POTOMAC Trial

FDA approves durvalumab for muscle invasive bladder cancer On March 28, 2025, the Food and Drug Administration approved durvalumab (Imfinzi, AstraZeneca) with gemcitabine and cisplatin as neoadjuvant treatment, followed by single agent durvalumab as adjuvant treatment following radical cystectomy, for adults with muscle invasive bladder cancer (MIBC). Full prescribing information for Imfinzi will be posted on Drugs@FDA. Efficacy and Safety Efficacy was evaluated in NIAGARA (NCT03732677), a randomized, open-label, multicenter, Phase III trial enrolling 1,063 patients who were candidates for radical cystectomy and had not received prior systemic therapy for bladder cancer. Patients were randomized (1:1) to receive neoadjuvant durvalumab with chemotherapy followed by adjuvant durvalumab after surgery or neoadjuvant chemotherapy followed by surgery alone. The major efficacy outcome was event-free survival (EFS) by blinded independent central review. Overall survival (OS) was an additional efficacy outcome. At a pre-specified interim analysis, the trial demonstrated a statistically significant improvement in EFS and OS. Median EFS was not reached (NR) (95% CI: NR, NR) in the durvalumab with chemotherapy arm and 46.1 months (95% CI: 32.2, NR) in the chemotherapy arm (hazard ratio 0.68 [95% CI: 0.56, 0.82]; two-sided p-value <0.0001). Median OS was not reached in either arm (hazard ratio 0.75 [95% CI: 0.59, 0.93]; two-sided p-value=0.0106). Adverse reactions were consistent with prior experience with durvalumab with platinum- based chemotherapy.

FDA approves a treatment for high-risk non-muscle invasive bladder cancer FDA

POTOMAC: Study Design A randomised, open-label, Phase 3, global study Durvalumab 1500 mg IV (Q4W X 13 cycles) Primary endpoint D+BCG (I+M) BCG Induction BCG Maintenance Study population N=339 DFS: D+BCG (I+M) vs BCG (I+M) 3 weekly doses at Age ≥18 years Weekly x 6 weeks 3ml 6m 12m 18m 24m NMIBC Key secondary endpoints BCG-naive High-risk tumour defined Durvalumab 1500 mg IV (Q4W X 13 cycles) DFS: D+BCG (I only) VS BCG (I+M) as any of the following: R D+BCG DFS at 24 months (1:1:1) T1 (I only) BCG Induction N=1018 CRR at 6 months N=339 High-grade/G3 Weekly X 6 weeksb CIS Other secondary endpoints Multiple and recurrent and large OS at 5 years (≥3 cm) BCG (I+M) N=340 BCG Induction BCG Maintenance Safety 3 weekly doses at EORTC QLQ-C30 Weekly x 6 weeks 3m 6m 12m 18m 24m Stratification factors: Higher risk papillary disease (yes VS no)a CIS (yes VS no) --- POTOMAC: Disease-Free Survival for D+BCG (I+M) vs BCG (I+M) - ITT POTOMAC met its primary endpoint with early and sustained DFS benefit D+BCG (I+M) BCG (I+M) N=339 N=340 Events, n (%) 67 (20) 98 (29) 1.0 92% Median DFS, months NR NR 87% (95% CI) (NR-NR) (74.0-NR) 82% 0.8 87% 82% 77% Probability of DFS 0.6 + 0.4 HR 0.68 (95% CI, 0.50-0.93) Stratified log-rank P value = 0.0154 0.2 Median follow-upb: 60.7 months 24% DFS maturity 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75 78 81 Time from randomisation (months) No of patients at risk D+BCG (I+M) 339 321 304 292 289 283 278 273 262 257 250 245 235 229 226 222 220 204 195 156 145 108 94 57 26 9 1 0 BCG (I+M) 340 322 303 292 283 276 271 265 258 254 249 244 237 235 231 227 225 209 196 160 150 101 86 50 20 8 0 0 --- POTOMAC: Disease-Free Survival for D+BCG (I Only) vs BCG (I+M) - ITT Difference in DFS between D+BCG (I only) vs BCG (I+M) arms was not statistically significant (key secondary endpoint) D+BCG (I only) BCG (I+M) N=339 N=340 Events, n (%) 105 (31) 98 (29) 1.0 Median DFS, months NR NR 87% (95% CI) (NR-NR) (74.0-NR) 82% 77% 0.8 86% 79% 74% Probability of DFS 0.6 0.4 HR 1.14 (95% CI, 0.86-1.50) Stratified log-rank