Drug pair beat cisplatin chemo before bladder surgery in a head-to-head trial

For patients with muscle-invasive bladder cancer who are fit enough for cisplatin — the group who have long received chemotherapy before bladder-removal surgery — a pairing of the antibody-drug conjugate enfortumab vedotin and the immunotherapy pembrolizumab beat that standard chemotherapy head to head: in the phase 3 KEYNOTE-B15/EV-304 trial, estimated event-free survival at two years was 79.4% with the drug pair against 66.2% with cisplatin-based chemotherapy [s1]. The pair also improved overall survival and cleared tumour from the removed bladder far more often, at the cost of more severe side effects [s1].

The result matters because it challenges a decades-old standard. Cisplatin-based chemotherapy before radical cystectomy — removal of the bladder and pelvic lymph nodes — has been the default for patients able to tolerate it, and it is the one setting in bladder cancer where a drug given before surgery already had proven benefit [s1]. A companion trial in patients unable to take cisplatin had already shown enfortumab vedotin and pembrolizumab sharply cutting relapse against surgery alone; the open question was whether the pair could also outdo chemotherapy in those who can take it. This trial answered it directly.

What they did

KEYNOTE-B15/EV-304 was a phase 3, open-label trial in adults with muscle-invasive bladder cancer eligible for both cisplatin and radical cystectomy [s1][s2]. It assigned 405 participants to perioperative enfortumab vedotin and pembrolizumab and 403 to neoadjuvant cisplatin–gemcitabine [s1]. In the drug-pair group, patients received four cycles of enfortumab vedotin (1.25 mg per kilogram on days 1 and 8) with pembrolizumab (200 mg on day 1) every three weeks before surgery, then five cycles of enfortumab vedotin and 13 cycles of pembrolizumab afterward [s1]. The chemotherapy group received four cycles of cisplatin (70 mg per square metre on day 1) plus gemcitabine (1000 mg per square metre on days 1 and 8) every three weeks before surgery [s1]. The primary endpoint was event-free survival; overall survival and pathological complete response — no viable tumour in the removed tissue — were key secondary endpoints [s1].

What it showed

At a median of 33.6 months from randomisation to the data cutoff, event-free survival at two years was 79.4% with enfortumab vedotin and pembrolizumab against 66.2% with cisplatin–gemcitabine, a hazard ratio for an event or death of 0.53 (95% confidence interval, 0.41 to 0.70; P<0.001) [s1]. Overall survival followed: estimated two-year survival was 86.9% versus 81.3%, a hazard ratio for death of 0.65 (95% confidence interval, 0.48 to 0.89; two-sided P=0.006) [s1]. A pathological complete response occurred in 55.8% of the drug-pair group against 32.5% of the chemotherapy group (P<0.001) [s1]. Similar proportions reached surgery — 86.7% in the drug-pair group and 89.6% in the chemotherapy group — so the newer regimen did not, on the whole, cost patients their operation [s1].

The cost side

The stronger result came with more toxicity. Grade 3 or higher adverse events of any cause occurred in 75.7% of the enfortumab vedotin–pembrolizumab group against 67.2% of the chemotherapy group [s1]. Both drugs in the pair carry recognised risks — skin, nerve and blood-sugar effects for the conjugate, immune-mediated inflammation for the checkpoint inhibitor — so the higher rate is not a surprise, but it is a real part of the ledger a patient and doctor weigh.

What to watch

The trial was funded by a maker of pembrolizumab and was open-label, so patients and doctors knew the assignment [s1]. With that caveat, a regimen that beats cisplatin-based chemotherapy on both relapse and survival, in the very patients for whom that chemotherapy was the established standard, is a landmark rather than an incremental gain — and it points to a future in which cisplatin's long primacy before bladder surgery may narrow. Whether regulators broaden the perioperative indication to cisplatin-eligible patients, and how the curves hold with longer follow-up, are the questions ahead. The finding also sits alongside the older reality that most bladder cancers are found only once symptoms such as blood in the urine appear, by which point many are already muscle-invasive.

Sources

• [s1] Galsky MD, Valderrama BP, Maruzzo M, et al. Enfortumab Vedotin and Pembrolizumab in Cisplatin-Eligible Bladder Cancer. New England Journal of Medicine. 22 July 2026.
• [s2] ClinicalTrials.gov. Perioperative Enfortumab Vedotin Plus Pembrolizumab Versus Chemotherapy in Muscle-Invasive Bladder Cancer (KEYNOTE-B15/EV-304, NCT04700124). U.S. National Library of Medicine.