NEO-BLAST: Neoadjuvant therapy for bladder cancer followed by active surveillance vs treatment.

TPS890 Background: Neoadjuvant therapy (NAT) followed by radical cystectomy (RC) is the standard of care for muscle-invasive bladder cancer (MIBC). Approximately 35-40% of patients have no residual cancer at the time of surgery, suggesting that these patients could potentially avoid definitive bladder treatments (DBT), including RC or trimodal therapy (TMT). However, the current clinical tools used to detect residual disease prior to cystectomy are inadequate. The question remains whether patients with complete response (CR) require DBT or if active surveillance (AS) could be a safe alternative. The NEO-BLAST trial investigates whether a combination of bladder MRI, circulating tumor DNA (ctDNA), urinary tumor DNA (utDNA) and transurethral bladder tumor resection (TURBT) can accurately identify MIBC patients with a clinical CR (cCR) following NAT, and whether AS is non-inferior to standard of care (SOC) in those who achieved cCR. Methods: This is a multicenter, phase II/III, non-inferiority open-label clinical trial that will randomize patients with MIBC who achieve cCR after NAT to AS versus SOC DBT, including either RC or trimodal therapy (TMT) (NCT06537154). The primary endpoint is feasibility of randomization for the phase II pilot-RCT, and metastasis-free survival (MFS) at two years for the phase III. Eligible patients will be adults with non-metastatic MIBC (≥T2, N0M0) who are candidates to SOC NAT followed by DBT as per the current practice. After enrolment, ctDNA and utDNA will be collected. Only participants who complete SOC NAT will then undergo a comprehensive clinical restaging process, including repeat ctDNA and utDNA, bladder mpMRI, urine cytology, and TURBT with template biopsies. Participants meeting criteria for cCR, defined as negative ctDNA, utDNA, MRI, and TURBT, will be randomized to either AS-arm or DBT-arm, while those without cCR will receive SOC. Participants will be monitored with cystoscopy and urine cytology (if bladder in situ) every three months for 2 years, along with ctDNA and imaging at 3, 6, 12, 18, and 24 months. The pilot-RCT will plan to enrol 72 patients, and if 25% is found to have cCR and accept to be randomized, the trial will be considered feasible. Assuming a 5% event rate at 2 years (MFS) in both groups and a type I error of 5% (1-sided), 78 per group will provide 80% power to reject the hypothesis of inferiority. We anticipate enrolling 688 patients for the phase 3 to have a total of 172 patients with cCR randomized, assuming 10% lost to follow-up. An independent Data Monitoring Committee will oversee safety and efficacy throughout the trial. Clinical trial information: NCT06537154 .

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