P value = 0.3530 0.2 Median follow-upᵃ: 60.7 months 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75 78 81 Time from randomisation (months) No of patients at risk D+BCG (I only) 339 314 296 281 269 261 250 246 240 236 227 219 217 212 210 201 198 186 173 145 130 92 79 47 20 13 1 0 BCG (I+M) 340 322 303 292 283 276 271 265 258 254 249 244 237 235 231 227 225 209 196 160 150 101 86 50 20 8 0 0 --- POTOMAC: Conclusions Durvalumab in combination with BCG (I+M) resulted in a statistically significant and clinically meaningful improvement in DFS VS BCG (I+M) alone in patients with BCG-naïve, high-risk NMIBC Scan the QR code to access: at a median of 5 years of follow-up Slide presentation Plain language summary 32% reduction in risk of a DFS event (HR 0.68; 95% CI, 0.50-0.93; P=0.0154) Copies of this presentation obtained through the QR code are for personal Early and sustained DFS benefit with durvalumab (starting at <4 months) use only and may not be reproduced without written permission of the authors After a median follow-up of >5 years (14% maturity), a descriptive analysis showed an OS HR of 0.80 (95% CI, 0.53-1.20), demonstrating no detriment to OS with the addition of durvalumab Durvalumab plus BCG (I+M) had a tolerable and manageable safety profile that was consistent with the known safety profiles of the individual agents, with no deaths due to treatment-related AEs POTOMAC supports 1 year of durvalumab in combination with BCG induction and maintenance as a potential new treatment for patients with BCG-naïve, high-risk NMIBC congress BERLIN 2025 ESMO AE, adverse event BCG, bacillus Calmette-Guénn CI, confidence interval DFS, disease-free survival, HR hazard ratio; I, induction M, maintenance, NMIBC non-muscle-invasive bladder cancer, OS, overall survival

Q = AstraZeneca Imfinzi approved in the US in first and only immunotherapy combination for patients with BCG-naïve, high-risk non-muscle-invasive bladder cancer. PUBLISHED 28 May 2026

FDA Approves Durvalumab in Combination with Bacillus Calmette-Guerin for High-Risk Non- Muscle Invasive Bladder Cancer As a service to our members, the American Association for Cancer Research will distribute information from the U.S. Food and Drug Administration about newly approved novel therapies for cancer patients. By doing so, we aim to help the FDA inform cancer researchers and oncologists of recent approvals in a timely manner. Included in the email from the FDA will be a link to the product label, which will provide the relevant clinical information on the indication, contraindications, dosing, and safety. In sharing this information, the AACR does not endorse any product or therapy and does not take any position on the safety or efficacy of the product or therapy described. On May 28, 2026, the Food and Drug Administration approved durvalumab (Imfinzi, AstraZeneca) in combination with Bacillus Calmette-Guerin (BCG) for the treatment of adult patients with BCG-naïve, high-risk non-muscle invasive bladder cancer (NMIBC). Full prescribing information for Imfinzi will be posted on Drugs@FDA. Efficacy was evaluated in the POTOMAC study (NCT03528694), a randomized, open-label, multicenter trial that enrolled 1,018 patients with high-risk NMIBC following transurethral resection of bladder tumor. High- risl aving one of the f 7: T1 e tumor, carcinoma d (CIS), or multiple, recurrent, and large tumors. Patients

