A phase III, randomized, open-label, multicenter, global study of durvalumab and bacillus calmette-guérin (BCG) versus BCG alone in high-risk, BCG-naïve non-muscle-invasive bladder cancer (NMIBC) patients (POTOMAC).

Abstract

TPS500 Background: Standard of care (SoC) for high-risk NMIBC patients is transurethral resection of the bladder tumor followed by BCG. Although several randomized clinical studies have demonstrated the efficacy of BCG in NMIBC, recurrence rates are as high as 50% in the first 3 yrs of follow up and can be even higher for aggressive histologic subtypes. Immunotherapy agents active in the programmed cell death (PD) pathway responsible for suppressing anti-tumor immunity present an emerging treatment opportunity. In trials treating patients with metastatic urothelial cancer who progressed after platinum-based chemotherapy, response rates doubling those with traditional chemotherapy have been reported for immunotherapies targeting programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1). Durvalumab is a selective, high affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80 with a manageable safety and tolerability profile. PD-L1 inhibition with durvalumab in combination with other immunotherapies, including SoC BCG, may improve response rate and duration of tumor response. Methods: POTOMAC is an open-label, multicenter, global Phase 3 trial enrolling approximately 1,300 patients ≥18 yrs with histologically confirmed high-risk NMIBC who have undergone complete resection of papillary tumors (patients with residual carcinoma in situ [CIS] are eligible) and are BCG-naïve. Of those, approximately 975 patients will be randomized (1:1:1) to durvalumab (1500 mg every 4 wks for 13 cycles) + BCG induction (6x every 1 wk instillation) and 2 yrs of maintenance (3 doses x every 1 wk at 3, 6, 12, 18, and 24 months), durvalumab + BCG (induction only) or BCG (induction and 2 yrs of maintenance). Randomization will be stratified by high-risk papillary disease (Y/N) and CIS (Y/N). The primary endpoint is disease-free survival. Secondary endpoints include proportion of patients alive and disease free at 24 months, overall survival at 5 yrs, pharmacokinetics, immunogenicity, safety and tolerability, and HRQoL. Clinical trial information: NCT03528694.