Research Summary:
For patients with bacillus Calmette-Guérin (BCG)–naïve, high-risk non-muscle invasive bladder cancer (NMIBC), the standard of care is transurethral resection of bladder tumor (TURBT) followed by BCG therapy. However, early recurrence rates remain high, and patients with early recurrence and high-risk NMIBC face an increased risk of progression to MIBC or metastatic disease; thus, there is an unmet need for improved treatments for this patient population. Immune checkpoint inhibitors have shown efficacy in high-risk NMIBC. In the phase 3 POTOMAC trial, researchers evaluated the efficacy and safety of durvalumab plus BCG induction and maintenance therapy vs BCG induction and maintenance therapy alone in patients with BCG-naïve, high-risk NMIBC. De Santis et al1 presented the final analysis of this trial.
The POTOMAC trial is a phase 3, open-label, randomized, multicenter clinical trial. Patients aged ≥18 years with BCG-naïve, high-risk NMIBC who underwent TURBT within 4 months of randomization were randomized 1:1:1 to receive durvalumab 1,500 mg intravenously every 4 weeks for 13 cycles plus intravesical BCG induction therapy weekly for 6 weeks and maintenance therapy, which was 3 doses at weekly intervals at Months 3, 6, 12, 18, and 24; durvalumab plus BCG induction therapy only; or BCG induction and maintenance therapy (comparison group). Patients were enrolled between June 18, 2018, and October 2, 2020.
In total, 1,018 patients were randomized (durvalumab plus BCG induction and maintenance, n=339; durvalumab plus BCG induction only, n=339; comparison group, n=340). Baseline characteristics were well balanced across groups. Most patients had papillary disease only (65%), and 37% had carcinoma in situ. At baseline, 59% of patients had T1 disease.
At the data cutoff date of April 3, 2025, all patients were off study treatment. The rate of treatment completion was 53% (n=180) in the durvalumab plus BCG induction and maintenance arm, 71% (n=239) in the durvalumab plus BCG induction only arm, and 54% (n=182) in the comparison group. In all arms, the most common reason for treatment discontinuation was occurrence of an adverse event (AE).
Median follow-up was 60.7 months. The percentage of disease-free survival (DFS) events was lower in the durvalumab plus BCG induction and maintenance arm compared to the comparison arm (20% [n=67] vs 29% [n=98]). Treatment with durvalumab plus BCG induction and maintenance was associated with a 32% decreased risk or recurrence of high-risk disease or any-cause death compared to BCG induction and maintenance alone (hazard ratio [HR]: 0.68; 95% confidence interval [CI]: 0.50–0.93; stratified log-rank P=0.015). The estimated proportion of patients who were alive and without high-risk disease recurrence at 24 months was greater in the durvalumab plus BCG induction and maintenance group vs the comparison group, at 86.5% (95% CI: 82.2–89.8%) vs 81.6% (95% CI: 76.9–85.3%). While the study was not powered for subgroup analysis, the DFS benefit with the addition of durvalumab was generally observed across predefined subgroups.
In the durvalumab plus BCG induction only arm, DFS events occurred in 31% of patients (n=105). There was no significant difference in risk of recurrence or death between the durvalumab plus BCG induction only group and the comparison group (HR: 1.14; 95% CI: 0.86–1.50; P=0.35).
The rate of complete response at 6 months in patients with carcinoma in situ was high in all groups, at 93% each in the durvalumab plus BCG induction and maintenance and comparison groups and 83% in the durvalumab plus BCG induction only group.
In the intention-to-treat population, the mortality rate was 12% (n=41) in the durvalumab plus BCG induction and maintenance group and 15% (n=52) in the comparison group (descriptive HR for death: 0.80; 95% CI: 0.53–1.20). Median overall survival (OS) was not reached in both arms.
European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C30) was administered at baseline and every 8 weeks, and ≥50% of patients in the durvalumab plus BCG induction and maintenance and comparison groups had completed it up to Week 138 (last study visit). Adjusted mean change from baseline in global health status/quality of life score was –7.6 (standard error [SE]: 0.79; 95% CI: –9.19 to –6.07) in the durvalumab plus BCG induction and maintenance group vs –4.9 (SE: 0.78; 95% CI: –6.46 to –3.41) in the comparison group (estimated difference: –2.7).
Treatment-related AEs (TRAEs) occurred in 89%, 80%, and 72% of patients in the durvalumab plus BCG induction and maintenance, durvalumab plus BCG induction only, and comparison arms, respectively, with grade 3 or 4 events reported in 21%, 15%, and 4%, respectively. The rate of discontinuation due to TRAEs was 27% in the durvalumab plus BCG induction and maintenance group, 16% in the durvalumab plus BCG induction only group, and 17% in the comparison group. The most common TRAEs included dysuria, hematuria, and pollakiuria.
These results demonstrate that the addition of durvalumab to BCG induction and maintenance therapy resulted in clinically meaningful benefit in DFS compared to BCG therapy alone in patients with BCG-naïve, high-risk NMIBC. Importantly, the addition of durvalumab did not impair OS, and the treatment regimen had a tolerable and manageable safety profile.
Reference
- De Santis M, Palou Redorta J, Nishiyama H, et al. Durvalumab in combination with BCG for BCG-naive, high-risk, non-muscle-invasive bladder cancer (POTOMAC): final analysis of a randomised, open-label, phase 3 trial. Lancet. 2025;406(10516):2221–2234.