14:12 5G 010 thelancet.com X THE LANCET of Search for. Q COMMENT - Online first, October 17, 2025 Front-line durvalumab and BCG in the treatment of non-muscle- invasive bladder cancer Andrea Necchi a,b X . Alberto Briganti a,c . Francesco Montorsi a,c Affiliations & Notes < Article Info < Linked Articles (1) > Over the past 5 years, systemic therapy for urothelial carcinoma has changed considerably throughout the clinical stages. 1 In addition to regulatory approvals of immune-checkpoint inhibitor (ICI)-based therapies for muscle-invasive or metastatic disease, advances have also been made for non-muscle-invasive bladder cancer (NMIBC). Nadofaragene firadenovec-vncg, nogapendekin alfa inbakicept-pmln, and gemcitabine % Get Access Outline Share More

BERLIN 2025 ESMO congress BERLIN GERMANY 17-21 OCTOBER 2025 --- POTOMAC: Study Design A randomised, open-label, Phase 3, global study Durvalumab 1500 mg IV (Q4W X 13 cycles) D+BCG (I+M) Primary endpoint Study population N=339 BCG Induction BCG Maintenance 3 weekly doses at DFS: D+BCG (I+M) vs BCG (1+M) Age ≥18 years Weekly X 6 weeks® NMIBC 3m 6m 12m 1 Pm 24m BCG-naive Key secondary endpoints High-risk tumour defined R D+BCG Durvalumab 1500 mg IV (Q4W X 13 cycles) DFS: D+BCG 0 only) vs BCG (I+M) as any of the following: (1:11) (I only) DFS at 24 months T1 N=1018 BCG Induction High-grade/G3 N=339 CRR at 6 months Weekly X 6 weeks CIS Multiple and Other secondary endpoints recurrent and large OS at 5 years (>3 cm) BCG (I+M) BCG Induction BCG Maintenance N=340 Safety 3 weekly doses at Weekly X 6 weeks EORTC QLQ-C30 3m 5m 12m 18m 24m Stratification factors: Higher risk papillary disease (yes VS no)* CIS (yes VS no) All disease assessments were performed by the investigator. Defined 05 T1G3/T1 high-grade or multiple and recument and large tumours (those with I diameter of 23 and For patients with persistent OS Income I 3 months, a single BCG re-induction was administered weekly for 6 weeks according to local standard practice. ClinicalTrials gov, NCT03528694; EudraCT number, 2017-002979-26 BCG bacilus Calinete-Guém, Questionnaire: G, grade; , induction IV, intravenous, m, month; M maintenance; NMBC, non-muscle-invasive bladder cancer OS, overall survival, Q4W, every 4 weeks, R rendomisation CIS, carcinoma in situ, CRR complete response rate, D, durvalumab, DFS, disease-free survival, EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer 30-tem Core Quality of Lie ESMO --- POTOMAC: Disease-Free Survival for D+BCG (I+M) VS BCG (I+M) - ITT POTOMAC met its primary endpoint with early and sustained DFS benefit D+BCG (I+M) BCG (I+M) N=339 N=340 1.0 Events, n (%) 92% 67(20) 98(29) Median DFS, months NR 87% NR (95% CI) 82% (NR-NR) (74.0-NR) 0.8 87% 82% 77% Probability of DFS 0.6 0.4 HR 0.68 (95% CI, 0.50-0.93) Stratified log-rank P value® = 0.0154 0.2 Median follow-upb: 60.7 months 24% DFS maturity 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75 78 81 Time from randomisation (months) No. of patients at risk D+BCG (I+M) 339 321 304 292 289 283 278 273 262 257 250 245 235 229 226 222 220 204 195 156 145 108 94 57 20 9 1 0 BCG (I+M) 340 322 303 292 283 276 271 265 258 254 249 244 237 235 231 227 225 209 196 160 150 101 86 50 20 8 0 0 DFS is defined as the time to the first: 1) recurrence of high-risk disease (recurrence of high-grade Ta, T1, or CIS, presentation with MIBC and/or metastatic disease or persistent CIS #6 months): 2) death by any cause in the absence of recurrence *The threshold to declare statistical significance was based on a generalized Haybittle-Peto spending function- with the observed number of events, the boundary for declaring statistical significance was 0.0317 for a 5% overall 2-sided alpha. Mn censored patients across all study arms. Data cutoff 03 April 2025 BCG, bacillus Calmette-Guénn; CL confidence interval, CIS, caronoma a sa, ESMO D, durvalumab; DFS, disease-free survival; HR, hazard ratio, I, induction; ITT, intent-to-treat population; M, maintenance, MIBC, muscle-invasive bladder