The combination therapy of Padcev (enfortumab vedotin), an antibody-drug conjugate (ADC), and Keytruda (pembrolizumab), an anti-PD-1 immunotherapy, has set a new standard for first-line treatment of metastatic urothelial carcinoma (mUC), a cancer that had seen stagnant progress for decades, experts said.

At a press conference on Thursday marking the expanded indication of Padcev for mUC, Park In-keun, Clinical Associate Professor in the Department of Oncology at Asan Medical Center, said that this new regimen offers an overall survival (OS) of 31.5 months. “It is unlikely that the first-line treatment landscape will change soon."

For 30 years, platinum-based chemotherapy, including cisplatin and carboplatin, was the standard treatment for mUC. The five-year survival rate for this severe cancer of the urinary tract is just 11 percent, with very few exceeding this statistic.

“In many instances, the disease progresses rapidly, creating a challenging scenario for both patients and healthcare providers,” Professor Park said.

Platinum-based regimens initially offer response rates of 50 to 70 percent but effectiveness wanes due to drug resistance and severe side effects, leading to progression-free survival of just six to eight months before alternative treatments are needed.

No treatment has yet surpassed platinum-based chemotherapy in improving overall survival for patients with previously untreated locally advanced or mUC. While immune checkpoint inhibitors have broadened treatment options since their introduction in 2010, the combination of Padcev with Keytruda represents a major advancement.

“Padcev, in combination therapy, is the first to show superior survival benefits over platinum-based chemotherapy,” said Professor Park. “It is set to become the new standard of care for advanced urothelial carcinoma.”

Padcev, developed by Astellas and Seagen, was first approved in July 2023 for mUC after other treatments failed. This July, it gained expanded approval from the Korean Ministry of Food and Drug Safety (MFDS) for use with MSD Korea's Keytruda as a first-line therapy.

The EV-302 trial, a global phase 3 study, compared the new combination therapy with platinum-based chemotherapy in patients with untreated locally advanced or mUC. The trial showed a median OS of 31.5 months with Padcev and Keytruda, nearly doubling the 16.1 months observed with traditional chemotherapy and representing a 53 percent reduction in the risk of death.

Progression-free survival (PFS) median was 12.5 months for the combination therapy, versus 6.3 months for platinum-based treatments, a 55 percent improvement. 

“Padcev combined with Keytruda has more than doubled the complete response rate compared to traditional platinum-based chemotherapy, enhancing the potential for cures,” said Park Kyung-ah, Director of Medical Affairs at Astellas' Oncology Team.

Safety data revealed no new adverse events beyond those previously documented for each drug. However, 97 percent of patients on the combination therapy experienced treatment-related adverse events, slightly more than the 95 percent with chemotherapy. 

Padcev targets nectin-4, a tumor-associated antigen on most urothelial carcinoma cells, delivering the potent cytotoxic agent monomethyl auristatin E (MMAE) directly into these cells. MMAE disrupts cell division, leading to cancer cell death. Enfortumab vedotin links a human anti-nectin-4 antibody to MMAE.

When paired with pembrolizumab, a monoclonal antibody that blocks the PD-1 receptor, Padcev's efficacy is boosted. This combination not only enhances cell death but also amplifies the immune response, helping to prevent cancer cells from evading detection.

Padcev is now approved for all patients with locally advanced or mUC, eliminating the need for prior nectin-4 screening.