“The combination may not only be more tolerable, but also more accessible globally, especially where BCG availability is limited”
At the 2025 American Society of Clinical Oncology Annual Meeting, Professor Dickon Hayne (Fiona Stanley Hospital, Perth, Australia) presented late-breaking results from the ANZUP 1301 trial – a study that could influence current clinical practice for high-risk non–muscle-invasive bladder cancer (NMIBC). The data suggest that combining mitomycin C with Bacillus Calmette–Guérin (BCG) could offer a more tolerable, resource-conscious alternative to BCG alone – a particularly timely finding amid persistent global BCG shortages. In this interview, Professor Hayne reveals the thinking behind the trial, the key results and current and ongoing further investigations.
The late-breaking abstract, ‘Mitomycin plus BCG as adjuvant intravesical therapy for high-risk, non–muscle-invasive bladder cancer: A randomized phase 3 trial (ANZUP 1301)’ (LBA4504) was presented at the American Society of Clinical Oncology on May 30 to June 3 2025 in Chicago, IL, USA.
Q1. What was the rationale for investigating the addition of mitomycin C to Bacillus Calmette-Guérin (BCG) therapy in high-risk, non-muscle-invasive bladder cancer patients?
BCG and maintenance therapy have been the mainstay of treatment for high-risk non–muscle-invasive bladder cancer (NMIBC) for almost half a century. And of course, we’re always looking for better options. The rationale for this study was to explore a better treatment for high-risk NMIBC.
There’s actually quite a lot of evidence suggesting that the addition of mitomycin to BCG may be beneficial, but no one had really completed a large, randomized phase III trial to answer that question definitively. There have been signals of efficacy from previous work, including studies using electromotive drug administration of mitomycin, however this involves a device and has not been widely adopted. The CUETO group published a study adding mitomycin to BCG. While they did see reductions in recurrence – so there was efficacy – they also observed quite high toxicity. Their regimen delivered the two drugs on alternate days, which may have contributed to that.
In addition, since 2013, we’ve experienced global shortages of BCG, which have made it difficult for patients to access what has long been considered standard treatment.
Q2. What was the design and methodology of the ANZUP 1301 trial?
We conducted an open-label, phase III randomzed controlled trial comparing BCG induction and maintenance with or without the addition of mitomycin C. We enrolled patients with high-grade Ta or any T1 disease. Patients with concomitant carcinoma in situ (CIS) were eligible, but those with pure CIS were excluded. Participants were randomised 1:1 to receive either BCG alone or BCG plus mitomycin. Blinding wasn’t feasible due to differences in the appearance and safety requirements of the two drugs, as well as differences in their administration schedules.
Q3. What were the key findings regarding recurrence-free survival and progression-free survival in the combination therapy group compared to the BCG-alone group?
Interestingly, because of the different treatment schedules, 40% less BCG was required in the BCG plus mitomycin arm. More patients in that group completed their treatment, suggesting it may have been better tolerated.
Importantly, while the primary endpoint – disease-free survival – was not significantly different between the groups, the BCG–mitomycin arm showed slightly better outcomes across several key efficacy endpoints: disease-free survival, time to recurrence, time to progression and overall survival. None of these differences reached statistical significance, but they all trended in favour of the combination.
We conducted subgroup analyses – a post-hoc subgroup analysis to compare outcomes by T stage, presence or absence of CIS, and also grouped patients into ‘higher risk’ (T1 or CIS) and ‘lower risk’ (high-grade Ta only). In this analysis, the addition of mitomycin appeared to provide greater benefit in the higher-risk subgroup, with a statistically significant interaction between subgroups. This suggests that mitomycin may provide added benefit in patients at higher risk.
At the time the study was designed, high-grade Ta disease alone was considered high-risk NMIBC. However, under more recent European Association of Urology (EAU) classifications, many of those patients would now be considered intermediate-risk.
This is a large, well-conducted trial, and data like this take years to accumulate. While we could wait for another trial, there’s already a substantial body of evidence here.
Q4. How did the addition of mitomycin C affect the safety and tolerability of the treatment regimen? Were there any unexpected adverse events?
Adverse events in both arms were similar to those seen in other intravesical therapy trials. Grade ≥3 adverse events were relatively uncommon in both groups. The overall profile of side effects was quite similar between the two arms.
