Mitomycin/BCG Combo Shows Similar Efficacy, Reduced BCG Use in NMIBC

A combination of BCG and mitomycin offers a comparable treatment option to BCG monotherapy for NMIBC, potentially lessening the impact of global BCG shortages.

In the phase 3 ANZUP 1301 trial (NCT02948543), intravesical BCG plus mitomycin showed similar efficacy and safety compared to BCG alone for patients with non–muscle-invasive bladder cancer (NMIBC), and resultedin a 40% reduction in the amount of BCG used, according to findings shared at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.

With a median follow-up of 48 months (IQR, 34-64), the disease-free survival (DFS) rate at 2 years was 75% (95% CI, 70%-81%) with BCG plus mitomycin (n = 249) compared with 71% (95% CI, 65%-77%) for BCG alone (n = 252; HR, 0.87; 95% CI, 0.65-1.16; P = .34). The complete response (CR) rate at 3 months was 90% with the combination and 86% with BCG alone (RR, 1.05; 95% CI, 0.98-1.12; P = .22). Adverse effects (AEs) were similar between the 2 arms, with fewer flu-like symptoms seen in the combination arm. Overall, 2056 doses of BCG were used in the investigational arm compared with 3383 in the monotherapy group.

“In ANZUP 1301, which is one of the largest NMIBC studies to be reported in recent times, BCG plus mitomycin shows similar efficacy and safety to BCG alone with fewer treatment discontinuations, and we’ve seen that high-risk patients may do better with the addition of the mitomycin,” principal investigator Dickon Hayne, MD, FRCS, MBBS, of UWA Medical School, University of Western Australia, said during a presentation of the results. “BCG plus mitomycin is a good alternative to BCG alone, and there were 40% fewer BCG doses required. Wide adoption of this regimen could go some way to alleviate the global BCG shortage.”

Assessing ANZUP 1301: Design, Objectives, Population

The study enrolled patients with high-risk NMIBC (high-grade Ta or any grade T1) who were suitable for intravesical chemotherapy. They were randomly assigned to receive either BCG plus mitomycin or BCG alone. During the induction period in the combination arm, BCG was given alone for weeks 1, 2, 4, 5, 7, and 8 with mitomycin delivered alone on weeks 3, 6, and 9. In the BCG-alone arm, the treatment was administered weekly from week 1 to 6. Induction lasted through 11 weeks, with a cystoscopy and biopsy completed at week 12 (3 months). Those with a response received maintenance therapy. In the combination arm, this consisted of mitomycin on weeks 13, 17, and 25 with BCG on week 21. In the BCG-alone arm, the treatment was given on weeks 13, 17, 21, and 25. Cystoscopy and biopsy were completed at the 3- and 9-month marks with a similar treatment pattern followed until 12 months.

The primary end point of the study was DFS. Additional end points included CR on cystoscopy and biopsy at 3 months, time to recurrence, time to progression, overall survival, safety, and health-related quality of life.

Baseline characteristics were well balanced in the study. There was no cap on age, Hayne noted; the mean age was 69 years, with several being well into their 90s, he added. The study was predominantly men, with 22% being female in the combination group and 16% in the monotherapy arm. In the combination and BCG-alone arms, respectively, patients were evenly split with regard to having T1 disease (46% vs 47%) and Ta disease (54% vs 53%). Carcinoma in situ was seen in 28% of patients in both arms. ECOG performance status was not limited, to reflect a real-world population, Hayne noted. The statuses in both groups were similar, with the combination arm having ECOG performance statuses of 0 (82%), 1 (18%), and 2 (0.4%); the monotherapy arm also had ECOG performance status of 0 (82%), 1 (17%), and 2 (1.6%).

Additional Efficacy Data

At 24 months, 80% (95% CI, 75%-85%) of patients remained recurrence free in the BCG-plus-mitomycin group compared with 75% (95% CI, 70%-81%) of those in the BCG alone group (sub HR, 0.85; 95% CI, 0.61-1.19). Additionally, at the 24-month milestone, 92% (95% CI, 89%-96%) of patients in the combination group were progression free compared with 90% (95% CI, 87%-94%) in the BCG group (sub HR, 0.68; 95% CI, 0.41-1.11).

There were 26 deaths in the combination arm and 23 in the BCG-alone arm. Of the deaths, 7 in the combination group were related to bladder cancer compared with 5 in the BCG monotherapy group. At 5 years, the OS rate was 88% for those in the BCG plus mitomycin arm compared with 87% in the BCG alone group (HR, 1.06; 95% CI, 0.60-1.86; P = .85).

An analysis of DFS was completed across various key subgroups. By tumor stage, there was a larger benefit seen with the combination in those with stage T1 disease. In this cohort (n = 234), the HR for DFS was 0.74 (95% CI, 0.49-1.11; P = .29). In those with Ta stage disease, the HR was 1.00 (95% CI, 0.67-1.50).

A post hoc analysis categorized patients by risk level, with higher risk including those with T1 stage and carcinoma in situ. In this group (n = 298), the HR for DFS was 0.69 (95% CI, 0.48-0.99; P = .043) favoring the combination arm. In lower-risk patients, defined as high-grade Ta and no carcinoma in situ, the HR was 1.28 (95% CI, 0.79-2.09).

Safety Spotlight

The most reported AEs were fatigue; this was followed by renal/urinary symptoms and flu-like symptoms. There were 3 deaths on treatment, 2 in the BCG-only arm in the form of myocardial infarction and sepsis and 1 in the combination arm in the form of BCG-related mycotic aortic aneurysm. Other serious AEs included 1 case of mycotic aortic aneurysm in the BCG-only group and 1 case of myasthenia gravis in the combination group, although this event was associated with BCG, Hayne noted.

There were 4033 total treatments administered in the BCG-plus-mitomycin group compared with 3383 in the BCG-only group. The median number of BCG doses administered in the combination group was 9 compared with 16 in the single-agent group. More patients received more than 75% of their planned doses in the combination group compared with the single-agent group (78% vs 68%; P = .02). Seventy-five percent of patients completed all doses in the combination group compared with 64% in the BCG group.

Contextualizing the Data

“The BCG shortage is really affecting everyone worldwide, and we need to understand better regimens that we can offer,” said invited discussant John Sfakianos, MD, from the Icahn School of Medicine at Mount Sinai. “BCG and mitomycin is a combination that is well tolerated, has similar efficacy to BCG alone, and it's something that I will probably now start to incorporate in my practice. This study should be applauded for actually being clinically changing.”

A pyelocalyceal solution of mitomycin is currently approved for the treatment of low-grade upper tract urothelial cancer, an indication it first received in 1974. The version of mitomycin used in the clinical study was manufactured and provided by Omegapharm, Hayne noted.

Including ANZUP, several other studies have looked to expand the role of various forms of mitomycin in the treatment of bladder cancer, particularly through the intravesical solution known as UGN-102. In late May 2025, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 5-to-4 against the risk/benefit profile of this version of mitomycinas a treatment for patients with recurrent, low-grade, intermediate-risk NMIBC.2

References

1. Hayne D, Zhang AY, Thomas H, et al. Mitomycin plus BCG as adjuvant intravesical therapy for high-risk, non–muscle-invasive bladder cancer: A randomized phase 3 trial (ANZUP 1301). J Clin Oncol. 2025;43 (suppl 17):LBA4504. doi:10.1200/JCO.2025.43.17_suppl.LBA4504
2. May 21, 2025, Meeting of the Oncologic Drugs Advisory Committee (ODAC). FDA. Accessed June 1, 2025. https://www.youtube.com/live/5ecyDbK9ezc