Intravesical bacillus Calmette-Guérin (BCG) plus mitomycin (MM) had not been compared rigorously with BCG alone in BCG-naïve, non–muscle-invasive bladder cancer (NMIBC) patients.
Participants with BCG-naïve NMIBC (high-grade pTa or any grade pT1; concurrent carcinoma in situ [CIS] allowed) were assigned randomly (1:1) to either the BCG + MM or the BCG-alone group after maximal transurethral resection. The primary endpoint was disease-free survival (DFS); the secondary endpoints included a complete response on cystoscopy at 3 mo (CR3mos), recurrence, progression, adverse events (AEs), and deaths from any cause.
We randomised 501 participants (249 to BCG + MM and 252 to BCG alone), with pTa in 53%, pT1 in 47%, and concurrent CIS in 28%. The median follow-up was 48 mo. DFS was not superior for BCG + MM versus BCG alone (2-yr DFS rate: 75% vs 71%; hazard ratio 0.87, 95% confidence interval 0.65–1.16; p = 0.3). The numbers of events for BCG + MM versus BCG alone were as follows: 214 versus 210 (CR3mos), 79 versus 86 (recurrence), 28 versus 44 (progression), and 26 versus 23 (death). Those assigned BCG + MM had more instillations (4033 vs 3383) but fewer doses of BCG (total 2056 vs 3383; median nine vs 16) than BCG alone. Grade 3–5 AEs occurred in 43 assigned BCG + MM versus 37 assigned BCG alone. A higher number of participants assigned BCG + MM than those assigned BCG alone had ≥75% of their planned doses (78% vs 68%, p = 0.02).
BCG + MM was not proved superior to BCG alone, but required 39% fewer doses of BCG and fewer treatment discontinuations. These findings support consideration of BCG + MM as a pragmatic alternative to BCG alone, which could mitigate the global shortage of BCG.
Intravesical bacillus Calmette-Guérin (BCG) has remained the reference adjuvant treatment for high-risk non-muscle-invasive bladder cancer (NMIBC) for several decades. However, it remains an imperfect treatment. A meaningful proportion of patients recur or progress despite adequate therapy; supply shortages continue to affect clinical practice in several countries; and, although toxicity is usually manageable, local and systemic adverse events are frequent and may lead to treatment discontinuation in a non-negligible minority of patients. These limitations have sustained long-standing efforts to improve the efficacy and deliverability of BCG-based regimens.
Combining BCG with intravesical mitomycin (MM) is one such strategy, supported by a plausible biological rationale. Beyond its direct cytotoxicity, MM may induce immunogenic cell death through mitochondrial metabolic reprogramming, with release of damage-associated signals capable of recruiting and activating innate immune cells [1]. In principle, these effects could prime or amplify the immune response elicited by BCG. Clinically, the Di Stasi trial of sequential BCG and electromotive MM first suggested improved recurrence, progression, and disease-free survival compared with BCG alone [2]. The phase III ANZUP 1301 trial [3] now asks whether this advantage extends to conventional, non-electromotive BCG plus MM in BCG-naïve disease.
For the primary endpoint, the answer is negative. Among 501 patients with high-grade pTa or any-grade pT1 disease, with concurrent CIS permitted, randomised 1:1 after maximal TURBT, the addition of MM did not improve DFS. The 2-year DFS rate was 75% with BCG plus MM versus 71% with BCG alone (HR 0.87, 95% CI 0.65–1.16; p=0.3). Because the trial was powered for superiority rather than non-inferiority, the conclusion is clear: BCG plus MM was not superior to BCG alone, and secondary findings must be interpreted within this framework.
Those secondary signals, however, are clinically relevant. Progression occurred in 28 versus 44 patients, corresponding to 24-month progression-free rates of 92% versus 88% (HR 0.63, 95% CI 0.39–1.01; p=0.053). In addition, a post hoc analysis suggested that the benefit of combination therapy was concentrated in higher-risk disease, defined as pT1 or pTa with CIS (HR 0.69, 95% CI 0.48–0.99), with no apparent benefit, and even a numerically opposite trend, in pTa disease without CIS (interaction p=0.04). These findings are biologically coherent and consistent with earlier combination-therapy data, but they remain exploratory, unadjusted for multiplicity, and should be regarded as hypothesis-generating.
