FOR DECADES, patients with advanced urothelial cancer—a type of bladder cancer that begins in the cells that line the bladder—received platinum-based chemotherapy as the standard of care. However, in December 2023, the Food and Drug Administration approved a new drug combination that may provide significantly better survival outcomes.

In fact, patients with advanced urothelial cancer treated with the combination of Padcev (enfortumab vedotin) plus the immunotherapy drug Keytruda (pembrolizumab) had survival durations nearly double those seen among people treated with traditional chemotherapy, according to the EV-302 study published March 7, 2024, in the New England Journal of Medicine.

In the study, 886 patients with locally advanced or metastatic urothelial cancer received either Padcev plus Keytruda or standard platinum-based chemotherapy. Tumors shrank in 68% of participants assigned to the new combination compared with 44% of those who received chemotherapy. The cancer completely disappeared—known as a complete response—in nearly 30% of patients treated with the combination compared with 12.5% of those given chemotherapy.

Progression-free survival—the time a patient lives with the disease where it does not get worse—was about twice as long in people given the combination—a median of 12.5 months compared with 6.3 months for those treated with chemotherapy. Overall survival was also about twice as long with Padcev plus Keytruda—a median of 31.5 months compared with about 16 months for chemotherapy.

“Chemotherapy for advanced urothelial cancer has worked relatively well, especially at the beginning of treatment, making it a very difficult treatment to beat,” says Michiel S. Van der Heijden, a medical oncologist at the Netherlands Cancer Institute in Amsterdam and an author of the study. “With [Padcev/Keytruda], though, patients are doing quite well over a longer period of time, and further follow-up will show just what the long-term survival is for this treatment.”

More people with urothelial cancer may be able to benefit from Padcev plus Keytruda than can benefit from platinum-based chemotherapy, explains Parminder Singh, a medical oncologist with Mayo Clinic in Phoenix, who was not involved with this study.

The average age of people diagnosed with bladder cancer is 73 years, and many of these older patients cannot tolerate aggressive chemotherapy combinations, Singh says. When deciding whether to assign patients for cisplatin-based treatments, doctors must consider their age, kidney function and heart health, as well as their performance status—a measure of how well a person can perform ordinary tasks and daily activities.

“We know historically that about one-quarter of patients [with advanced disease] would not be suitable for any form of combination chemotherapy at the outset,” says Singh. “Within the 75% of remaining patients, only about half would be able to tolerate a cisplatin-based regimen; the other half would receive alternative regimens that are much inferior to cisplatin-based combinations.”

Singh says the results of the EV-302 trial upended the existing treatment paradigm. “[Padcev with Keytruda] opens up the possibility for those 6 out of 10 patients who would not otherwise be eligible for cisplatin-based chemotherapy to now get [Padcev/Keytruda],” if doctors can manage the side effects, Singh says.

Padcev is a type of treatment called an antibody-drug conjugate (ADC). ADCs work by targeting a specific protein or receptor on the surface of a cancer cell and delivering a drug, typically a chemotherapy, directly to that cancer cell. This design allows the drug to destroy cancer cells while limiting harm to other cells in the body.

“The side effects with [Padcev plus Keytruda] are certainly different than traditional chemotherapy though, and the treating physician should explain them and monitor patients closely, especially at the beginning of treatment,” Van der Heijden says.

People treated with the new combination may experience skin reactions like rash, increased blood glucose levels or peripheral neuropathy, a type of nerve damage. The combination can have different effects on people with certain health conditions, including people who have a history of autoimmune disease or have uncontrolled diabetes, which should be discussed with one’s medical team.

“A patient receiving these medicines should also talk to their doctor regarding existing nerve problems or problems with their gait or balance,” Singh says. For example, at his practice in Arizona where the ground can get quite hot, Singh advises patients to always wear shoes or socks when walking outside.

Singh says because this combination is new, it is still making its way to individual practices. Patients being treated in the community should ask their physicians if they are eligible.