotherapy in a large study [9, 7, 2, 3].
- An FGFR3 gene test on the tumour sample shows whether the targeted tablet erdafitinib may suit you later [1, 21].
- The particular side effects of enfortumab vedotin affect the skin, the nerves of the hands and feet, the eyes and blood sugar; the sooner they are reported, the better they are controlled [19].
- If the cancer has reached the bladder muscle but has not spread, drug treatment before surgery increases the chance of cure; in some patients the bladder is kept, using radiotherapy and chemotherapy [1, 14, 15, 16, 18].
The story of treating advanced bladder cancer
When bladder cancer has spread to distant lymph nodes or other organs, surgery alone is not enough and the main treatment is drugs [1]. For years this treatment was only chemotherapy with the drug cisplatin. In 2000, a large study showed that the combination of gemcitabine and cisplatin lengthened patients' lives just as much as an older four-drug combination, but with fewer severe side effects [4]; since then this combination has been the usual treatment. Even so, with chemotherapy alone fewer than 2 in every 10 patients were alive 5 years later [5].
The first big change was modern immunotherapy: drugs such as pembrolizumab that take the brakes off the immune system so that it fights the cancer better [20]. In 2017, in patients whose cancer had grown again after chemotherapy, pembrolizumab lengthened life more than a second chemotherapy and had fewer serious side effects [6]. In 2020 "maintenance" immunotherapy arrived: if the disease had not progressed after 4 to 6 cycles of chemotherapy, continuing treatment with the drug avelumab lengthened life [7, 8]. In 2023, adding nivolumab to gemcitabine-cisplatin also lengthened patients' lives [9].
The second big change was enfortumab vedotin, an "antibody-drug conjugate" that, like a guided missile, sticks to a protein called nectin-4 on the cancer cell and carries an anticancer drug straight inside it [19, 15]. This drug was first tested in patients for whom chemotherapy and immunotherapy no longer worked, and it lengthened their lives [10]. Then in 2024, in a large study of nearly 900 patients who had not yet had any treatment, the combination of enfortumab vedotin with pembrolizumab was compared with platinum chemotherapy: with this combination, both the time the disease was kept under control and patients' length of life almost doubled [2]. It was the first treatment that was used instead of platinum chemotherapy and lengthened patients' lives more than it did [2]; this advantage held up with longer follow-up [3].
Treatment today, step by step
- 1
Tests before treatment
The tumour sample is examined in the laboratory, and an FGFR3 gene test on the tumour tissue is recommended for later decisions [1, 21]. A blood test of kidney function, together with your physical fitness and other illnesses, shows whether cisplatin suits you: if your kidneys work less well, your physical fitness is low, or you have hearing loss, numbness of the hands and feet or heart failure, usually not [19]. If you have diabetes, good control of your blood sugar before starting enfortumab vedotin is important [19].
- 2
First treatment: three main paths
- If cisplatin suits you: gemcitabine-cisplatin with nivolumab for up to 6 cycles, then nivolumab on its own for up to 2 years; this combination lengthened patients' lives more than chemotherapy alone [9].
- Enfortumab vedotin with pembrolizumab, whether or not cisplatin suits you: in the large study it made patients live almost twice as long as chemotherapy, and the European guideline considers it the preferred first treatment [2, 3, 1].
- Chemotherapy followed by maintenance immunotherapy: 4 to 6 cycles of gemcitabine with cisplatin or carboplatin and, if the disease has not progressed, continuing with avelumab [7, 1].
- 3
If you are having enfortumab vedotin with pembrolizumab
Each cycle lasts 3 weeks: enfortumab vedotin on days 1 and 8 as a half-hour drip into a vein, and pembrolizumab on day 1 after it [19, 20]. Treatment continues as long as it works and the side effects are bearable; pembrolizumab is given for no more than 2 years [19, 20]. Blood tests (including sugar, liver and kidney function and thyroid) are done regularly [19, 20].
