Mitomycin plus BCG as adjuvant intravesical therapy for high-risk, non–muscle-invasive bladder cancer: A randomized phase 3 trial (ANZUP 1301).

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LBA4504 Background: Intravesical BCG is the standard of care for high-risk non-muscle invasive bladder (NMIBC) after maximal transurethral resection. Availability and access to BCG have been a global challenge since 2013. We sought to determine the efficacy and safety of intravesical treatment with BCG plus mitomycin (BCG+MM) compared with BCG-alone for high-risk, BCG-naïve NMIBC. Methods: This was an open-label, randomized, phase 3 trial. Eligible participants (pts) had high-grade papillary urothelial cancer stages pTa/pT1; concurrent CIS was allowed. Pts were randomly assigned BCG+MM vs BCG-alone. The BCG+MM regimen was weekly induction x 9 (BCG wks 1, 2, 4, 5, 7, and 8; MM wks 3, 6, and 9) followed by 4-weekly maintenance x 9 (MM wks 13, 17, 25, 29, 37, and 41; BCG wks 21, 33, and 45: total of 9 BCG doses). The BCG-alone regimen was weekly induction x 6, then 4-weekly maintenance x 10: total of 16 BCG doses. The primary endpoint was disease-free survival (DFS) at 2 years; secondary outcomes included complete response on cystoscopy at 3 months (CR3mos), time-to-recurrence (TTR), time-to-progression (TTP), overall survival (OS) and adverse events (AE). The target sample size of 500 provided 85% power to detect an absolute improvement of 10% in DFS at 2 years with a type-1 error rate of 0.05. Cox regression was used to calculate hazard ratios (HR), confidence intervals (CI), and account for competing risks. P-values are 2-sided and not adjusted for multiple comparisons. Clinicaltrials.gov NCT02948543. Results: We enrolled 501 pts from DEC2013 to MAY2023: median age 70 years (IQR 63-77); pTa 53%, pT1 47%, concurrent CIS 28%. In this primary analysis, the median follow-up was 47 months (IQR 31-64) at the data cut-off of 06DEC2024. Analyses of all key endpoints (DFS, CR3mos, TTR, TTP and OS) supported similar efficacy in the 2 treatment groups (see table), but none with p<0.05. The total numbers of instillations were higher for BCG+MM than BCG-alone (4,034 vs 3,383), whereas the total doses of BCG (2,056 vs 3,383), and median doses of BCG per pt (9 vs 16) were lower for BCG+MM than BCG-alone. The numbers of pts with grade 3-5 AEs were 43 in BCG-MM vs 37 in BCG-alone. The AE (of any grade) reported by the highest numbers of pts (BCG+MM vs BCG-alone) were fatigue (109 vs 110), renal/urinary (78 vs 83), and flu-like symptoms (34 vs 60). More pts had ≥75% of their planned doses with BCG+MM than BCG-alone (78% vs 68%; p=0.02). Conclusions: BCG+MM had similar efficacy and safety, but with fewer treatment discontinuations and fewer doses of BCG than BCG-alone. BCG+MM is a good alternative to BCG-alone. Clinical trial information: NCT02948543 . BCG+MM N=248 BCG-aloneN=252 HR (95% CI) p-value DFS at 2 years 76% 71% 0.86 (0.64-1.14) 0.30 CR at 3 months 90% 86% 1.05 (0.98-1.12) 0.22 Recurrence-free at 2 years 81% 75% 0.84 (0.61-1.18) 0.31 Progression-free at 5 years 87% 81% 0.74 (0.45-1.21) 0.23 OS at 5 years 87% 87% 1.07 (0.61-1.88) 0.81

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