Bladder Cancer Treatment Before and After Surgery Rewritten: Keytruda and Padcev Combination Gains Muscle-Invasive Indication

For patients with muscle-invasive bladder cancer, surgery is often not a single event, but the core of a long treatment pathway. When a tumor has invaded the bladder muscle layer, radical cystectomy may be a key option; however, not every patient can tolerate traditional cisplatin chemotherapy. The U.S. FDA approval of pembrolizumab in combination with enfortumab vedotin-ejfv for treatment before and after surgery in certain patients is precisely aimed at filling this clinical gap.

This indication covers adult patients with muscle-invasive bladder cancer who are unable to receive cisplatin treatment, and the treatment design is linked to radical cystectomy: pembrolizumab and enfortumab vedotin-ejfv are given before surgery, followed by adjuvant treatment after surgery. The FDA approval page shows a content date of November 21, 2025; pharmacy media recently organized and reported on it again, bringing this approval back into clinical discussion.

The two drugs represent different anticancer strategies. Pembrolizumab is a PD-1 immune checkpoint inhibitor, intended to release the tumor’s suppression of the immune response; enfortumab vedotin is an antibody-drug conjugate targeting Nectin-4, delivering a cytotoxic drug to cancer cells expressing that target. The rationale for using them together is to increase immune recognition and attack on one side, while delivering a cell-killing signal in a more precise way on the other.

The approval is mainly based on the KEYNOTE-905/EV-303 trial. This was an open-label, randomized, multicenter study that enrolled 344 patients who had not previously received treatment, were eligible for radical cystectomy and pelvic lymph node dissection, but were ineligible for or declined cisplatin chemotherapy. Compared with immediate surgery, patients receiving the preoperative and postoperative combination treatment achieved statistically significant improvements in both event-free survival and overall survival; data released by the FDA showed a hazard ratio of 0.40 for event-free survival and a hazard ratio of 0.50 for overall survival.

The significance of these figures lies not only in delaying recurrence, but also in moving the timing of treatment earlier. In the past, discussion of antibody-drug conjugates and immunotherapy in urothelial cancer was mostly concentrated on locally advanced or metastatic disease; now that they have been placed into perioperative treatment, it means physicians are trying to reduce the chance that residual microscopic disease in the body will flare up again while the disease is still visibly resectable.

However, this is not an approval that can be simplified into a “chemotherapy-free alternative.” Enfortumab vedotin is known to potentially cause skin reactions, hyperglycemia, peripheral neuropathy, eye problems, and risks of pneumonitis or interstitial lung disease; pembrolizumab may also trigger immune-related adverse reactions. For patients who are already unsuitable for cisplatin because of age, kidney function, or comorbidities, how to balance treatment intensity, the preoperative timeline, and postoperative recovery will be the most nuanced and difficult part of real-world implementation.

What can currently be confirmed is that this approval adds a perioperative pathway supported by a randomized trial for patients with cisplatin-ineligible muscle-invasive bladder cancer. It does not remove the importance of surgery, nor does it mean that all patients are suitable for the same combination; it is more like pushing bladder cancer treatment from a single-point intervention toward a more continuous strategy: lowering tumor risk before the knife, pursuing residual disease after the knife, while taking on more complex safety management.