Evaluating neoadjuvant intravesical mitomycin C in NMIBC: A phase III randomized clinical trial.

803 Background: The primary treatment for non-muscle invasive bladder cancer (NMIBC) is transurethral resection (TUR), often followed by adjuvant intravesical therapies. Given the variable response to intravesical therapy, enhancing its efficacy is critical to reducing recurrence and progression to MIBC. Recent studies have shown that MMC induces immunogenic cell death, suggesting its potential in enhancing the effectiveness of other intravesical therapies, such as BCG, activating acquired immunity. This study aimed to evaluate the safety and efficacy of neoadjuvant MMC in patients with NMIBC. Methods: This is a prospective, phase III randomized clinical trial in patients with primary or recurrent BC who had not received intravesical therapy between May 2022 and June 2024 (EudraCT 2021-003751-42; ICH-013). Patients were randomized 1:1 to either the neoadjuvant MMC arm (neoA) or the standard treatment arm (StA). In the two weeks preceding the scheduled TURBT (day 0), patients in the neoA arm received intravesical MMC (40 mg/40 ml) on days -14 and -7, along with cystoscopy and cold-cup biopsy on day -14. Clinical decisions regarding adjuvant therapy and follow-up (FU) schedules in both groups were based on the tumor histology according the European Association of Urology (EAU) guidelines. The primary endpoint was to evaluate the safety, and efficacy of neoadjuvant MMC in reducing the recurrence rate of BC. Patients with MIBC or pT0 were excluded from survival analyses. Results: A total of 63 patients were included: 31 (49%) in the StA group and 32 (51%) in the neoA group. The groups were homogeneous in clinical and pathological characteristics.In the neoA group, 8 adverse events (AEs) were reported in 5 patients (14%), all mild (Grade 1 and 2). Following TUR, 26 AEs grade 1 and 2 were observed in 16 (50%) patients in the StA group, and 24 AEs in 14 (45%) patients in the neoA group, with no significant differences between the groups (p=0.6).In the neoA group, 16 patients had TaLG, 9 had TaHG, 3 had T1HG, 1 had CIS, and 2 had benign findings. No complete tumor ablation occurred, with only 2 cases showing reduced tumor size. In the StA group, 17 had TaLG, 6 had TaHG, 5 had T1HG, and 3 had T2 tumors. After a median FU of 14.5 months, 5 patients in the StA group and 4 in the neoA group recurred. Only one patient, in the neoA group, progressed to MIBC. The 12-month recurrence-free survival (RFS) was 91% (95% CI: 68-98) in the StA group and 84% (95% CI: 62-94) in the neoA group, with no statistically significant difference between the two groups (log-rank test p=0.8). Conclusions: Neoadjuvant MMC showed a favorable safety and tolerability profile. Although no significant RFS difference was found between the neoA and standard arms, a larger cohort and longer FU are needed for definitive conclusions on MMC's oncological efficacy. The upcoming analysis of the adjuvant BCG subgroup will further clarify MMC's role in enhancing BCG efficacy.