First-Line Treatment Options for Advanced Urothelial Carcinoma
Published on April 14, 2026
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Over the past several years, first-line treatment (the type doctors try first) for advanced urothelial carcinoma has changed. Before the discovery of newer options and combinations, chemotherapy that included platinum medications like cisplatin or carboplatin was the first choice, says Christopher Wee, MD, a genitourinary medical oncologist at Cleveland Clinic in Ohio.
“[And] although platinum-based chemotherapy regimens can work for many patients, they often stop working, and side effects can become problematic,” he says.
Now first‑line treatment recommendations for advanced bladder cancer have shifted from traditional chemotherapy toward more targeted and immune‑based therapies, says Paul Gellhaus, MD, a urologic surgical oncologist and the medical director of the genitourinary program at City of Hope Cancer Center in Phoenix.
The New Gold Standard
Recent research shows that the combination of two bladder cancer medications — enfortumab vedotin (Padcev) and pembrolizumab (Keytruda) — may treat advanced bladder cancer better than standard platinum-based chemotherapy.
Enfortumab Vedotin Plus Pembrolizumab (EVP)
Enfortumab, an antibody-drug conjugate, attaches to cancer cells and delivers medication that destroys them. Pembrolizumab is an immune checkpoint inhibitor — a type of immunotherapy that helps your body’s natural defenses attack cancer cells.
Both drugs are approved by the U.S. Food and Drug Administration (FDA) for treatment of advanced bladder cancer. But in 2023, the FDA approved combined enfortumab vedotin plus pembrolizumab (EVP) to treat bladder cancer in those who aren’t eligible for cisplatin chemotherapy due to certain health conditions like heart failure.
Since then, studies have continued to show treatment success with EVP, and now you can get this treatment first — regardless of your ability to take cisplatin. In fact, many specialists now consider EVP a leading first‑line option for eligible patients, Dr. Gellhaus says.
Benefits of EVP
“One of the major advantages of EVP is that it delivers strong anti‑cancer activity while maintaining — and in some cases improving — patients’ quality of life compared with standard chemotherapy,” says Gellhaus.
People have reported better pain control after they start taking EVP, which also lets them move around more easily, says Gellhaus.
“The biggest benefit of EV + P is improvement in survival,” says Dr. Wee — a view confirmed by recent research studies.
What the Research Shows
In one study, 886 people with advanced urothelial carcinoma took either EVP or platinum-based chemotherapy. Those who took EVP had almost double the survival time of those who were treated with chemo.
In another study of 195 people with advanced bladder cancer, about 3 out of 4 who took EVP experienced disease control. This means their tumor disappeared, shrank, or stopped growing.
“In clinical studies, many patients [also] reported stable or improved day‑to‑day well‑being on EVP, while traditional chemotherapy was more often associated with worse overall health and symptoms,” says Gellhaus.
Who Can Take EVP?
Most adults with metastatic urothelial carcinoma can take EVP. Prescribing information for both enfortumab vedotin and pembrolizumab lists important warnings and precautions.
Risks include:
- Allergic or infusion-related reactions
- Severe skin reactions
- High blood sugar
- Lung inflammation
- Numbness or tingling in your hands and feet (peripheral neuropathy)
- Immune system problems which can lead to infections
- Eye or vision problems
Both medications can also cause harm to a developing fetus, so you shouldn’t take them while pregnant or breastfeeding. You may also be unable to take EVP if you have:
- Neuropathy
- Liver failure
- Prior radiation for bladder cancer
- Active hepatitis A or B infection
Other First-Line Options
The best treatment for advanced bladder cancer depends on certain details about your cancer (like type and stage) and other health conditions. Besides EVP, first-line treatment is typically platinum-based chemotherapy with or without immunotherapy. But based on your cancer type and spread, first-line options can also include:
- Partial or full bladder removal surgery (cystectomy)
- Surgical creation of a new pathway for urine (urinary diversion)
- External-beam radiation therapy (EBRT)
“Even with the enthusiasm surrounding EVP, there are still circumstances where more traditional treatment approaches may be the better starting point,” says Gellhaus.
Chemotherapy and Immunotherapy
If you’re not a good candidate for EVP, chemotherapy may be your next best option. The most effective chemo medication combinations for bladder cancer include cisplatin, but to take it, you must be “cisplatin eligible.” For example, you may not be able to take it if you have poor hearing, heart failure, peripheral neuropathy, or kidney issues.
Along with chemotherapy, your provider may recommend immunotherapy treatments like nivolumab (Opdivo) or avelumab (Bavencio), which help your immune system destroy cancer cells.
External Beam Radiation Therapy
Treatment with radiation isn’t usually a first-line choice, but your provider may recommend it along with other treatments, such as EVP. They may also offer it first if you cannot have surgery or take typical medication options, but this rarely happens.
Radiation therapy can damage cancer cells by aiming a powerful beam of radiation at cancer sites from outside your body. This treatment can both decrease a tumor’s size and improve symptoms like trouble urinating, pain, fatigue, and poor appetite.
Cystectomy for Symptom Relief
If your tumor causes major symptoms like heavy bleeding, repeated urinary blockages, or severe pain, your provider may recommend surgical procedures like bladder removal or urinary diversion for symptom relief, says Gellhaus.
“Although these surgeries may not extend life, they can greatly improve comfort and quality of life,” he says.
Side Effects
Each first-line treatment for advanced bladder cancer has possible side effects. They all destroy cancer cells, but can also damage other healthy cells. For example, many cancer treatments decrease the amount of immune cells in your blood that help fight disease, so you can develop infections more easily.
