Bladder Cancer Treatment Takes Key Steps Forward

Two practice-changing studies are providing clinicians with data to better inform decisions for treating various populations with muscle-invasive bladder cancer.

First treatment in decades for frail patients who are ineligible for platinum chemotherapy

Enfortumab vedotin (EV) plus pembrolizumab (pembro) administered perioperatively in cisplatin-ineligible patients with muscle-invasive bladder cancer resulted in a significant improvement in disease-free survival, along with unprecedented pathologic complete responses (pCR). In a phase 3 study, the combination therapy is the first to show demonstrable efficacy for patients not eligible for cisplatin-based chemotherapy or who decline the treatment.

“Previously in bladder cancer, the best pathologic responses were 30-40% with gemcitabine cisplatin,” explains lead principal investigator Shilpa Gupta, MD, genitourinary oncologist at Cleveland Clinic Cancer Institute and Professor of Medicine at Cleveland Clinic Lerner College of Medicine at Case Comprehensive Cancer Center. “With EV/Pembro, those numbers jumped to 57%, which is remarkable, especially in this patient population.”

Background

“We already knew that there was a survival benefit for cisplatin-based neoadjuvant chemotherapy, followed by surgery, but over half of patients aren’t candidates for cisplatin,” explains Dr. Gupta.

Patients with kidney or cardiac issues, neuropathy, hearing issues or poor ECOG status cannot take cisplatin. Bladder cancer patients have a median age of 71 years, and many have these comorbidities. Thus, treating these patients has historically been a challenge. Since the alternative, carboplatin, was not effective, patients in this situation typically received surgery alone. Disease burden was high and recurrence tended to occur quickly. Thus, there was a large unmet need for treating this population.

Study design

Of the patients enrolled in the study, 46% were 75 years of age or older and 82% had T3/T4 and N1 disease.

Patients were randomized to receive EV/pembro (three cycles of EV 1.26 mg/kg on days 1 and 8 and pembro 200 mg on day 1), followed by radical cystectomy and pelvic lymph node dissection, and then six cycles of EV and 14 cycles of pembro. Patients in the control arm were treated with radical cystectomy and pelvic lymph node dissection alone. One hundred seventy patients were randomized to the EV/pembro arm and 174 patients to the control arm. Median follow-up was 25.6 months.

Study outcomes

Patients in the EV/pembro arm experienced significant improvements. Event-free survival was 15.7 months in the control arm and was not reached in the EV/pembro arm. Overall survival was 41.7 months in the control arm and was not reached in the EV/pembro arm.

In the control arm, pCR rates were 8.6%, compared to 57.1% in the EV/pembro arm.

“What is notable is the remarkable event-free survival and overall survival benefit and the pathologic complete response rates despite many patients having a high stage of disease, including some that were node positive,” says Dr. Gupta. “This study is significant because we now have effective treatment for frail patients.” Based in part on this study, EV/pembro received FDA approval in December 2025 and is now the new standard of care in this setting.

Only 67% of patients in the EV/pembro arm received the six cycles of adjuvant EV/pembro, either due to physician preferences or due to struggles recovering from surgery. Despite this, patients still benefited from the combination therapy.

The primary adverse events were rash and neuropathy. In the EV/pembro arm, 71.3% of patients experienced grade 3 or higher treatment-related side effects, compared to 45.9% in the control arm. It is crucial to monitor for toxicity and dose reduce/discontinue promptly. "Despite only around two thirds of patients receiving adjuvant therapy, we saw a tremendous benefit," says Dr. Gupta.

Future studies should focus on treatment de-escalation, using tools like circulating tumor DNA (CtDNA) and efforts for bladder preservation in those attaining clinical complete response.

First study to show role of circulating tumor DNA in informing adjuvant treatment decisions

Circulating tumor DNA (ctDNA)–based detection of molecular residual disease may identify patients at high risk for recurrence after cystectomy who can benefit from adjuvant immunotherapy, thus sparing patients at lower risk from unnecessary treatment burden. In the phase 3 ImVigor011 trial, investigators monitored patients for up to a year after surgery via ctDNA testing. Those who tested ctDNA-positive during that time received atezolizumab administered intravenously or placebo every four weeks for one year.

Study design

In this study, 761 patients were enrolled, of which 250 patients tested ctDNA-positive. Of those, 167 were randomized to the atezolizumab arm and 83 to the placebo arm.

Study outcomes

The median disease-free survival was improved in patients receiving atezolizumab, at 9.9 months compared to 4.8 months in the placebo arm. The median overall survival was 32.8 in the atezolizumab arm compared to 21.1 months in the placebo arm. Of those patients who remained ctDNA-negative, disease-free survival was 88% at two years. The study outcomes were published in the New England Journal of Medicine.

“Looking forward, this data will help us optimize who will benefit from treatment and spare unnecessary toxicity and financial burden for patients who don’t need treatment,” says Dr. Gupta.