cancer, NR not reached. --- POTOMAC: Conclusions Durvalumab in combination with BCG (I+M) resulted in a statistically significant and clinically meaningful improvement in DFS VS BCG (I+M) alone in patients with BCG-naive, high-risk NMIBC at a median of 5 years of follow-up Scan the OR code to access Side presentation 32% reduction in risk of a DFS event (HR 0.68; 95% CI, 0.50-0.93; P=0.0154) Plan language surmary Crass If is - and trugh to DI - is " - Early and sustained DFS benefit with durvalumab (starting at <4 months) - (6) as ray - etc. - # for ukin After a median follow-up of >5 years (14% maturity), a descriptive analysis showed an OS HR of 0.80 (95% CI, 0.53-1.20), demonstrating no detriment to OS with the addition of durvalumab Durvalumab plus BCG (I+M) had a tolerable and manageable safety profile that was consistent with the known safety profiles of the individual agents, with no deaths due to treatment-related AEs POTOMAC supports 1 year of durvalumab in combination with BCG induction and maintenance as a potential new treatment for patients with BCG-naïve, high-risk NMIBC an AE, adverse event, BCG, bacillus Calmette-Guérin CI, confidence interval; DFS, disease free survival, HR, hazard ratio, 1, induction M. mantenance, NMBC, non made name Madder canar, 05, overall und ESMO

M R Mill IIICR Maria De Santis Chair, Interdisciplinary Uro-Oncology Section, Charité Universitätsmedizin, Berlin, Germany

POTOMAC: Study Design A randomised, open-label, Phase 3, global study Durvalumab 1500 mg IV (Q4W X 13 cycles) Primary endpoint D+BCG (I+M) BCG Induction BCG Maintenance Study population N=339 DFS: D+BCG (I+M) vs BCG (I+M) 3 weekly doses at Age ≥18 years Weekly x 6 weeks 3ml 6m 12m 18m 24m NMIBC Key secondary endpoints BCG-naive High-risk tumour defined Durvalumab 1500 mg IV (Q4W X 13 cycles) DFS: D+BCG (I only) VS BCG (I+M) as any of the following: R D+BCG DFS at 24 months (1:1:1) T1 (I only) BCG Induction N=1018 CRR at 6 months N=339 High-grade/G3 Weekly X 6 weeksb CIS Other secondary endpoints Multiple and recurrent and large OS at 5 years (≥3 cm) BCG (I+M) N=340 BCG Induction BCG Maintenance Safety 3 weekly doses at EORTC QLQ-C30 Weekly x 6 weeks 3m 6m 12m 18m 24m Stratification factors: Higher risk papillary disease (yes VS no)a CIS (yes VS no) --- POTOMAC: Disease-Free Survival for D+BCG (I+M) VS BCG (I+M) - ITT POTOMAC met its primary endpoint with early and sustained DFS benefit D+BCG (I+M) BCG (I+M) N=339 N=340 Events, n (%) 67 (20) 98 (29) 1.0 92% Median DFS, months NR NR 87% (95% CI) (NR-NR) (74.0-NR) 82% 0.8 87% 82% 77% Probability of DFS 0.6 + 0.4 HR 0.68 (95% CI, 0.50-0.93) Stratified log-rank P valueᵃ = 0.0154 0.2 Median follow-upb: 60.7 months 24% DFS maturity 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75 78 81 Time from randomisation (months) No of patients at risk D+BCG (I+M) 339 321 304 292 289 283 278 273 262 257 250 245 235 229 226 222 220 204 195 156 145 108 94 57 26 9 1 0 BCG (I+M) 340 322 303 292 283 276 271 265 258 254 249 244 237 235 231 227 225 209 196 160 150 101 86 50 20 8 0 0 --- POTOMAC: Disease-Free Survival for D+BCG (I Only) vs BCG (I+M) - ITT Difference in DFS between D+BCG (I only) vs BCG (I+M) arms was not statistically significant (key secondary endpoint) D+BCG (I only) BCG (I+M) N=339 N=340 Events, n (%) 105 (31) 98 (29) 1.0 Median DFS, months NR NR 87% (95% CI) (NR-NR) (74.0-NR) 82% 77% 0.8 86% 79% 74% Probability of DFS 0.6 0.4 HR 1.14 (95% CI, 0.86-1.50) Stratified log-rank P value = 0.3530 0.2 Median follow-upᵃ: 60.7 months 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75 78 81 Time from randomisation (months) No of patients at risk D+BCG (I only) 339 314 296 281 269 261 250 246 240 236 