- 4
If the disease progresses
If your first treatment was chemotherapy and you have not had immunotherapy, pembrolizumab is the next option [6, 1]; if your first treatment was enfortumab vedotin with pembrolizumab, platinum chemotherapy is given [1]. If the tumour has an FGFR3 gene change, the tablet erdafitinib is used; after immunotherapy it lengthened life more than chemotherapy [11, 1]. Enfortumab vedotin on its own also lengthened life after chemotherapy and immunotherapy [10]. In tumours with a very large amount of the HER2 protein, trastuzumab deruxtecan is also an option [1].
FGFR3 gene test and the tablet erdafitinib
FGFR3 is a gene that is changed in some bladder cancers; the tablet erdafitinib blocks the action of the protein made from this gene [12, 21]. At one large centre, about 1 in every 4 samples of cancer that had spread carried this change [13]. The test is done on tumour tissue [21]. Sometimes the result from an old bladder sample differs from the result in the cancer that has spread, so testing an old sample is not always enough [13].
If the change is present, erdafitinib is taken once a day [21]. In a large study of patients whose disease had progressed after immunotherapy, erdafitinib lengthened life more than chemotherapy, and fewer patients died from treatment side effects [11]. Its common side effects are nail changes, diarrhoea, mouth sores and dry mouth, dry skin and eyes, and a rise in blood phosphate [21]. Your doctor may ask you to cut down on foods rich in phosphate [21]. This tablet sometimes damages the retina of the eye, so an eye examination is needed once a month for the first 4 months and then every 3 months, and any change in your vision must be reported straight away [21].
Side effects of enfortumab vedotin: skin, nerves, eyes and blood sugar
The side effects of this combination differ from those of standard chemotherapy: low blood counts and nausea are less common, but skin, nerve and eye problems are more common [19]. Other common side effects are tiredness, itching, diarrhoea, hair loss, loss of appetite and weight, and a change in the taste of food [19]. Your doctor manages most of these side effects by pausing the drug, lowering the dose or giving supportive medicines; the key is to report them early [19].
Skin
A skin rash is the most common side effect: almost 7 in every 10 patients had one, and in most it was not severe [19]. Severe skin reactions happen mostly in the first cycle of treatment [19]. Report a new rash early; your doctor may give a steroid cream or an anti-itch medicine or stop the drug for a while [19]. Report blistering, peeling skin or painful sores in the mouth, nose, throat or genital area straight away [19].
Nerves of the hands and feet
Numbness, tingling or burning in the hands and feet, or muscle weakness, occurred in about 7 in every 10 patients; the more troublesome form usually appears after several months of treatment [19]. In many patients this problem does not go away completely even after the drug is stopped, so tell your doctor at the first sign so that the drug can be paused or reduced in time [19]. See: Numbness and tingling in the hands and feet
Eyes
Blood sugar
This drug can raise blood sugar, even in people who do not have diabetes; sometimes so much that it becomes dangerous [19]. Blood sugar is checked during treatment, and if it is very high, the drug is stopped until the sugar comes down [19]. Report passing a lot of urine, great thirst, blurred vision, confusion, drowsiness or a fruity smell on the breath straight away [19].
Immunotherapy (pembrolizumab)
Pembrolizumab can make the immune system react against healthy organs too: the lungs, bowel, liver, kidneys, thyroid and other glands [20]. Inflammation of the lungs occurred in about 1 in every 10 patients with this combination [19]. These side effects can appear even after treatment has ended [20]. See: Side effects of immunotherapy
If the cancer has reached the bladder muscle but has not spread
At this stage the aim is cure [1]. Cisplatin-based chemotherapy is usually given before the bladder is removed [1]; in one study, at the time of surgery no cancer was left in the bladder in more patients (more than twice as many) [17]. In recent studies, adding the immunotherapy drug durvalumab to chemotherapy before and after surgery [14], and enfortumab vedotin with pembrolizumab before and after surgery, both in people who do not receive cisplatin [15] and in those who can receive it [16], lengthened patients' lives.
Another path for suitable patients is keeping the bladder: complete removal of the tumour through a scope, then radiotherapy together with chemotherapy [1, 18]. In a large study, adding chemotherapy to radiotherapy made the cancer come back in the bladder and pelvis less often [18]. With this approach, follow-up with cystoscopy is needed for life [1]. See the details in Treatment when the tumour has reached the muscle.
