Key Ideas

Two changes are reshaping how muscle-invasive bladder cancer is treated around the time of surgery. A combination of pembrolizumab and enfortumab vedotin, given before and after radical cystectomy, has replaced platinum-based chemotherapy as an option for eligible patients. Separately, a blood test for circulating tumor DNA can now identify which patients benefit most from immunotherapy after surgery, sparing others unnecessary treatment.

A New Standard Before Cystectomy

For more than two decades, cisplatin-based chemotherapy followed by radical cystectomy has been the standard approach to muscle-invasive bladder cancer (MIBC), a disease that still carries a recurrence risk exceeding 50 percent despite curative-intent surgery. That standard shifted this year. On July 10, 2026, the FDA approved enfortumab vedotin plus pembrolizumab, an antibody-drug conjugate directed at Nectin-4, as perioperative treatment for adults with MIBC who are candidates for cystectomy, regardless of cisplatin eligibility.

The approval rests on the phase 3 KEYNOTE-B15/EV-304 trial, which enrolled 808 patients with previously untreated, cisplatin-eligible MIBC. Patients received four cycles of neoadjuvant enfortumab vedotin plus pembrolizumab before cystectomy, then continued the combination after surgery before completing roughly a year of pembrolizumab alone; the comparison arm received standard neoadjuvant gemcitabine and cisplatin. Median event-free survival was not reached with the new combination versus 48.5 months with chemotherapy, a 47 percent reduction in the risk of recurrence, progression, or death (hazard ratio, 0.53; P<.0001). Overall survival also favored the combination (hazard ratio, 0.65), and pathologic complete response rose to 55.8 percent from 32.5 percent with chemotherapy. The majority of patients enrolled had T3 or T4 disease, and benefit did not appear to depend on PD-L1 expression status.

Letting a Blood Test Guide Who Needs Treatment After Surgery

A second shift addresses a different question: among patients who have already had surgery and show no visible disease, who actually needs adjuvant immunotherapy? Earlier trials of adjuvant checkpoint inhibition in unselected bladder cancer patients had mixed results, in part because most patients who undergo cystectomy will never recur, making unselected treatment a poor trade-off between benefit and toxicity.

The phase 3 IMvigor011 trial addressed this by using serial circulating tumor DNA (ctDNA) testing after cystectomy to identify patients with detectable molecular residual disease, testing blood every six weeks for up to a year. Patients who tested ctDNA-positive were randomized to adjuvant atezolizumab or placebo; those who remained persistently ctDNA-negative were followed with surveillance alone rather than being randomized to treatment. Among ctDNA-positive patients, atezolizumab reduced the risk of recurrence or death by 36 percent and reduced the risk of death by 41 percent compared with placebo. Just as notably, patients who tested ctDNA-negative throughout the surveillance period had a favorable prognosis without any additional treatment, with disease-free and overall survival rates exceeding 88 and 97 percent at two years. This is the first prospective, randomized trial to demonstrate that a positive ctDNA result can be used to select patients for treatment, rather than simply serving as a prognostic marker after the fact.

Why Both Advances Matter Together

Taken together, these two developments move bladder cancer treatment in a more individualized direction on both ends of the surgical timeline: a more effective, chemotherapy-sparing option before and immediately after cystectomy, and a molecular test that can identify, among patients who look disease-free, which ones are most likely to benefit from further treatment and which can safely avoid it. Ongoing research is now asking whether ctDNA can also help guide bladder-preserving strategies and further tailor how aggressively different patients are treated.

For Patients

If you or a loved one is facing surgery for muscle-invasive bladder cancer, two things are worth discussing with your care team. First, a newer drug combination, enfortumab vedotin plus pembrolizumab, given before and after bladder removal surgery, has been shown to lower the chance of the cancer coming back and to extend survival compared with standard chemotherapy, and as of July 2026 it's approved for use regardless of whether you're a candidate for cisplatin-based chemotherapy.

Second, if you've already had surgery and there's no visible sign of cancer on scans, ask whether ctDNA testing (a blood test that can detect traces of cancer DNA circulating in the bloodstream) is appropriate for you. This test, done periodically for up to a year after surgery, can help identify whether additional treatment with immunotherapy is likely to help. Encouragingly, patients who test negative on this assay throughout follow-up have a very good prognosis without further treatment, which means this approach can spare many people from side effects of treatment they don't need while directing it to those who stand to benefit most.

Key Takeaways

  • The FDA approved enfortumab vedotin plus pembrolizumab as perioperative treatment for muscle-invasive bladder cancer on July 10, 2026, for all patients eligible for cystectomy, regardless of cisplatin eligibility.

  • In the phase 3 EV-304/KEYNOTE-B15 trial, the combination reduced the risk of recurrence, progression, or death by 47 percent compared with standard chemotherapy, with a higher rate of pathologic complete response.

  • The phase 3 IMvigor011 trial showed that circulating tumor DNA testing after cystectomy can identify patients who benefit from adjuvant atezolizumab, reducing recurrence risk by 36 percent in ctDNA-positive patients.

  • Patients who test ctDNA-negative throughout the first year after surgery have a favorable prognosis without additional treatment, allowing many patients to avoid unnecessary therapy.

  • Together, these advances support a more individualized approach to treatment timing and selection in muscle-invasive bladder cancer.

References

  1. Vulsteke C, Kaimakliotis HZ, Danchaivijitr P, et al. Perioperative enfortumab vedotin plus pembrolizumab in participants with muscle-invasive bladder cancer (KEYNOTE-B15/EV-304). Presented at 2026 ASCO Genitourinary Cancers Symposium; published in the New England Journal of Medicine, 2026.

  2. U.S. Food and Drug Administration. FDA approves pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph, each with enfortumab vedotin-ejfv, for muscle-invasive bladder cancer. July 10, 2026.

  3. Powles T, Kann AG, Castellano D, et al. IMvigor011: ctDNA-guided adjuvant atezolizumab versus placebo in muscle-invasive bladder cancer. Presented at ESMO Congress 2025; published in the New England Journal of Medicine, 2025.

  4. Cold KM, Vásquez JL. Perioperative enfortumab vedotin and pembrolizumab in bladder cancer. New England Journal of Medicine, 2026.