227 219 217 212 210 201 198 186 173 145 130 92 79 47 20 13 1 0 BCG (I+M) 340 322 303 292 283 276 271 265 258 254 249 244 237 235 231 227 225 209 196 160 150 101 86 50 20 8 0 0 --- POTOMAC: Conclusions Durvalumab in combination with BCG (I+M) resulted in a statistically significant and clinically meaningful improvement in DFS VS BCG (I+M) alone in patients with BCG-naïve, high-risk NMIBC Scan the QR code to access: at a median of 5 years of follow-up Slide presentation Plain language summary 32% reduction in risk of a DFS event (HR 0.68; 95% CI, 0.50-0.93; P=0.0154) Copies of this presentation obtained through the QR code are for personal Early and sustained DFS benefit with durvalumab (starting at <4 months) use only and may not be reproduced without written permission of the authors After a median follow-up of >5 years (14% maturity), a descriptive analysis showed an OS HR of 0.80 (95% CI, 0.53-1.20), demonstrating no detriment to OS with the addition of durvalumab Durvalumab plus BCG (I+M) had a tolerable and manageable safety profile that was consistent with the known safety profiles of the individual agents, with no deaths due to treatment-related AEs POTOMAC supports 1 year of durvalumab in combination with BCG induction and maintenance as a potential new treatment for patients with BCG-naïve, high-risk NMIBC congress BERLIN 2025 ESMO AE, adverse event BCG, bacillus Calmette-Guénn CI, confidence interval, DFS, disease-free survival HR hazard ratio, I, induction M. maintenance, NMIBC non-muscle-invasive bladder cancer, OS, overall survival

POTOMAC: Study Design A randomised, open-label, Phase 3, global study Durvalumab 1500 mg IV (Q4W x 13 cycles) Primary endpoint D+BCG (I+M) BCG Induction BCG Maintenance Study population N=339 DFS: D+BCG (I+M) vs BCG (I+M) 3 weekly doses at Age ≥18 years Weekly x 6 weeks 3ml. 6m 12m 18m 24m NMIBC Key secondary endpoints BCG-naive High-risk tumour defined Durvalumab 1500 mg IV (Q4W X 13 cycles) DFS: D+BCG (I only) VS BCG (I+M) as any of the following: R D+BCG DFS at 24 months (1:1:1) T1 (I only) BCG Induction N=1018 CRR at 6 months N=339 High-grade/G3 Weekly X 6 weeksb CIS Other secondary endpoints Multiple and recurrent and large OS at 5 years (≥3 cm) BCG (I+M) N=340 BCG Induction BCG Maintenance Safety 3 weekly doses at EORTC QLQ-C30 Weekly x 6 weeks 3m 6m 12m 18m 24m Stratification factors: Higher risk papillary disease (yes VS no)a CIS (yes VS no) --- POTOMAC: Disease-Free Survival for D+BCG (I+M) VS BCG (I+M) - ITT POTOMAC met its primary endpoint with early and sustained DFS benefit D+BCG (I+M) BCG (I+M) N=339 N=340 Events, n (%) 67 (20) 98 (29) 1.0 92% Median DFS, months NR NR 87% (95% CI) (NR-NR) (74.0-NR) 82% 0.8 87% 82% 77% Probability of DFS 0.6 + 0.4 HR 0.68 (95% CI, 0.50-0.93) Stratified log-rank P valueᵃ = 0.0154 0.2 Median follow-upb: 60.7 months 24% DFS maturity 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75 78 81 Time from randomisation (months) No of patients at risk D+BCG (I+M) 339 321 304 292 289 283 278 273 262 257 250 245 235 229 226 222 220 204 195 156 145 108 94 57 26 9 1 0 BCG (I+M) 340 322 303 292 283 276 271 265 258 254 249 244 237 235 231 227 225 209 196 160 150 101 86 50 20 8 0 0 --- POTOMAC: Disease-Free Survival for D+BCG (I Only) vs BCG (I+M) - ITT Difference in DFS between D+BCG (I only) vs BCG (I+M) arms was not statistically significant (key secondary endpoint) D+BCG (I only) BCG (I+M) N=339 N=340 Events, n (%) 105 (31) 98 (29) 1.0 Median DFS, months NR NR 87% (95% CI) (NR-NR) (74.0-NR) 82% 77% 0.8 86% 79% 74% Probability of DFS 0.6 0.4 HR 1.14 (95% CI, 0.86-1.50) Stratified log-rank P value = 0.3530 0.2 Median follow-upᵃ: 60.7 months 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75 