Oncology drug development is no longer a singles market as pharmaceutical companies increasingly rely on combination therapies to boost cancer-fighting power and overcome drug resistance. One power couple, the Keytruda and Padcev combination from Merck & Co. and Pfizer/Astellas Pharma, has distinguished itself amid the crowd.
The duo has significantly improved survival compared to chemotherapy in bladder cancer, where it notched two FDA approvals with additional indications in sight.
Most recently, a phase 3 trial showed that the PD-1 inhibitor and antibody drug conjugate combination nearly halved the risk of tumor recurrence, progression and death compared with standard chemotherapy in patients with muscle-invasive bladder cancer. More than 79% of patients were event-free at two years, compared with just over 66% in the chemotherapy group.
It still remains to be seen, however, whether this couple’s chemistry will endure in other types of cancer.
Two is better than one
On their own, Keytruda and Padcev have made their mark in many areas of oncology.
Merck’s checkpoint inhibitor Keytruda, which until recently was the top-selling drug in the world, is approved to treat around 40 types of cancer. Although the drug’s blockbuster sales are expected to peak at $32.7 billion this year, Keytruda will start losing market exclusivity in a few years and face biosimilar competition.
While Keytruda has seen enviable success, only an estimated 20% to 30% of patients benefit from the treatment as a monotherapy. Keytruda also came up short as a first-line therapy in bladder cancer, failing to beat chemotherapy in overall and progression-free survival. Although it improved disease-free survival, it didn’t increase overall survival compared with standard chemotherapy, according to an analysis published by the journal Cancers.
Padcev earned an approval in bladder cancer but generated modest outcomes when used alone to treat patients with the most common type of the disease. Approximately 44% of patients responded to the ADC and the drug’s effects lasted a median of 7.6 months, according to Cancers.
Together, though, the two drugs have overcome some of these shortcomings.
Targeting nectin-4
Trials are now exploring whether the efficacy gains seen when pairing Keytruda and Padcev in bladder cancer can carry over into new indications. The combination has potential because Padcev is designed to precisely target nectin-4 positive tumor cells, which are common not only in bladder cancer, but also in other types including gastroesophageal, prostate, breast, lung, pancreatic and ovarian cancer.
Early signs point to the drug combination working outside of the bladder. In October 2025, Astellas released new favorable phase 2 trial results from a trial using Padcev as a first-line add-on therapy to Keytruda in patients with PD-L1 positive head and neck cancer. More than 80% of these cancers are nectin-4 positive. Of the 41 patients in the trial, 16 responded to the treatment, including four patients who had a complete response. Fifteen patients also saw their disease stabilize during the trial, adding up to a “disease control rate” of over 75%.
Astellas is also testing Padcev alone and in combination with Keytruda in solid tumors.
While the Padcev-Keytruda combination is rapidly becoming the standard of care in bladder cancer, it will need to clear several hurdles to successfully broaden into new indications. This includes determining which patients are most likely to benefit from the combination in an increasingly biomarker-driven market. To cement a marriage with staying power, they will also need to confirm their ability to overcome drug resistance and their safety profile.