- "Does cisplatin suit me?" [19, 1]
- "Has an FGFR3 test been done on my tumour?" [1, 21]
- "Is enfortumab vedotin with pembrolizumab better for me, or chemotherapy with immunotherapy? Why?" [1, 2, 9]
- "What precautions do I need because of the diabetes or numbness in my hands and feet that I already have?" [19]
- "If I get a rash, numbness or a change in my vision, whom should I tell, and how quickly?" [19]
When should I call my doctor?
With enfortumab vedotin: report a new or worsening rash early; report blistering, peeling skin, sores in the mouth or genital area, or fever and flu-like symptoms with a rash straight away [19]. Also report straight away new numbness or weakness of the hands or feet, any change in your vision, a new cough or breathlessness, passing a lot of urine and great thirst (signs of high blood sugar), and redness, swelling or blistering where the drip went in [19]. With pembrolizumab: report diarrhoea or severe stomach pain, yellowing of the skin or eyes, and severe tiredness or an unusual headache; these side effects can appear even after treatment has ended [20]. With chemotherapy: report a temperature of 38 °C or higher straight away [23]. If you have severe breathlessness, confusion or reduced consciousness, call your local emergency number.
Frequently asked questions
Can advanced bladder cancer be cured?
Usually the aim is long-term control of the disease and a better life [1]. But with the new treatments, in some patients the tumour disappears completely on scans: with enfortumab vedotin plus pembrolizumab, in nearly 3 in every 10 patients [19]. With chemotherapy plus nivolumab, too, in those whose tumour disappeared completely, the response lasted for years in many of them [9].
Is enfortumab vedotin chemotherapy?
Not exactly. This drug is an antibody that carries an anticancer drug attached to it, and takes it straight to cells that have the protein nectin-4 [19, 15]. That is why its side effects differ from those of standard chemotherapy: fewer low blood counts and less nausea, but more rash, numbness and dry eyes [19]. See: Antibody-drug conjugates
How long does this treatment go on?
I have diabetes; can I have this drug?
What if cisplatin does not suit me?
My cancer has reached the bladder muscle; are these drugs given before surgery too?
Cisplatin-based chemotherapy before surgery is the established approach [1]. In recent studies, adding durvalumab to it, and enfortumab vedotin with pembrolizumab before and after surgery, lengthened patients' lives [14, 15, 16]. Decide between these paths, and keeping the bladder, with your treatment team (urology, oncology and radiotherapy) [1].
For physicians
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Background: Gemcitabine-cisplatin versus MVAC (405 patients): similar overall survival (HR 1.04), response 49% versus 46% and toxic death 1% versus 3% [4]; in long-term follow-up, median OS 14.0 versus 15.2 months and 5-year OS 13.0% versus 15.3% [5]. KEYNOTE-045 (542 patients after platinum): pembrolizumab 200 mg every 3 weeks versus second-line chemotherapy, median OS 10.3 versus 7.4 months (HR 0.73), no PFS difference (HR 0.98); grade 3 to 5 treatment-related adverse events 15.0% versus 49.4% [6]. EV-301 (608 patients after platinum and anti-PD-1/PD-L1): enfortumab vedotin 1.25 mg/kg on days 1, 8 and 15 every 28 days versus chemotherapy, median OS 12.88 versus 8.97 months (HR 0.70) [10].
