The combination of Padcev and Keytruda has once again delivered strong results, this time significantly improving overall survival (OS) for patients with cisplatin-eligible muscle-invasive bladder cancer (MIBC). Yet questions remain about its impact on practice due to a changing treatment landscape.
Results from the Keynote-B15 (EV-304) trial showed a major 47% reduction in patients’ risk of tumor recurrence, disease worsening or death for the Padcev-Keytruda combination compared with neoadjuvant cisplatin-based chemotherapy alone.
Presented at the American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, the data also showed that using Padcev and Keytruda both before and after surgical removal of patients’ bladders lowered their risk of death by 35% compared with presurgical chemotherapy.
The statistically significant OS number was gleaned during an interim analysis, when the majority of patients in both arms were still alive, study presenter Matthew Galsky, M.D., from the Mount Sinai Tisch Cancer Center, told reporters during a press briefing. As of a data cutoff on Oct. 27, 2025, 83% of patients in the perioperative combo arm, versus 75.4% of those in the control arm, were alive.
“The Keynote-B15 study marks an exciting development in establishing a potential new treatment option and standard of care for these patients,” Kevin Kelly, an ASCO expert in genitourinary cancer from Thomas Jefferson University, said in a statement.
Merck & Co. sponsored the study and offered Keytruda, while Pfizer and Astellas contributed Padcev, an antibody-drug conjugate.
The trial win in cisplatin-eligible patients with MIBC follows a similarly positive readout from the Keynote-905 (EV-303) study, which showed the Padcev-Keytruda combo can improve survival in cisplatin-ineligible patients, leading to a groundbreaking FDA approval in November 2025.
However, unlike the conclusiveness of the combo’s prowess in that previous trial, the latest triumph comes with some questions as the treatment landscape in bladder cancer has gotten more complicated—both in early-stage and metastatic settings—since the Keynote-B15 study started in 2021. By Galsky’s estimate, eligibility for cisplatin divides MIBC patients roughly 50-50.
Among the uncertainties, clinicians are left wondering whether the trial’s neoadjuvant chemo-only control arm remains a relevant comparator. As Kelly noted, the study’s control arm lacked an adjuvant therapy.
In August 2021, merely four months after Keynote-B15’s launch, the FDA approved Bristol Myers Squibb’s Opdivo for the adjuvant treatment of bladder cancer patients who are at high risk of recurrence after undergoing radical resection.
More recently, the FDA last year blessed AstraZeneca’s Imfinzi as perioperative regimen in MIBC.
Opdivo adjuvant therapy has not shown an OS benefit in bladder cancer, Galsky, who’s also the lead author of the CheckMate-274 trial that supported Opdivo’s adjuvant nod, noted during the press briefing. Last year, Galsky presented updated long-term follow-up data from the BMS trial. While OS data remained immature, adjuvant Opdivo was linked to a favorable trend toward a 27% death-risk reduction versus placebo in MIBC patients.
Besides, Opdivo’s indication only covers a subset of patients at high risk of recurrence after surgery, he pointed out.
As for Imfinzi, Galsky cautioned against making a cross-trial comparison, but he still pointed to some differences in the two regimens’ effect sizes. For example, on the secondary endpoint of rate of pathological complete response (pCR), which measures the absence of cancer in the resected tumor tissues, the Padcev-Keytruda cocktail reached 55.8%, versus 32.5% for the control arm in the current Keynote-B15 trial. In the Niagra trial, the Imfinzi regimen recorded a 33.8% pCR rate, versus 25.8% in the comparison group.
The Niagra perioperative regimen was the first immunotherapy to deliver a survival win against cisplatin chemo for MIBC patients, showing a death-risk reduction of 25%. The regimen includes Imfinzi and cisplatin-based chemo before surgery followed by Imfinzi alone post-surgery. The Padcev-Keytruda combo foregoes any systemic chemo, leading to fewer hematological toxicities such as neutropenia, anemia and thrombocytopenia despite higher rates of skin reactions, diarrhea and hair loss, according to the Keynote-B15 results.
To further complicate clinicians’ treatment decisions, Padcev-Keytruda has become the new standard of care in first-line metastatic bladder cancer, raising the possibility that some physicians might reserve the combo as an option for patients who eventually progress rather than using it upfront in early-stage MIBC.
Despite this reluctance, it’s better to give patients the best treatment upfront, which improves long-term outcomes, Catherine Pietanza, M.D., vice president of global clinical development at Merck Research Laboratories, argued.
Patients who receive Padcev-Keytruda as a perioperative treatment for MIBC would have to look for a different regimen if their cancer progresses to advanced disease, she acknowledged in an interview with Fierce Pharma. But that won’t be problem for all bladder cancer patients considering the PD-1/ADC combo, because only about 25% of bladder cancer patients are diagnosed at the MIBC stage, whereas the majority are first diagnosed with metastatic disease.
“Having [Padcev-Keytruda] treatments in both the perioperative setting and the first-line setting allows patients to have both available to them, whether they are diagnosed in early-stage or in the metastatic setting,” Pietanza said.
In another potential advantage over AZ’s Niagra regimen, as Pietanza noted, the twin triumphs of Keynote-905 and now Keynote-B15 mean that the combo, if approved in cisplatin-eligible patients, would simplify treatment for doctors as they wouldn’t have to think about whether a patient is eligible for cisplatin.
There’s also the perennial question of whether all patients need treatment both before and after surgery. Galsky acknowledged that the field doesn’t have an answer to this because researchers have only recently started to think about treatment de-escalation. He raised circulating tumor DNA as a powerful tool that may be incorporated in future trials to identify patients for personalized treatment escalation.