78 81 Time from randomisation (months) No of patients at risk D+BCG (I only) 339 314 296 281 269 261 250 246 240 236 227 219 217 212 210 201 198 186 173 145 130 92 79 47 20 13 1 0 BCG (I+M) 340 322 303 292 283 276 271 265 258 254 249 244 237 235 231 227 225 209 196 160 150 101 86 50 20 8 0 0 --- POTOMAC: Conclusions Durvalumab in combination with BCG (I+M) resulted in a statistically significant and clinically meaningful improvement in DFS VS BCG (I+M) alone in patients with BCG-naïve, high-risk NMIBC Scan the QR code to access: at a median of 5 years of follow-up Slide presentation Plain language summary 32% reduction in risk of a DFS event (HR 0.68; 95% CI, 0.50-0.93; P=0.0154) Copies of this presentation obtained through the QR code are for personal Early and sustained DFS benefit with durvalumab (starting at <4 months) use only and may not be reproduced without written permission of the authors After a median follow-up of >5 years (14% maturity), a descriptive analysis showed an OS HR of 0.80 (95% CI, 0.53-1.20), demonstrating no detriment to OS with the addition of durvalumab Durvalumab plus BCG (I+M) had a tolerable and manageable safety profile that was consistent with the known safety profiles of the individual agents, with no deaths due to treatment-related AEs POTOMAC supports 1 year of durvalumab in combination with BCG induction and maintenance as a potential new treatment for patients with BCG-naïve, high-risk NMIBC congress BERLIN 2025 ESMO AE, adverse event BCG, bacillus Calmette-Guénn CI, confidence interval, DFS, disease-free survival HR hazard ratio, I, induction M. maintenance NMIBC non-muscle-invasive bladder cancer, OS, overall survival

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 Maria De Santis, Joan Palou Redorta, Hiroyuki Nishiyama, Michal Krawczyński, Artur Seyitkuliev, Andrey Novikov, Félix Guerrero-Ramos, Ruslan Zukov, Minoru Kato, Takashi Kawahara, Lieven Goeman, Javier Puente, Eva Hellmis, Thomas Powles, Piotr Radziszewski, Kilian M Gust, Paul Vasey, Pierre Bigot, Yves Fradet, Jarmo Hunting, Jon Armstrong, Suliman Boulos, Stephan Hois, Neal D Shore, on behalf of the POTOMAC Investigators* Summary Background Patients with high-risk non-muscle-invasive bladder cancer (NMIBC) often have recurrence or progression after transurethral resection of bladder tumour (TURBT) and subsequent BCG therapy. We aimed to evaluate whether 1 year of durvalumab with BCG could improve outcomes versus BCG alone for these patients. Methods This randomised, open-label, phase 3 trial enrolled patients aged 18 years or older with BCG-naive, high-risk NMIBC who underwent TURBT. Patients were randomly allocated (1:1:1) to receive intravenous durvalumab (every 4 weeks for 13 cycles) plus intravesical BCG induction (weekly for 6 weeks) and maintenance (three doses at weekly intervals at 3, 6, 12, 18, and 24 months), durvalumab plus BCG induction, or BCG induction and maintenance (comparison group). The primary endpoint was investigator-assessed disease-free survival in the durvalumab plus BCG induction and maintenance group versus the comparison group in the intention-to-treat population. This study is registered at ClinicalTrials.gov (NCT03528694) and EudraCT (2017-002979-26) and is ongoing but is no longer enrolling patients. Findings Between June 18, 2018, and Oct 2, 2020, 1350 patients were assessed for eligibility, among whom 1018 patients were randomly allocated: 339 to the durvalumab plus BCG induction and maintenance group (of whom 336 [99%] initiated and 180 [53%] completed treatment), 339 to the durvalumab plus BCG induction group (337 [99%] initiated and 239 [71%] completed treatment), and 340 to the comparison