First and only treatment regimen for adults with MIBC, regardless of cisplatin eligibility, representing a platinum-free potential standard of care
Broadened approval supported by Phase 3 EV-304 data showing a nearly 50% reduction in the risk of tumor recurrence, progression or death, and a 35% reduction in the risk of death, versus standard of care in cisplatin-eligible patients

NEW YORK & TOKYO–(BUSINESS WIRE)–Pfizer Inc. (NYSE: PFE) and Astellas Pharma Inc. (TSE: 4503, President and CEO: Naoki Okamura, “Astellas”) today announced that the U.S. Food and Drug Administration (FDA) has approved PADCEV^® (enfortumab vedotin-ejfv), a Nectin-4 directed antibody-drug conjugate, plus the PD-1 inhibitor, Keytruda^® (pembrolizumab) or Keytruda QLEX™ (pembrolizumab and berahyaluronidase alfa-pmph) as neoadjuvant and adjuvant (before and after surgery) treatment for adult patients with muscle-invasive bladder cancer regardless of cisplatin eligibilityⁱ. This now marks the first platinum-free regimen approved for adult patients with MIBC, regardless of cisplatin eligibility.

The approval was based on results from the pivotal Phase 3 EV-304 clinical trial (also known as KEYNOTE-B15), which were presented at the 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU). This expanded indication builds on the November 2025 U.S. FDA approval of the combination for use as neoadjuvant and adjuvant treatment in cisplatin-ineligible adult patients with MIBC, based on results from the EV-303 Phase 3 clinical trial (also known as KEYNOTE-905) that were published in the New England Journal of Medicine.

Christopher Hoimes, DO, Director of the Bladder Cancer Program and Center for Cancer Immunotherapy at Duke Cancer Institute, and an EV-304 Principal Investigator

“For muscle-invasive bladder cancer, a comprehensive treatment approach is important; the neoadjuvant phase can help shrink the tumor and target undetectable cancer cells early before surgery, while the adjuvant phase can be critical in eliminating residual, undetectable cancer cells following surgery. These data from EV-304 and this approval show that by delivering this regimen across both the neoadjuvant and adjuvant phases, without platinum-based chemotherapy, we can significantly reduce the risk of recurrence and improve overall survival — offering a potential new standard of care for adult patients with muscle-invasive bladder cancer.”

Aamir Malik, Executive Vice President, Chief U.S. Commercial Officer, Pfizer

“Today’s approval marks a historic turning point for the treatment of muscle-invasive bladder cancer, providing adult patients with the first approved platinum-free combination regimen shown to significantly improve survival over the current standard of care – regardless of cisplatin-eligibility. PADCEV plus pembrolizumab has established itself as the standard of care for first line therapy of advanced stages of bladder cancer, and we’re thrilled to be able to provide this community a much-needed new treatment option in an earlier, potentially curative-intent setting.”

Moitreyee Chatterjee-Kishore, PhD, MBA, Head of Oncology Development, Astellas

“The approval of neoadjuvant and adjuvant PADCEV plus pembrolizumab expands the established impact of this combination and represents a critical leap forward in how muscle-invasive bladder cancer can be treated. By delivering a clinically meaningful survival benefit, with profound event-free survival and pathological complete response rates, this regimen is the first platinum-free treatment option in nearly 25 years to outperform standard of care chemotherapy, offering new hope to patients living with this disease.”

In the EV-304 clinical trial, patients were randomized to receive surgery with neoadjuvant and adjuvant PADCEV plus pembrolizumab or surgery with neoadjuvant chemotherapy. PADCEV plus pembrolizumab was administered as a planned total of 9 cycles of PADCEV and 17 cycles of pembrolizumab split before and after surgery.ⁱⁱ PADCEV plus pembrolizumab demonstrated:

A 47% reduction in the risk of tumor recurrence, progression or death compared to patients treated with standard of care neoadjuvant gemcitabine and cisplatin (Hazard Ratio (HR) of 0.53; 95% Confidence Interval (CI), 0.41–0.70; 1-sided p<0.0001).ⁱⁱ
An estimated 79.4% of patients were event-free at two years, compared with 66.2% treated with standard of care.ⁱⁱ
A 35% reduction in the risk of death compared to neoadjuvant chemotherapy (HR of 0.65; 95% CI, 0.48-0.89; 1-sided p=0.0029).ⁱⁱ
A pathological complete response (pCR) rate of 55.8% compared with 32.5% with chemotherapy at the time of surgery (estimated difference 23.4%; 95% CI 16.7-29.8; 1-sided p<0.0001).ⁱⁱ
A safety profile consistent with prior experience with this combination, and no new identifiable safety signals. Grade ≥3 adverse events (AEs) due to any cause occurred in 75.7% of patients treated with neoadjuvant and adjuvant PADCEV plus pembrolizumab compared to 67.2% of patients treated with neoadjuvant chemotherapy.ⁱⁱ