First line: EV-302 (886 patients, regardless of cisplatin eligibility; control: gemcitabine with cisplatin or carboplatin): median PFS 12.5 versus 6.3 months (HR 0.45) and OS 31.5 versus 16.1 months (HR 0.47); grade 3 or higher treatment-related adverse events 55.9% versus 69.5% [2]. At 2.5 years of follow-up, OS 33.8 versus 15.9 months (HR 0.51) and PFS HR 0.48 [3]. Objective response 67.7% versus 44.4% and complete response 29.1% versus 12.5%; patients with HbA1c 8% or higher (or 7% or higher with diabetes symptoms), grade 2 or higher neuropathy and active CNS metastases were excluded [19]. CheckMate 901 (608 cisplatin-eligible patients): nivolumab 360 mg with gemcitabine-cisplatin every 3 weeks for up to 6 cycles, then nivolumab 480 mg every 4 weeks for up to 2 years; median OS 21.7 versus 18.9 months (HR 0.78), PFS HR 0.72 (median 7.9 versus 7.6 months; 12-month PFS 34.2% versus 21.8%), complete response 21.7% versus 11.8% with median duration 37.1 versus 13.2 months, grade 3 or higher adverse events 61.8% versus 51.7% [9]. JAVELIN Bladder 100 (700 patients without progression after 4 to 6 cycles of gemcitabine with cisplatin or carboplatin): maintenance avelumab, 1-year OS 71.3% versus 58.4% and median 21.4 versus 14.3 months (HR 0.69), PFS 3.7 versus 2.0 months (HR 0.62) [7]; with at least 2 years of follow-up HR 0.76 [8]. Avelumab dose in the label: 800 mg IV over 60 minutes every 2 weeks, with antihistamine and paracetamol (acetaminophen) premedication before the first 4 infusions [22]. EAU 2025: EV + pembrolizumab in patients suitable for combination therapy (strong); if EV is contraindicated, platinum + gemcitabine followed by maintenance avelumab in patients with at least stable disease, and in cisplatin-eligible patients cisplatin/gemcitabine + nivolumab [1]. Label criteria for cisplatin ineligibility: creatinine clearance below 60 mL/min, ECOG 2 or higher, grade 2 or higher hearing loss or peripheral neuropathy, or NYHA class III or higher heart failure [19]. Doses: EV + pembrolizumab · nivolumab + gemcitabine-cisplatin · gemcitabine-cisplatin and maintenance avelumab.
EV + pembrolizumab essentials (FDA label): enfortumab vedotin 1.25 mg/kg (maximum 125 mg for patients weighing 100 kg or more) IV over 30 minutes on days 1 and 8 every 21 days until progression or unacceptable toxicity, before pembrolizumab on the same day [19]; pembrolizumab 200 mg every 3 weeks or 400 mg every 6 weeks for up to 24 months [20]. In EV-302: rash 68% (grade 3–4 15%), peripheral neuropathy 67% (grade 3–4 8%), fatigue 51%, pruritus 41%, diarrhoea 38%, alopecia 35%, weight loss 33%, dry eye 24%, pneumonitis/ILD 10% and raised glucose on laboratory testing 66% (grade 3–4 14%); fatal adverse reactions 3.9% and EV discontinuation for adverse reactions 35% (mostly neuropathy, 15%) [19]. Neuropathy with combination therapy in advanced disease: median time to onset of grade 2 or higher 6 months, and complete resolution in only 13% [19]. EV dose-reduction levels: 1, 0.75 and 0.5 mg/kg; glucose above 250 mg/dL: withhold until 250 or lower; grade 2 neuropathy: withhold until grade 1 or lower (on recurrence, resume one level lower), grade 3 or higher: discontinue permanently; grade 3 or higher pneumonitis: discontinue permanently; confirmed SJS/TEN, grade 4 or recurrent grade 3 skin reaction: discontinue permanently [19]. Managing immune toxicity: immunotherapy toxicity lesson.
Later lines and FGFR3: THOR (266 patients with FGFR3/2 alterations after one or two lines including anti-PD-1/PD-L1): erdafitinib versus docetaxel or vinflunine, median OS 12.1 versus 7.8 months (HR 0.64) and PFS 5.6 versus 2.7 months (HR 0.58); grade 3–4 treatment-related adverse events 45.9% versus 46.4% and treatment-related death 0.7% versus 5.4% [11]. BLC2001 (99 patients): confirmed response 40% [12]. In a single-centre series, susceptible FGFR3 alterations in 26% of metastatic samples (59 of 228) and 14% of MIBC samples; FGFR3 discordance between primary tumour and metastasis in 7 of 27 paired samples (26%) [13]. Label dose of erdafitinib: 8 mg once daily, increased to 9 mg on days 14 to 21 if phosphate is below 9.0 mg/dL and there is no eye disorder or grade 2 or higher adverse reaction; dietary phosphate restriction to 600 to 800 mg a day; eye examination (with OCT) monthly for the first 4 months and then every 3 months; CSR/RPED in 22% and raised phosphate in 73%; not recommended for eligible patients who have not had anti-PD-1/PD-L1 [21]. EAU: erdafitinib for actionable FGFR alterations after a checkpoint inhibitor (strong); after EV + pembrolizumab, platinum-based chemotherapy; after platinum without a checkpoint inhibitor, pembrolizumab; trastuzumab deruxtecan for HER2 overexpression (IHC 3+) [1]. Doses: pembrolizumab after platinum · erdafitinib.
