Neoadjuvant Mitomycin C Demonstrates Favorable Safety and Potential RFS Benefit in NMIBC

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Treatment with neoadjuvant mitomycin C prior to transurethral resection of bladder tumor (TURBT) demonstrated a favorable safety profile in patients with non–muscle-invasive bladder cancer (NMIBC). Although an improvement in recurrence-free survival (RFS) compared with standard management was not observed at 12 months, an improvement in 18-month RFS rate with mitomycin C could point to a potential delayed benefit with the neoadjuvant approach, according to findings from a phase 3, prospective, single-center, randomized trial (EudraCT 2021-003751-42) presented at the 2025 American Urological Association Annual Meeting.

At a median follow-up of 19.4 months, findings showed that the Kaplan-Meier–estimated 12-months RFS rate was 88% (95% CI, 67%-96%) in both the standard arm (n = 27) and the neoadjuvant mitomycin C arm (n = 28; HR, 0.97; 95% CI, 0.2-4.8; P = .9). The 18-month RFS rates were 71% (95% CI, 46%-86%) in the standard arm vs 88% (95% CI, 67%-96%) in the neoadjuvant mitomycin C arm (HR, 0.4; 95% CI, 0.1-1.8; P = .27).

“Even if statistical significance was not reached, the improvement in RFS at 18 months for the mitomycin C group could suggest a potential delayed benefit of the neoadjuvant approach,” lead study author Roberto Contieri, MD,said in presentation of the data. Contieri is a resident in urology at Humanitas University in Milan, Italy.

Phase 3 Trial Design

The randomized, open-label, single-center trial enrolled 63 patients with primary or recurrent NMIBC who had not received prior adjuvant intravesical therapy. Additional inclusion criteria required the presence of at least 1 tumor larger than 1 cm identified via imaging or cystoscopy; an ECOG performance status of less than 2; and a negative urine culture prior to enrollment.

Patients were randomly assigned to receive either neoadjuvant mitomycin C or no neoadjuvant therapy (control arm) prior to TURBT. In the experimental arm, patients underwent cystoscopy and tumor biopsy followed by mitomycin C instillation on day –14 and a second mitomycin C instillation on day –7. All patients underwent TURBT on day 0, followed by adjuvant intravesical therapy in accordance with European Association of Urology (EAU) guidelines. Follow-up cystoscopies were performed at 3 months and beyond.

The primary end point was RFS rate assessed at 12 and 18 months post-TURBT. Secondary end points included the safety profile of neoadjuvant mitomycin C and assessment of differences in histologic findings between pre-instillation biopsies and TURBT specimens. A sensitivity analysis was also conducted, including only patients who received adjuvant intravesical instillation with BCG or mitomycin C.

Baseline Patient Demographics

The baseline demographics and disease characteristics were well balanced between the neoadjuvant mitomycin C cohort (n = 30) and the control cohort (n = 31). Among patients in the neoadjuvant mitomycin C arm, all had a primary tumor at baseline compared with 94% in the control arm. According to the 2004/2022 World Health Organization (WHO) classification, 50% of patients in the neoadjuvant mitomycin C cohort had low-grade tumors, and 43% had high-grade tumors; 6.7% were classified as benign. In the control arm, 55% had low-grade tumors and 45% had high-grade tumors. Based on the 1973 WHO classification, the distribution of tumor grade was also comparable between groups, with 50% vs 52% classified as grade 1; 20% vs 10% as grade 2; and 33% vs 39% as grade 3 in the neoadjuvant mitomycin C and control arms, respectively.

Clinical T stage distribution indicated that the majority of patients in both groups had Ta disease (neoadjuvant mitomycin C arm, 80%; control arm, 74%). Carcinoma in situ (CIS) was present in 3.3% of patients in the neoadjuvant mitomycin C cohort and 10% in the control cohort. Presence of urothelial subtypes was observed in 6.7% vs 16% of patients, respectively. Rates of tumors larger than 3 cm were similar between groups (37% vs 35%), as were rates of multifocal tumors (30% vs 35%).

Most patients had negative surgical margins after TURBT; 87% of patients in both groups had no evidence of detrusor muscle invasion (DM negative). Re-TURBT was performed in 10% of patients receiving neoadjuvant mitomycin C and in 19% of those in the control group.

Within the neoadjuvant mitomycin C group, results of pre-mitomycin C biopsies showed that 67% of patients had low-grade disease, 20% had high-grade disease, and 13% had specimens deemed non-evaluable. Histologic comparisons between biopsy and TURBT specimens demonstrated that tumor grade was confirmed in 67% of cases, with upgrading at TURBT occurring in 20% of patients. Additionally, visual evaluation of tumor response indicated that 7% of patients experienced tumor size reduction, and the majority (93%) had no visible change.

Safety Analysis

Findings showed neoadjuvant mitomycin C was generally well tolerated. Among patients who experienced treatment-related adverse effects (AE; n = 8), all were grade 1 or 2 in severity.

The most commonly reported AE was hematuria, occurring in 3 patients (37.5%). Dysuria and itchy scalp were each reported in 2 patients (25%), and skin erythema was noted in 1 patient (12.5%). No grade 3 or higher AEs were observed.

Reference

Contieri R, Saita A, Paciotti M, et al. Evaluating neoadjuvant intravesical mitomycin C in NMIBC: A phase III randomized clinical trial. Presented at: 2025 AUA Annual Meeting; April 26-29, 2025; Las Vegas, NV. Abstract PD12-04.