group (339 [>99%] initiated and 182 [54%] completed treatment). At a median follow-up of 60.7 months (IQR 51.5-66.5), there were 67 (20%) disease- free survival events in the durvalumab plus BCG induction and maintenance group and 98 (29%) events in the comparison group, resulting in a 32% reduction in the risk of recurrence of high-risk disease or death by any cause with durvalumab plus BCG induction and maintenance versus the comparison group (hazard ratio 0.68 [95% CI .50-0.93]; log-rank p=0.015). Among patients who received at least one dose of study treatment, grade 3 or 4 treatment-related adverse events occurred in 71 (21%) of 336 patients in the durvalumab plus BCG induction and maintenance group, 52 (15%) in the durvalumab plus BCG induction only group, and 13 (4%) of 339 patients in the comparison group. No treatment-related adverse events led to death. Interpretation Among patients with BCG-naive, high-risk NMIBC, 1 year of durvalumab combined with BCG induction and maintenance therapy showed a statistically significant and clinically meaningful improvement in disease-free survival versus BCG induction and maintenance alone. The combination had a manageable safety profile, consistent with that of the individual therapies. These results support 1 year of durvalumab in combination with BCG induction and maintenance therapy as a potential new treatment for this patient population. Funding AstraZeneca. --- 1350 patients assessed for eligibility 332 excluded 314 not eligible 15 withdrew consent 3 other reasons 1018 randomly assigned 339 assigned to durvalumab plus BCG 339 assigned to durvalumab plus BCG 340 assigned to BCG induction and induction and maintenance (included induction (included in intention-to- maintenance alone (comparison in intention-to-treat analysis) treat analysis) group; included in intention-to-treat analysis) 3 untreated 2 untreated 1 untreated 2 withdrew consent 1 withdrew consent 1 withdrew consent 1 missing reason 1 other reason 336 received at least one dose of study 337 received at least one dose of study 339 received at least one dose of study treatment (included in safety analysis) treatment (included in safety analysis) treatment (included in safety analysis) 180 completed treatment 239 completed treatment 182 completed treatment 156 discontinued treatment 98 discontinued treatment 157 discontinued treatment 61 adverse event 38 adverse event 74 adverse event 45 patient decision 13 patient decision 22 patient decision 31 met discontinuation criteria 37 met discontinuation criteria 52 met discontinuation criteria 2 due to COVID-19 pandemic 8 due to COVID-19 pandemic 1 due to COVID-19 pandemic 1 lost to follow-up 2 other reasons 8 other reasons 16 other reasons 0 still on treatment at data cutoff 0 still on treatment at data cutoff 0 still on treatment at data cutoff 270 still in study at data cutoff* 272 still in study at data cutoff* 263 still in study at data cutoff* --- Durvalumab plus Durvalumab plus Comparison BCG induction and BCG induction group group maintenance group (n=339) (n=340) (n=339) Age, years Median (IQR) 68 (61-74) 68 (61-73) 67 (61-73) <65 121 (36%) 123 (36%) 137 (40%) >65 218 (64%) 216 (64%) 203 (60%) Sex Male 276 (81%) 272 (80%) 271 (80%) Female 63 (19%) 67 (20%) 69 (20%) Race White 267 (79%) 267 (79%) 268 (79%) Asian 61 (18%) 63 (19%) 60 (18%) Other 4 (1%) 6 (2%) 8 (2%) Missing 7 (2%) 3 (1%) 4 (1%) Ethnicity Hispanic or Latino 17 (5%) 14 (4%) 10 (3%) Not Hispanic or Latino 322 (95%) 325 (96%) 330 (97%) Region Western Europe 143 (42%) 126 (37%) 135 (40%) Rest of world 196 (58%) 213 (63%) 205 (60%) ECOG performance status score 0 294 (87%) 305 (90%) 304 (89%) 1 45 (13%) 34 (10%) 36 (11%) Smoking