POTOMAC Trial: Durvalumab Plus BCG Improves Disease-Free Survival in BCG-Naïve High-Risk NMIBC

High-risk non-muscle-invasive bladder cancer (NMIBC) remains a clinically challenging disease state despite intravesical bacillus Calmette-Guérin (BCG), with substantial rates of recurrence and progression. Enhancing upfront immunologic control in BCG-naïve patients represents a critical opportunity to improve long-term outcomes.

The phase III POTOMAC trial evaluated whether adding systemic programmed death-ligand 1 (PD-L1) inhibition with durvalumab to standard BCG therapy could improve disease control in patients with BCG-naïve, high-risk NMIBC following complete transurethral resection of bladder tumor (TURBT).

Clinical Takeaway

Adding durvalumab to BCG induction and maintenance significantly improved disease-free survival (DFS) compared with BCG induction and maintenance alone in BCG-naïve, high-risk NMIBC, whereas induction-only durvalumab did not confer benefit, highlighting the importance of sustained immune modulation.

Drug Profile & Mechanism

• Agent:  
  • durvalumab (Imfinzi)
  • Bacillus Calmette–Guérin (BCG)
• Class & Mechanism of Action:
  • durvalumab: Human IgG1 monoclonal antibody targeting PD-L1, restoring antitumor T-cell activity by blocking PD-L1-mediated immune evasion
  • BCG: Intravesical immunotherapy that induces localized innate and adaptive immune activation within the bladder mucosa
• Route of Administration & Dosing Schedule:
  • durvalumab: 1500 mg IV every 4 weeks for up to 13 cycles (approximately 12 months)
  • BCG: Standard intravesical induction (weekly x6 treatments) with maintenance per protocol at months 3, 6, 12, 18, and 24 in applicable arms

Target Population

• Adults with BCG-naïve, high-risk NMIBC following complete TURBT, including high-grade Ta, T1, and/or carcinoma in situ.

POTOMAC Study Design (NCT03528694)

• Study Type: Randomized, international, open-label, phase III clinical trial
• Population: 1,018 patients
• Randomization: 1:1:1
  • durvalumab plus BCG induction and maintenance
  • durvalumab plus BCG induction only
  • BCG induction and maintenance alone
• Follow-Up Duration: Long-term follow-up planned
  • Median follow-up: ~60.7 months
• Primary completion: April 3, 2025
• Estimated Study Completion: October 3, 2028

Endpoints

• Primary Endpoint:
  • Investigator-assessed DFS comparing durvalumab plus BCG induction and maintenance versus BCG induction and maintenance alone
• Secondary Endpoints:
  • DFS for induction-only durvalumab arm
  • Time to recurrence or progression
  • Safety and tolerability
  • Overall survival (exploratory)

Efficacy Outcomes

• Primary Endpoint Results:
  • Durvalumab plus BCG induction and maintenance significantly improved DFS compared with BCG induction and maintenance alone
  • The risk of disease recurrence or death was reduced by 32%
    • Hazard ratio (HR): 0.68
    • P = 0.015
  • Durvalumab plus BCG induction only did not demonstrate a significant DFS benefit, underscoring the importance of maintenance therapy

Safety

• Overall Safety Profile: Consistent with known profiles of durvalumab and BCG
• Grade ≥3 Events: A higher incidence was observed in the durvalumab-containing arms compared with BCG induction and maintenance alone
• Treatment discontinuation: Occurred more frequently in combination arms, primarily due to immune-related adverse events
• Notable toxicity patterns:
  • Immune-related adverse events typical of PD-L1 inhibition
  • Local BCG-related urinary symptoms
  • No treatment-related deaths reported

No new safety signals were identified, and adverse events were generally manageable with standard supportive care and dose modifications.

Regulatory Milestones

• Approval Status: Not yet approved for NMIBC at time of reporting
• Current Standard of Care: BCG induction with maintenance remains standard for BCG-naïve, high-risk NMIBC
• Regulatory Pathway: Data may support regulatory consideration for durvalumab plus BCG induction and maintenance as an upfront strategy

Key Clinical Implications

✔ Demonstrates meaningful DFS improvement with systemic immunotherapy added to intravesical BCG

✔ Highlights the importance of maintenance durvalumab, not induction alone

✔ Supports immune intensification early in high-risk NMIBC

✔ May reshape frontline management if adopted into guidelines

✔ Reinforces combined local and systemic immunotherapy strategies

Bottom Line

The POTOMAC trial demonstrates a statistically significant improvement in disease-free survival in BCG-naïve, high-risk NMIBC, with a safety profile consistent with known agents and evidence that sustained immunotherapy is required for benefit.

Sources:

• UroToday. (2025). ESMO 2025: Durvalumab in combination with BCG for BCG-naïve high-risk non–muscle-invasive bladder cancer—Final analysis of the phase 3, open-label, randomized POTOMAC trial. https://www.urotoday.com/conference-highlights/esmo-2025/esmo-2025-bladder-cancer/164000-esmo-2025-durvalumab-in-combination-with-bcg-for-bcg-naive-high-risk-nmibc-final-analysis-of-the-phase-3-open-label-randomized-potomac-trial.html
• ClinicalTrials.gov. (2025). Durvalumab with bacillus Calmette–Guérin (BCG) in high-risk non–muscle-invasive bladder cancer (POTOMAC) (NCT03528694). U.S. National Library of Medicine. https://clinicaltrials.gov/study/NCT03528694