Many treatments also cause nausea, vomiting, and fatigue. Here’s how bladder cancer treatment side effects compare:
EVP
Chemotherapy
Immunotherapy
Radiation
Peripheral neuropathy
x
x
Immune system depression
x
x
x
x
Skin reactions
x
x
x
Diarrhea
x
x
x
x
Constipation
x
x
Nausea and vomiting
x
x
x
x
High blood sugar
x
Poor appetite
x
Hair loss
x
Mouth sores
x
Bruising and bleeding more easily
x
x
Fatigue
x
x
x
Pain, swelling, and redness at the injection site
x
Fever and chills
x
Dizziness
x
Weakness
x
Aching muscles or joints
x
Headache
x
Blood pressure changes
x
Heart palpitations
x
Pain with urination
x
Blood in stool or urine
x
No matter what side effects you experience, it’s important to let your care team know. They may be able to offer additional treatments to help manage your symptoms so you can stay more comfortable.
The Takeaway
- First-line treatment for advanced urothelial cancer can include chemotherapy and surgery, but newer immunotherapy options may be used more as a first option.
- The combination of enfortumab vedotin (Padcev) and pembrolizumab (Keytruda) has shown promise in research, increasing survival rates with fewer side effects.
- If you want to know more about your options for advanced bladder cancer treatment, you can ask your care team which kind may work best for you.
Resources We Trust
- Mayo Clinic: Bladder Cancer: Diagnosis and Treatment
- Cleveland Clinic: A New Standard Emerges in Advanced Urothelial Carcinoma After Decades of First-Line Chemotherapy
- National Cancer Institute: Bladder Cancer Treatment
- Cancer Research Institute: What Makes Immunotherapy for Bladder Cancer a Promising Treatment?
- American Cancer Society: Treating Bladder Cancer
EDITORIAL SOURCES
Everyday Health follows strict sourcing guidelines to ensure the accuracy of its content, outlined in our editorial policy. We use only trustworthy sources, including peer-reviewed studies, board-certified medical experts, patients with lived experience, and information from top institutions.
Resources
- Grande E et al. Guiding First-Line Treatment Decisions in Advanced Urothelial Carcinoma: A Global Survey. The Oncologist. September 6, 2025.
- Brave MH et al. FDA Approval Summary: Enfortumab Vedotin Plus Pembrolizumab for Locally Advanced or Metastatic Urothelial Carcinoma. Clinical Cancer Research. November 1, 2024.
- Enfortumab Vedotin-ejfv. National Cancer Institute. December 15, 2023.
- Pembrolizumab. National Cancer Institute. March 20, 2025.
- Bladder Cancer Treatment (PDQ®)–Health Professional Version. National Cancer Institute. May 2, 2025.
- FDA Approves Enfortumab Vedotin-Ejfv With Pembrolizumab for Locally Advanced or Metastatic Urothelial Cancer. U.S. Food and Drug Administration. December 15, 2023.
- Gupta S et al. Enfortumab Vedotin Plus Pembrolizumab Versus Chemotherapy in Patients With Previously Untreated Locally Advanced or Metastatic Urothelial Cancer (EV-302): Patient-Reported Outcomes From an Open-Label, Randomised, Controlled, Phase 3 Study. The Lancet Oncology. June 2025.
- Brower B et al. Managing Potential Adverse Events During Treatment With Enfortumab Vedotin + Pembrolizumab in Patients With Advanced Urothelial Cancer. Frontiers in Oncology. April 22, 2024.
- Niedersuess‐Beke D et al. Enfortumab Vedotin Plus Pembrolizumab in Treatment‐Naïve Metastatic Urothelial Carcinoma Patients: An Austrian Real‐World Analysis. International Journal of Cancer. October 22, 2025.
- Delgado A et al. Clinical Endpoints in Oncology — a Primer. American Journal of Cancer Research. April 25, 2021.
- PADCEV (enfortumab vedotin-ejfv): Prescribing Information. U.S. Food and Drug Administration. April 2023.
- KEYTRUDA® (pembrolizumab): Prescribing Information. U.S. Food and Drug Administration. March 2021.
- Enfortumab Vedotin Plus Pembrolizumab With Selective Bladder Sparing for Treatment of Muscle-invasive Bladder Cancer. Mount Sinai.
- Bladder Cancer Treatment. National Cancer Institute. September 12, 2024.
- Stecca CE et al. Is Cisplatin Eligibility Still Relevant in the First-Line Treatment of Patients With Metastatic Urothelial Carcinoma? American Society of Clinical Oncology. December 18, 2024.
- Immunotherapy for Bladder Cancer. American Cancer Society. November 26, 2025.
- Radiation Therapy for Bladder Cancer. Moffitt Cancer Center.
- Radiation Therapy for Bladder Cancer. American Cancer Society. March 12, 2024.
- What Are the Symptoms of Advanced Bladder Cancer? Moffitt Cancer Center.
- Infection and Neutropenia during Cancer Treatment. National Cancer Institute. January 23, 2020.
- Chemotherapy for Bladder Cancer. American Cancer Society. March 12, 2024.
- Immunotherapy Side Effects. National Cancer Institute. February 16, 2023.
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Christopher Wolter, MD
Medical Reviewer
Christopher Wolter, MD, is an assistant professor in urology at Mayo Clinic in Phoenix, Arizona. He has been in practice since 2008, specializing in the areas of urinary incontinen...
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Abby McCoy is an experienced registered nurse who has worked with adults and pediatric patients encompassing trauma, orthopedics, home care, transplant, and case management. She is...