status Current 62 (18%) 60 (18%) 63 (19%) Former 175 (52%) 182 (54%) 173 (51%) Never 102 (30%) 97 (29%) 104 (31%) Carcinoma in situ* Yes 125 (37%) 125 (37%) 125 (37%) No 214 (63%) 214 (63%) 215 (63%) Papillary disease only Yes 217 (64%) 222 (65%) 220 (65%) No 122 (36%) 117 (35%) 120 (35%) T1 diseaset 195 (58%) 191 (56%) 211 (62%) Ta diseaset 112 (33%) 114 (34%) 99 (29%) Tumour PD-L1 expression High$ 81 (24%) 90 (27%) 85 (25%) Low or negative 235 (69%) 228 (67%) 232 (68%) Missing or non-evaluable 23 (7%) 21 (6%) 23 (7%) Data are median (IQR) or n (%). ECOG=Eastern Cooperative Oncology Group. *Per interactive voice response system; data represent patients who had carcinoma in situ (with or without papillary disease) at baseline. +Data represent patients who had papillary disease (with or without carcinoma in situ). #PD-L1 status was determined by the percentage of tumour cells with any membrane staining above background or by the percentage of tumour-associated immune cells with staining at any intensity above background; ICP represents the percentage of tumour area occupied by any tumour-associated immune cells; IC+ represents the percentage area of ICP showing PD-L1 positive immune cell staining. SPD-L1 status was considered high if any of the following criteria were met: >25% of tumour cells showed membrane staining; or ICPwas 1% and IC+ was >25%; or ICP was 1% and IC+ was 100%. Table 1: Baseline demographic and disease characteristics of patients in the intention-to-treat population --- A 100 91.7% Durvalumab plus BCG (I+M) group 86-5% Comparison group 81-8% HR 0-68 (95% CI 0-50-0-93); p=0-015 80 86.8% 81-6% 77-4% Disease-free survival (%) 60 40 20 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75 78 81 Number at risk Time from randomisation (months) (censored) Durvalumab plus BCG (I+M) group 339 321 304 292 289 283 278 273 262 257 250 245 235 229 226 222 220 204 195 156 145 108 94 57 26 9 1 0 (0) (11) (18) (22) (23) (24) (25) (27) (34) (35) (38) (41) (47) (50) (53) (57) (58) (72) (79) (117) (128) (165) (179) (216) (246) (263) (271) (271) Comparison group 340 322 303 292 283 276 271 265 258 254 249 244 237 235 231 227 225 209 196 160 150 101 86 50 20 8 0 0 (0) (4) (8) (9) (13) (13) (15) (19) (21) (22) (24) (27) (29) (30) (32) (34) (34) (49) (59) (93) (100) (147) (161) (194) (223) (234) (241) (241) B Disease-free survival events, n/N (%) HR (95% CI) Durvalumab plus BCG (I+M) group Comparison group All patients 67/339 (20%) 98/340 (29%) 0.68 (0-50-0-93) Age at randomisation, years <65 21/121 (17%) 32/137 (23%) 0.74 (0-42-1-27) >65 46/218 (21%) 66/203 (33%) 0.64 (0-44-0-93) Sex Male 50/276 (18%) 82/271 (30%) 0.59 (0-41-0-83) Female 17/63 (27%) 16/69 (23%) 1-21 (0-61-2-42) Region Western Europe 27/143 (19%) 40/135 (30%) 0.59 (0-36-0-95) Rest of world 40/196 (20%) 58/205 (28%) 0.75 (0-50-1-12) ECOG Performance Status 0 51/294 (17%) 82/304 (27%) 0-64 (0-45-0-90) 1 16/45 (36%) 16/36 (44%) 0.77 (0-38-1-56) Smoking status Current 9/62 (15%) 22/63 (35%) 0.38 (0-17-0-80) Former 38/175 (22%) 48/173 (28%) 0.80 (0-52-1-22) Never 20/102 (20%) 28/104 (27%) 0.74 (0-41-1-31) BCG strain TICE 20/87 (23%) 23/75 (31%) 0-68 (0-37-1-23) Other 46/249 (18%) 75/264 (28%) 0-66 (0-46-0-95) Carcinoma in situ* Yes 32/125 (26%) 33/125 (26%) 1-01 (0-62-1-64) No 35/214 (16%) 65/215 (30%) 0.53 (0-34-0-79) Higher-risk papillary diseaset Yes 32/173 (18%) 57/173 (33%) 0.54 (0-35-0-83) No 35/166 (21%) 41/167 (25%) 0.88 (0-56-1-38) PD-L1 status: HighS 15/81 (19%) 30/85 (35%) 0.50 (0-26-0-91) Low or negative 44/235 (19%) 61/232 (26%) 0.72 (0-48-1-05) Missing or non-evaluable 8/23 (35%) 7/23 (30%) NC (NC-NC) 0-10 0-25 0-50 1-00 1.50 2.50 Favours durvalumab plus BCG (I+M) Favours BCG (I+M)