Please see Important Safety Information at the end of this press release, including BOXED WARNING for PADCEV (enfortumab vedotin-ejfv).

+++

About the EV-304/KEYNOTE-B15 Trial

The EV-304 trial is an ongoing, open-label, randomized, controlled, Phase 3 study evaluating neoadjuvant and adjuvant enfortumab vedotin in combination with pembrolizumab versus neoadjuvant chemotherapy (gemcitabine and cisplatin) in patients with MIBC who are eligible for cisplatin-based chemotherapy. Patients were randomized to receive either neoadjuvant and adjuvant (before and after surgery) enfortumab vedotin in combination with pembrolizumab (arm A) or neoadjuvant gemcitabine-cisplatin chemotherapy (arm B). Curative-intent surgery (cystectomy) was performed in both arms. Enfortumab vedotin in combination with pembrolizumab was administered as a planned total of 9 cycles of enfortumab vedotin and 17 cycles of pembrolizumab split before and after surgery.ⁱⁱ

The primary endpoint of this trial is EFS, defined as the time from randomization to the first occurrence of any of the following events: progression of disease that precludes radical cystectomy (RC) or failure to undergo RC in participants with residual disease, gross residual disease left behind at the time of surgery, local or distant recurrence based on blinded independent central review (BICR) or death due to any cause. Key secondary endpoints include OS and pCR rate.ⁱⁱⁱ

For more information on the global EV-304 trial, go to clinicaltrials.gov.

About Muscle-Invasive Bladder Cancer

Bladder cancer is the ninth most common cancer worldwide, diagnosed in more than 614,000 people each year globally, including an estimated 85,000 people in the U.S.^iii,ivMIBC represents approximately 30% of all bladder cancer cases.^vThe standard treatment for patients with MIBC is neoadjuvant cisplatin-based chemotherapy followed by surgery.^vi Even after undergoing surgery to have their bladder removed, approximately half of patients with MIBC experience disease recurrence.^vii

About PADCEV^®(enfortumab vedotin-ejfv)

PADCEV^®(enfortumab vedotin-ejfv) is a first-in-class antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer.^viii Nonclinical data suggest the anticancer activity of PADCEV is due to its binding to Nectin-4-expressing cells, followed by the internalization and release of the anti-tumor agent monomethyl auristatin E (MMAE) into the cell, which result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis).ⁱ

PADCEV plus pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph is approved for the treatment of adult patients with MIBC in the United States and for cisplatin-ineligible patients with MIBC in the European Union.

PADCEV plus pembrolizumab is also approved for the treatment of adult patients with locally advanced or metastatic urothelial cancer (la/mUC) in the United States, the European Union, Japan and a number of other countries around the world. PADCEV is also approved as a single agent for the treatment of adult patients with la/mUC who have previously received a PD-1/PD-L1 inhibitor and platinum-containing chemotherapy or are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy.ⁱ

PADCEV^® (enfortumab vedotin-ejfv) U.S. Indication & Important Safety Information

BOXED WARNING: SERIOUS SKIN REACTIONS

PADCEV (enfortumab vedotin-ejfv) can cause severe and fatal cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), which occurred predominantly during the first cycle of treatment, but may occur later.
Closely monitor patients for skin reactions.
Immediately withhold PADCEV and consider referral for specialized care for suspected SJS or TEN or severe skin reactions.
Permanently discontinue PADCEV in patients with confirmed SJS or TEN; or Grade 4 or recurrent Grade 3 skin reactions.

INDICATIONS

PADCEV, in combination with pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph, as neoadjuvant treatment and then continued after cystectomy as adjuvant treatment, is indicated for the treatment of adult patients with muscle invasive bladder cancer (MIBC).

PADCEV, in combination with pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer (la/mUC).