There were some serious adverse events. Three deaths occurred on treatment – one from myocardial infarction, one from sepsis and one from a BCG-induced mycotic aortic aneurysm. Another patient also developed a BCG-induced aortic aneurysm, and one developed myasthenia gravis – a known complication of BCG. These cases illustrate that serious adverse events can occur even with intravesical BCG. However, the side-effect profile of intravesical BCG remains significantly more favourable than that of systemic immunotherapy, which is increasingly being explored in this setting.
We have collected detailed quality of life data, which are still being analysed and will be presented in due course.
Q5. Based on the study results, how might this combination therapy influence current clinical practice guidelines for high-risk NMIBC?
The trial showed comparable or slightly improved efficacy with the combination compared to BCG alone – and used 40% less BCG, which is significant in the context of a global shortage. This is a large, randomized study using TICE® BCG – which is still widely available and the only formulation approved by the Therapeutic Goods Administration (TGA) in Australia.
I imagine that guidelines might support the use of either BCG maintenance or the combination of BCG and mitomycin. This could be particularly relevant in higher-risk patients, although you could also argue for its broader use given the BCG supply constraints.
Certainly in our own practice, we’ll be offering the BCG–mitomycin combination upfront to most of our high-risk NMIBC patients. There was strong support at the meeting – Professor John P Sfakianos (Memorial Sloan Kettering Cancer Center, USA) was the discussant during the session at ASCO, and he commented: “This is probably one of the most important bladder cancer studies we’ve had in the past few years and will likely change my practice.”
Q6. What are the next steps? Are there plans for further studies to explore this combination therapy?
Absolutely. We have a number of important next steps.
First, we’re finalising the analysis of the health-related quality of life data. Although the overall side-effect profiles appeared similar, the higher completion rate in the BCG–mitomycin arm is worth exploring in more detail. As mentioned, in the CUETO study, BCG plus mitomycin was much more toxic than BCG alone – that doesn’t seem to be the case in our trial.
We also collected tissue samples from all patients, with consent for translational research. We’ve already begun analysing biomarkers that might be predictive or prognostic, and have seen some early signals suggesting certain markers may predict response to mitomycin.
In addition, we’re collaborating with an AI company called Velar Labs, which has developed a tool for AI-based histological assessment of tumour samples. We’re evaluating its performance in patients from both arms of the trial.
We’re also closely following developments with systemic immunotherapy. Recent trials adding systemic immunotherapy to BCG have shown some improvements in recurrence, but at the cost of serious risks – including treatment-related deaths. There may be limited appetite among urologists to expose patients with NMIBC, who might respond well to intravesical therapy, to those kinds of risks.
There are several other intravesical agents under investigation in the primary treatment of high-risk NMIBC, and we’ll need to see robust data before moving towards systemic treatments.
For now, this study presents a strong case for the combination of BCG and mitomycin – especially in light of the global BCG shortage. These are both inexpensive, widely available drugs with well-established safety profiles. Mitomycin was developed in the 1950s. In countries like the UK and many parts of Europe, both drugs are accessible and affordable.
Q7. What final conclusions can be drawn from the data you presented?
Looking ahead, another important consideration is the broader applicability of this combination, particularly in the context of ongoing BCG shortages and the growing trend toward recommending costly systemic or novel intravesical therapies.
Both BCG and mitomycin are long-established, well-studied drugs that are widely available and inexpensive – especially in regions like the UK and much of Europe, where they’re often provided through public health systems. Mitomycin was developed in the 1950s and remains a low-cost option. While BCG tends to be slightly more expensive, both agents are still very affordable compared to newer alternatives.
Of course, pricing and access can vary significantly between countries. But from a global health perspective – where resource constraints are a major factor – the ability to combine two widely available, safe, and proven therapies offers a highly practical and effective option. That’s an important point to keep in mind as treatment strategies for NMIBC continue to evolve.
View full #ASCO25 coverage here!
Disclosures: Dickon Hayne is a member of the Editorial Board and Trial Executive for AstraZeneca, he is a member of the Speakers’ Bureau for BMS and has received research funding from Telix and AstraZeneca.
This content has been developed independently by Touch Medical Media for touchONCOLOGY. It is not affiliated with the American Society of Clinical Oncology (ASCO). Views expressed are the speaker’s own and do not necessarily reflect the views of Touch Medical Media.
Interviewer/Editor: Sophie Nickelson
Cite: #ASCO25 Highlights: Q&A with Prof Dickon Hayne: Can Mitomycin Boost BCG in High-Risk NMIBC? touchONCOLOGY. June 12, 2025.
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