The principal advantage of the trial may therefore be logistical rather than strictly oncological, but it should not be dismissed. The combination arm required 39% fewer BCG doses, with a median of 9 versus 16, yet achieved higher treatment completion. Overall, 78% versus 68% of patients received at least 75% of planned instillations (p=0.02), and 75% versus 64% completed the full schedule (p=0.009). Since adherence to intravesical therapy is itself prognostically relevant in NMIBC, a regimen that more patients can complete has real-world value, even in the absence of superiority for DFS.
One nuance is important. Higher completion was achieved despite a greater total number of instillations in the combination arm, 4033 versus 3383, because MM replaced part of the BCG course rather than reducing the number of visits. The gain in completion, therefore may reflect better tolerability and fewer discontinuations when MM substitutes for some BCG doses, not a lighter treatment burden. This distinction matters when counselling patients on what “less BCG” means in practice.
A protocol-level issue also warrants consideration. The control arm consisted of six weekly induction instillations followed by monthly maintenance for one year. This is a pragmatic and deliverable schedule, but it differs from the Lamm-SWOG regimen, consisting of three weekly instillations at 3, 6, 12, 18, 24, 30, and 36 months, on which the recurrence- and progression-reducing benefit of maintenance BCG was originally established [4]. Direct evidence comparing monthly maintenance with the SWOG schedule remains limited to retrospective series and small randomised studies, while EORTC data suggest that shortening maintenance from three years to one year modestly worsens recurrence outcomes in higher-risk disease [5]. Therefore, ANZUP 1301 addresses whether BCG plus MM improves outcomes over a pragmatic one-year monthly BCG schedule, rather than whether it matches optimally delivered BCG monotherapy. The authors reasonably note that the SWOG schedule is difficult to deliver in routine practice, with only 16% of patients completing it in the original trial. Nevertheless, deliverability and benchmark efficacy are distinct concepts.
Taken together, ANZUP 1301 provides timely randomised evidence that BCG plus MM is a credible, inexpensive, and broadly deployable BCG-sparing option. It offers a real advantage in treatment completion and generates an intriguing signal in higher-risk disease, but it does not demonstrate superiority for DFS. As a negative superiority trial using a pragmatic rather than SWOG-based comparator, it refines the discussion around BCG-sparing strategies more than it resolves it.
References
[1] Oresta B, Pozzi C, Braga D, et al. Mitochondrial metabolic reprogramming controls the induction of immunogenic cell death and efficacy of chemotherapy in bladder cancer. Sci Transl Med. 2021;13(575):eaba6110.
[2] Di Stasi SM, Giannantoni A, Giurioli A, et al. Sequential BCG and electromotive mitomycin versus BCG alone for high-risk superficial bladder cancer: a randomised controlled trial. Lancet Oncol. 2006;7:43–51.
[3] Hayne D, Zhang AY, Thomas H, et al. Bacillus Calmette-Guérin Plus Mitomycin Versus Bacillus Calmette-Guérin Alone for Bacillus Calmette-Guérin–naïve Non–muscle-invasive Bladder Cancer: A Randomised Phase 3 Trial (ANZUP 1301). Eur Urol. 2026;89:446–453.
[4] Lamm DL, Blumenstein BA, Crissman JD, et al. Maintenance bacillus Calmette-Guerin immunotherapy for recurrent Ta, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol. 2000;163:1124–1129.
[5] Cambier S, Sylvester RJ, Collette L, et al. EORTC nomograms and risk groups for predicting recurrence, progression, and disease-specific and overall survival in non-muscle-invasive stage Ta-T1 urothelial bladder cancer patients treated with 1-3 years of maintenance bacillus Calmette-Guérin. Eur Urol. 2016;69:60–69.