PADCEV, as a single agent, is indicated for the treatment of adult patients with la/mUC who:

have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and platinum-containing chemotherapy, or
are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Skin reactions Severe cutaneous adverse reactions, including fatal cases of SJS or TEN occurred in patients treated with PADCEV. SJS and TEN occurred predominantly during the first cycle of treatment but may occur later.

Skin reactions occurred in 65% (all grades) of the 570 patients treated with PADCEV in combination with intravenous pembrolizumab for the treatment of MIBC in clinical trials. The majority of the skin reactions that occurred with combination therapy included rash and maculo-papular rash. Grade 3-4 skin reactions occurred in 13% of patients (Grade 3: 12%, Grade 4: 1.1%), including maculo-papular rash, rash, SJS, dermatitis, exfoliative generalized dermatitis, toxic skin eruption, acute generalized exanthematous pustulosis, bullous dermatitis, erythema, macular rash, and pruritic rash. A fatal reaction of TEN occurred in one patient (0.2%). The median time to onset of severe skin reactions was 0.6 months (range: 0.1 to 24 months). Skin reactions led to discontinuation of PADCEV in 8% of patients. Of the patients who experienced a skin reaction and had data regarding resolution (n=367), 87% had complete resolution and 13% had residual skin reactions at their last evaluation. Of the patients with residual skin reactions at last evaluation, 31% (15/49) had Grade ≥2 skin reactions.

Skin reactions occurred in 70% (all grades) of the 564 patients treated with PADCEV in combination with intravenous pembrolizumab for the treatment of la/mUC in clinical trials. The majority of skin reactions that occurred included maculo-papular rash, macular rash, and papular rash. Grade 3-4 skin reactions occurred in 17% of patients (Grade 3: 16%, Grade 4: 1%), including maculo-papular rash, bullous dermatitis, dermatitis, exfoliative dermatitis, pemphigoid, rash, erythematous rash, macular rash, and papular rash. A fatal reaction of bullous dermatitis occurred in one patient (0.2%). The median time to onset of severe skin reactions was 1.7 months (range: 0.1 to 17.2 months). Skin reactions led to discontinuation of PADCEV in 6% of patients. Of the patients who experienced a skin reaction and had data regarding resolution (n=391), 59% had complete resolution and 41% had residual skin reactions at their last evaluation. Of the patients with residual skin reactions at last evaluation, 27% (43/159) had Grade ≥2 skin reactions.

Skin reactions occurred in 58% (all grades) of the 720 patients treated with PADCEV as a single agent in clinical trials. Twenty-three percent (23%) of patients had maculo-papular rash and 34% had pruritus. Grade 3-4 skin reactions occurred in 14% of patients, including maculo-papular rash, erythematous rash, rash or drug eruption, symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), bullous dermatitis, exfoliative dermatitis, and palmar-plantar erythrodysesthesia. The median time to onset of severe skin reactions was 0.6 months (range: 0.1 to 8 months). Among patients experiencing a skin reaction leading to dose interruption who then restarted PADCEV (n=75), 24% of patients restarting at the same dose and 24% of patients restarting at a reduced dose experienced recurrent severe skin reactions. Skin reactions led to discontinuation of PADCEV in 3.1% of patients. Of the patients who experienced a skin reaction and had data regarding resolution (n=328), 58% had complete resolution and 42% had residual skin reactions at their last evaluation. Of the patients with residual skin reactions at last evaluation, 39% (53/137) had Grade ≥2 skin reactions.

Monitor patients closely throughout treatment for skin reactions. Consider topical corticosteroids and antihistamines, as clinically indicated. For persistent or recurrent Grade 2 skin reactions, consider withholding PADCEV until Grade ≤1. Withhold PADCEV and refer for specialized care for suspected SJS, TEN or for Grade 3 skin reactions. Permanently discontinue PADCEV in patients with confirmed SJS or TEN; or Grade 4 or recurrent Grade 3 skin reactions.

