FDA Approves Keytruda and Padcev for Muscle Invasive Bladder Cancer

The U.S. Food and Drug Administration approved Keytruda (pembrolizumab) or Keytruda Qlex (pembrolizumab and berahyaluronidase alfa-pmph) with Padcev (enfortumab vedotin-ejfv) as neoadjuvant treatment followed by adjuvant treatment after cystectomy for adults with muscle invasive bladder cancer who are ineligible for cisplatin.

The approval was based off trial results from the KEYNOTE-905/EV-303 study.

Median event-free survival was not reached with Keytruda, Padcev and surgery and was 15.7 months with radical cystectomy and lymph node removal alone. Median overall survival was not reached with Keytruda, Padcev and surgery and was 41.7 months with radical cystectomy and lymph node removal alone.

The overall safety of Padcev with Keytruda was similar to what has been seen in earlier studies in advanced urothelial cancer. Keytruda carries warnings for immune-related side effects, infusion reactions, complications of stem cell transplantation and risks to a developing fetus. Padcev carries warnings for skin reactions, high blood sugar, lung inflammation, nerve damage, eye problems, infusion site issues and risks to a developing fetus.

KEYNOTE-905/EV-303 was an open-label, randomized, multicenter trial in 344 patients who were candidates for radical cystectomy with pelvic lymph node removal but were unable or unwilling to receive cisplatin chemotherapy. Patients were assigned to receive either neoadjuvant Keytruda and Padcev before surgery followed by adjuvant therapy with the same drugs, or immediate surgery alone. Event-free survival was the main goal, and overall survival was also evaluated. The study showed significant improvements in both outcomes for patients treated with the drug combination compared with surgery alone.

The recommended neoadjuvant dose is Keytruda 200 milligrams (mg) intravenously (IV) every three weeks with Padcev 1.25 mg per kilogram (mg/kg) IV, up to 125 mg for patients whose weight is 100 kg or more, on days 1 and 8 for three cycles, totaling nine weeks. In the adjuvant phase, Padcev continues for six cycles with Keytruda, given as 200 mg IV every three weeks for 14 cycles or 400 mg IV every six weeks for seven cycles. The combination lasts 18 weeks, and total adjuvant therapy, including Keytruda alone, is 42 weeks. Keytruda should be given after Padcev when both are given the same day.

How We Got Here

The FDA approved Padcev and Keytruda for patients with locally advanced or metastatic bladder cancer in December 2023, less than a year after granting the combination accelerated approval for patients who could not receive cisplatin-based chemotherapy.

Padcev first received accelerated approval in 2019 for patients with locally advanced or metastatic urothelial cancer who had received a PD-1 or PD-L1 inhibitor and platinum chemotherapy in the postsurgical or metastatic setting.

It received full approval in 2021 for patients who had received a PD-1 or PD-L1 inhibitor and platinum chemotherapy or were ineligible for cisplatin and had at least one prior therapy.

How Does Padcev Work to Treat Bladder Cancer?

“[Padcev] really made an evolution, if you will, in the urothelial or bladder cancer world,” Dr. Yousef Zakharia, co-leader of the Genitourinary Oncology Program at the University of Iowa in Iowa City, told CURE in an interview last year.

“It is an antibody that is directed toward certain receptors on the cancer cells,” he says. “In bladder cancer more specifically, we have NECTIN4 and TROP2. Both of them have antibody-drug conjugates manufactured toward those and are specific toward those receptors. And basically, this antibody is attached to a payload, which is a very effective chemotherapy.”

Zakharia continued, “And the way it works [is that] it takes that chemotherapy, carries it directly to the cancer cells, and it gets internalized within the cancer cells. And basically, that payload or chemotherapy gets integrated within the microtubules and starts disrupting the cell growth, and that results in cell killing. In other words, it is basically carrying the cytotoxic material directly and specifically to the cancer cells with the hope to save the normal cells from the toxic side effects associated with that if they do not have that specific receptor expressed.”

Reference

1. “FDA approves pembrolizumab with enfortumab vedotin-ejfv for muscle invasive bladder cancer.” FDA. Nov. 21, 2025.

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