Muscle-invasive disease: SWOG (307 eligible patients): three cycles of neoadjuvant MVAC, pT0 38% versus 15% and median OS 77 versus 46 months (P=0.06) [17]. NIAGARA (1063 cisplatin-eligible patients): durvalumab + gemcitabine-cisplatin for 4 cycles, then adjuvant durvalumab for 8 cycles, 24-month EFS 67.8% versus 59.8% (HR 0.68) and 24-month OS 82.2% versus 75.2% (HR 0.75); grade 3–4 treatment-related adverse events 40.6% versus 40.9% [14]. KEYNOTE-905 (344 patients ineligible for or declining cisplatin): perioperative EV + pembrolizumab versus surgery alone, 2-year EFS 74.7% versus 39.4% (HR 0.40), 2-year OS 79.7% versus 63.1% (HR 0.50) and pCR 57.1% versus 8.6% [15]. EV-304 (808 cisplatin-eligible patients): versus neoadjuvant cisplatin-gemcitabine, 2-year EFS 79.4% versus 66.2% (HR 0.53), 2-year OS 86.9% versus 81.3% (HR 0.65) and pCR 55.8% versus 32.5%; grade 3 or higher adverse events 75.7% versus 67.2% [16]. BC2001 (360 patients): fluorouracil + mitomycin C with radiotherapy, 2-year locoregional disease-free survival 67% versus 54% (HR 0.68); 5-year OS 48% versus 35% (HR 0.82; P=0.16) [18]. Doses: durvalumab + GC (NIAGARA) · perioperative EV + pembrolizumab · bladder-sparing chemoradiotherapy.
Scientific evidence
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Scientific evidence
13 itemsNivolumab plus Gemcitabine-Cisplatin in Advanced Urothelial Carcinoma
Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma
Radiotherapy with or without Chemotherapy in Muscle-Invasive Bladder Cancer
Neoadjuvant Chemotherapy plus Cystectomy Compared with Cystectomy Alone for Locally Advanced Bladder Cancer
Enfortumab vedotin plus pembrolizumab in untreated locally advanced or metastatic urothelial carcinoma: 2.5-year median follow-up of the phase III EV-302/KEYNOTE-A39 trial
Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer
Avelumab First-Line Maintenance for Advanced Urothelial Carcinoma: Results From the JAVELIN Bladder 100 Trial After ≥2 Years of Follow-Up
Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma
Perioperative Enfortumab Vedotin and Pembrolizumab in Bladder Cancer
Enfortumab Vedotin and Pembrolizumab in Cisplatin-Eligible Bladder Cancer
Perioperative Durvalumab with Neoadjuvant Chemotherapy in Operable Bladder Cancer
Erdafitinib or Chemotherapy in Advanced or Metastatic Urothelial Carcinoma
European Association of Urology Guidelines on Muscle-invasive and Metastatic Bladder Cancer: Summary of the 2025 Guidelines
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Related links
Related cancer types
References
23 referencesShow all references, 13 with a study cardClose the reference list
Numbers in the text, such as [1], refer to these sources. Sources with a “Study card” button are summarised in the site’s evidence library.
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- 8Avelumab First-Line Maintenance for Advanced Urothelial Carcinoma: Results From the JAVELIN Bladder 100 Trial After ≥2 Years of Follow-Up
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- 17Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer
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- 22BAVENCIO (avelumab) injection, for intravenous use — Prescribing Information
- 23Infection and Neutropenia during Cancer Treatment
This page is based on reputable scientific sources and was last updated on 29 October 2026. The content of this website is for educational and informational purposes only and does not replace consultation, diagnosis or treatment by a specialist physician. Consult your treating physician about any treatment decision.
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