Hyperglycemia and diabetic ketoacidosis (DKA), including fatal events, occurred in patients with and without preexisting diabetes mellitus, treated with PADCEV. Patients with baseline hemoglobin A1C ≥8% were excluded from clinical trials. In clinical trials of PADCEV as a single agent, 17% of the 720 patients treated with PADCEV developed hyperglycemia of any grade; 7% of patients developed Grade 3-4 hyperglycemia (Grade 3: 6.5%, Grade 4: 0.6%). Fatal events of hyperglycemia and DKA occurred in one patient each (0.1%). The incidence of Grade 3-4 hyperglycemia increased consistently in patients with higher body mass index and in patients with higher baseline A1C. The median time to onset of hyperglycemia was 0.5 months (range: 0 to 20 months). Hyperglycemia led to discontinuation of PADCEV in 0.7% of patients. Five percent (5%) of patients required initiation of insulin therapy for treatment of hyperglycemia. Of the patients who initiated insulin therapy for treatment of hyperglycemia, 66% (23/35) discontinued insulin by the time of last evaluation. Closely monitor blood glucose levels in patients with, or at risk for, diabetes mellitus or hyperglycemia. If blood glucose is elevated (>250 mg/dL), withhold PADCEV.

Pneumonitis/Interstitial lung disease (ILD) Severe, life-threatening or fatal pneumonitis/ILD occurred in patients treated with PADCEV.

When PADCEV was given in combination with intravenous pembrolizumab for the treatment of MIBC, 7% of the 570 patients treated with combination therapy had pneumonitis/ILD of any grade and 1.8% had Grade 3-4. The median time to onset of any grade pneumonitis/ILD was 3.2 months (range: 0.7 to 13 months).

When PADCEV was given in combination with intravenous pembrolizumab for the treatment of la/mUC, 10% of the 564 patients had pneumonitis/ILD of any grade and 4% had Grade 3-4. A fatal event of pneumonitis/ILD occurred in 2 patients (0.4%). The median time to onset of any grade pneumonitis/ILD was 4 months (range: 0.3 to 26 months).

In clinical trials of PADCEV as a single agent, 3% of the 720 patients treated with PADCEV had pneumonitis/ILD of any grade and 0.8% had Grade 3-4. The median time to onset of any grade pneumonitis/ILD was 2.9 months (range: 0.6 to 6 months).

Monitor patients for signs and symptoms indicative of pneumonitis/ILD such as hypoxia, cough, dyspnea or interstitial infiltrates on radiologic exams. Evaluate and exclude infectious, neoplastic and other causes for such signs and symptoms through appropriate investigations. Withhold PADCEV for patients who develop Grade 2 pneumonitis/ILD and consider dose reduction. Permanently discontinue PADCEV in all patients with Grade 3 or 4 pneumonitis/ILD.

Peripheral neuropathy (PN) When PADCEV was given in combination with intravenous pembrolizumab for the treatment of MIBC, 42% of the 570 patients treated with combination therapy had PN of any grade, 14% had Grade 2 neuropathy, and 3% had Grade 3 neuropathy. The median time to onset of Grade ≥2 PN was 4.9 months (range: 0.2 to 23 months). Of the patients who experienced neuropathy and had data regarding resolution (n=239), 41% had complete resolution, and 59% of patients had residual neuropathy at last evaluation. Of the patients with residual neuropathy at last evaluation, 30% (42/142) had Grade ≥2 neuropathy.

When PADCEV was given in combination with intravenous pembrolizumab for the treatment of la/mUC, 67% of the 564 patients had PN of any grade, 36% had Grade 2 neuropathy, and 7% had Grade 3 neuropathy. The median time to onset of Grade ≥2 PN was 6 months (range: 0.3 to 25 months). Of the patients who experienced neuropathy and had data regarding resolution (n=373), 13% had complete resolution, and 87% of patients had residual neuropathy at last evaluation. Of the patients with residual neuropathy at last evaluation, 45% (146/326) had Grade ≥2 neuropathy.

PN occurred in 53% of the 720 patients treated with PADCEV as a single agent in clinical trials including 38% with sensory neuropathy, 8% with muscular weakness, and 7% with motor neuropathy. Thirty percent of patients experienced Grade 2 reactions and 5% experienced Grade 3-4 reactions. PN occurred in patients treated with PADCEV with or without preexisting PN. The median time to onset of Grade ≥2 PN was 4.9 months (range: 0.1 to 20 months). Neuropathy led to treatment discontinuation in 6% of patients. Of the patients who experienced neuropathy who had data regarding resolution (n=296), 11% had complete resolution, and 89% had residual neuropathy at the time of their last evaluation. Of the patients with residual neuropathy at last evaluation, 50% (132/262) had Grade ≥2 neuropathy.

