Patients with extensive transurethrally unresectable very-high-risk non-muscle-invasive bladder cancer (NMIBC) may achieve a tumor-free status after systemic immunotherapy-based bladder-sparing treatment combined with transurethral resection of bladder tumor (TURBT). However, the optimal duration of systemic immunotherapy after achieving a tumor-free status remains uncertain. Prolonged treatment may increase toxicity, treatment burden, and cost, while some patients may maintain durable disease control without continued therapy.
This randomized study aims to evaluate whether active surveillance after achieving tumor-free status is a feasible alternative to continued systemic immunotherapy in patients with extensive transurethrally unresectable very-high-risk NMIBC.
Patients will initially receive systemic immunotherapy-based treatment followed by disease evaluation using cystoscopy with biopsy and/or TURBT, urine cytology, urinary tumor DNA (utDNA), and imaging assessments. Patients who achieve tumor-free status after treatment and complete resection of visible disease will be randomized to either active surveillance or continued systemic immunotherapy.
The study will evaluate recurrence outcomes, bladder preservation, progression, safety, and patient management strategies following achievement of tumor-free status. The trial also aims to explore the role of urinary tumor DNA in identifying patients who may safely undergo treatment de-escalation and active surveillance.
Has histologically confirmed very-high-risk non-muscle-invasive urothelial carcinoma of the bladder.
Has transurethrally unresectable bladder tumor, defined as visually incomplete TURBT and/or extensive high-volume disease considered unsuitable for complete and oncologically adequate transurethral resection.
Has undergone cystoscopy and TURBT evaluation before study enrollment.
Has received systemic PD-1/PD-L1 inhibitor-based bladder-sparing therapy before randomization.
Has muscle-invasive bladder cancer (≥T2), locally advanced unresectable disease, nodal disease, or distant metastasis.
Has concurrent upper tract urothelial carcinoma.
Has persistent visible tumor, positive bladder pathology, positive urine cytology, or positive utDNA before randomization.
Has received prior systemic immunotherapy for metastatic urothelial carcinoma.
Parallel
Active Surveillance
BehavioralPatients undergo protocol-defined surveillance after achieving tumor-free status, including cystoscopy, biopsy as clinically indicated, urine cytology, urinary tumor DNA testing, and imaging assessments, without continued systemic PD-1/PD-L1 inhibitor therapy unless disease recurrence or progression occurs.
PD-1/PD-L1 Inhibitor-Based Systemic Immunotherapy
DrugPatients continue protocol-defined systemic PD-1/PD-L1 inhibitor therapy after achieving tumor-free status for up to approximately 1 year, with ongoing surveillance including cystoscopy, urine cytology, urinary tumor DNA testing, and imaging assessments.
Bladder-intact event-free survival (BI-EFS)
Time from randomization to the first occurrence of high-risk NMIBC recurrence, progression to muscle-invasive bladder cancer, distant metastasis, radical cystectomy, or death from any cause.
Recurrence-free survival (RFS)
Time from randomization to the first documented recurrence of bladder cancer or death from any cause.
Progression-free survival (PFS)
Time from randomization to progression to muscle-invasive, locally advanced, or metastatic bladder cancer, or death from any cause.
Radical cystectomy-free survival (RCFS)
Time from randomization to radical cystectomy or death from any cause.
Overall survival (OS)
Time from randomization to death from any cause.
Recurrence-Free Survival According to Urinary Tumor DNA Status
Recurrence-free survival will be evaluated according to urinary tumor DNA status after achieving tumor-free status. Urinary tumor DNA status will be assessed using a urine-based tumor DNA assay and categorized as positive or negative.
utDNA conversion during surveillance
Proportion of patients with conversion from urinary tumor DNA negative to positive during follow-up.
Bladder-Intact Event-Free Survival According to Response Cohort in the Active Surveillance Arm
Bladder-intact event-free survival will be compared between participants assigned to active surveillance in Cohort A and Cohort B.
Recurrence-Free Survival According to Response Cohort in the Active Surveillance Arm
Recurrence-free survival will be compared between participants assigned to active surveillance in Cohort A and Cohort B.
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