Monitor patients for symptoms of new or worsening PN and consider dose interruption or dose reduction of PADCEV when PN occurs. Permanently discontinue PADCEV in patients who develop Grade ≥3 PN.

Ocular disorders were reported in 40% of the 384 patients treated with PADCEV as a single agent in clinical trials in which ophthalmologic exams were scheduled. The majority of these events involved the cornea and included events associated with dry eye such as keratitis, blurred vision, increased lacrimation, conjunctivitis, limbal stem cell deficiency, and keratopathy. Dry eye symptoms occurred in 30% of patients, and blurred vision occurred in 10% of patients, during treatment with PADCEV. The median time to onset to symptomatic ocular disorder was 1.7 months (range: 0 to 30.6 months). Monitor patients for ocular disorders. Consider artificial tears for prophylaxis of dry eyes and ophthalmologic evaluation if ocular symptoms occur or do not resolve. Consider treatment with ophthalmic topical steroids, if indicated after an ophthalmic exam. Consider dose interruption or dose reduction of PADCEV for symptomatic ocular disorders.

Infusion site extravasation Skin and soft tissue reactions secondary to extravasation have been observed after administration of PADCEV. Of the 720 patients treated with PADCEV as a single agent in clinical trials, 1% of patients experienced skin and soft tissue reactions, including 0.3% who experienced Grade 3-4 reactions. Reactions may be delayed. Erythema, swelling, increased temperature, and pain worsened until 2-7 days after extravasation and resolved within 1-4 weeks of peak. Two patients (0.3%) developed extravasation reactions with secondary cellulitis, bullae, or exfoliation. Ensure adequate venous access prior to starting PADCEV and monitor for possible extravasation during administration. If extravasation occurs, stop the infusion and monitor for adverse reactions.

Embryo-fetal toxicity PADCEV can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during PADCEV treatment and for 2 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with PADCEV and for 4 months after the last dose.

ADVERSE REACTIONS

Most common adverse reactions, including laboratory abnormalities (≥20%):

PADCEV in combination with intravenous pembrolizumab for the treatment of MIBC: decreased hemoglobin, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), rash, increased creatinine, decreased lymphocytes, fatigue, pruritus, decreased sodium, PN, increased potassium, diarrhea, alopecia, dysgeusia, decreased appetite, nausea, constipation, urinary tract infection (UTI), dry eye, increased glucose, decreased weight, decreased potassium, hyperglycemia, decreased phosphate, and decreased neutrophils.
PADCEV in combination with intravenous pembrolizumab for the treatment of la/mUC: increased AST, increased creatinine, rash, increased glucose, PN, increased lipase, decreased lymphocytes, increased ALT, decreased hemoglobin, fatigue, decreased sodium, decreased phosphate, decreased albumin, pruritus, diarrhea, alopecia, decreased weight, decreased appetite, increased urate, decreased neutrophils, decreased potassium, dry eye, nausea, constipation, increased potassium, dysgeusia, UTI, and decreased platelets.
PADCEV as a single agent: increased glucose, increased AST, decreased lymphocytes, increased creatinine, rash, fatigue, PN, decreased albumin, decreased hemoglobin, alopecia, decreased appetite, decreased neutrophils, decreased sodium, increased ALT, decreased phosphate, diarrhea, nausea, pruritus, increased urate, dry eye, dysgeusia, constipation, increased lipase, decreased weight, decreased platelets, abdominal pain, and dry skin.

EV-304 Study: Patients with cisplatin-eligible MIBC (PADCEV in combination with intravenous pembrolizumab)

Neoadjuvant phase: Of a total of 403 patients, serious adverse reactions occurred in 27% of patients receiving PADCEV in combination with intravenous pembrolizumab; the most common (≥1.5%) were rash (3.2%), pneumonitis/ILD (2.2%), and diarrhea (1.7%). Fatal adverse reactions occurred in 1.7% of patients, including multiple organ dysfunction syndrome (0.5%) and COVID-19 pneumonia, cardiac arrest, pneumonia, septic shock, and urosepsis (0.2% each). Additional fatal adverse reactions were reported in 2 patients in the post-surgery phase before adjuvant treatment started, including pneumonia and sepsis (1 patient each). Adverse reactions leading

Contacts

Pfizer Contacts:
[email protected]

For Investors
[email protected]

Astellas Contacts:
[email protected]

Read full story here