Editor’s note: Bacillus Calmette–Guérin (BCG) is the standard intravesical therapy for patients with high-risk non–muscle-invasive bladder cancer (NMIBC). However, in some countries and regions, BCG shortages remain a challenge, limiting treatment accessibility. The clinical community is actively exploring alternative or optimized treatment approaches. At the 2025 ASCO Annual Meeting, Professor Dickon Hayne from the University of Western Australia (UWA) presented findings from the phase III ANZUP 1301 trial, which explored combining mitomycin with BCG for intravesical therapy in high-risk NMIBC. The results demonstrated efficacy and prognosis comparable to BCG monotherapy, with a higher treatment completion rate and reduced BCG usage.Study Overview
Mitomycin plus BCG as Adjuvant Intravesical Therapy for High-Risk NMIBC: A Phase III Randomized Trial (ANZUP 1301)
Background: For high-risk NMIBC patients, BCG remains the standard intravesical therapy following maximal transurethral resection of bladder tumor (TURBt). Since 2013, however, global access to BCG has been limited. This trial aimed to determine whether a combination of BCG and mitomycin (BCG+MM) offers comparable efficacy and safety to BCG monotherapy in high-risk, BCG-naïve NMIBC patients.
Methods: This was an open-label, randomized phase III trial. Enrolled patients had high-grade papillary urothelial carcinoma staged as pTa or pT1; concomitant carcinoma in situ (CIS) was allowed. Patients were randomly assigned to receive either BCG+MM or BCG alone.
In the BCG+MM arm, induction therapy was administered weekly over nine weeks: BCG in weeks 1, 2, 4, 5, 7, and 8, and mitomycin in weeks 3, 6, and 9. Maintenance therapy was given every four weeks for nine cycles: mitomycin at weeks 13, 17, 25, 29, 37, and 41; BCG at weeks 21, 33, and 45—a total of nine BCG doses. In the BCG monotherapy arm, patients received weekly induction for six weeks, followed by maintenance every four weeks for ten cycles, totaling sixteen BCG doses.
The primary endpoint was two-year disease-free survival (DFS). Secondary endpoints included complete response at 3 months on cystoscopy (CR3mos), time to recurrence (TTR), time to progression (TTP), overall survival (OS), and adverse events (AEs). The planned enrollment was 500 patients, with 85% power to detect a 10% absolute improvement in 2-year DFS at a type I error rate of 0.05. Cox regression was used to calculate hazard ratios (HRs) and confidence intervals (CIs), accounting for competing risks. P-values were two-sided and not adjusted for multiplicity. ClinicalTrials.gov ID: NCT02948543.
Results
From December 2013 to May 2023, a total of 501 participants were enrolled. The median age was 70 years (interquartile range: 63–77). Pathological stage was pTa in 53% and pT1 in 47% of patients, with 28% having concomitant CIS.
As of the primary analysis data cutoff on December 6, 2024, the median follow-up was 47 months (IQR: 31–64). Across all key endpoints (DFS, CR3mos, TTR, TTP, and OS), the efficacy of both treatment groups was similar. However, none of the P-values reached statistical significance (<0.05).
The total number of intravesical instillations was higher in the BCG+MM group (4,034 vs. 3,383), but total BCG doses (2,056 vs. 3,383) and median BCG doses per patient (9 vs. 16) were lower in the combination group.
Grade 3–5 adverse events occurred in 43 patients in the BCG+MM group and 37 in the BCG-only group. The most frequently reported AEs (any grade) were fatigue (109 vs. 110), genitourinary symptoms (78 vs. 83), and flu-like symptoms (34 vs. 60) in the BCG+MM and BCG-only groups, respectively.
Notably, a higher proportion of patients in the BCG+MM group completed ≥75% of the planned treatment doses compared to the BCG monotherapy group (78% vs. 68%, P = 0.02).
Conclusion: BCG+MM demonstrated comparable efficacy and safety to BCG alone, with fewer treatment interruptions and reduced BCG dosage. BCG+MM represents a strong alternative to standard BCG monotherapy.
Investigator Insights
Oncology Frontier: Intravesical BCG remains the standard treatment for patients with high-risk non–muscle-invasive bladder cancer (NMIBC), yet approximately 30% of patients still experience recurrence. Based on your clinical experience, could you share some of the current unmet needs in treating high-risk NMIBC?
Professor Dickon Hayne: We’ve long been searching for ways to improve treatment outcomes for patients with high-risk NMIBC. It’s quite remarkable that BCG monotherapy has remained the primary treatment for this group for over half a century. Of course, new drugs are under development, and some systemic therapies beyond BCG are now being explored.
However, NMIBC is a localized disease, and applying systemic immunotherapy to such a condition may introduce unnecessary treatment-related side effects. That’s why many studies have investigated the addition of chemotherapy agents—such as combining mitomycin with BCG—but until now, this strategy had not been rigorously tested in a large-scale randomized trial. That’s exactly what we aimed to accomplish with the ANZUP 1301 study evaluating BCG plus mitomycin.
Oncology Frontier: Your study on BCG combined with mitomycin as adjuvant therapy has been featured multiple times at ASCO, offering a new treatment option for NMIBC. Could you share the specific efficacy results of this research? In your view, what impact might it have on clinical practice?
Professor Dickon Hayne: Yes, this study has previously been presented at earlier meetings as a trial in progress. It is a randomized phase III clinical trial designed to evaluate the safety and efficacy of BCG combined with mitomycin as intravesical therapy. In fact, we began enrolling patients as early as 2013. Between 2013 and 2023, we randomized 501 patients to receive either BCG alone or BCG in combination with mitomycin.
The primary results showed that the combination of BCG and mitomycin achieved similar efficacy and safety compared to BCG monotherapy. However, we observed a higher treatment completion rate in the BCG plus mitomycin group. Importantly, the total BCG dosage was reduced by 40%.
We also conducted a retrospective subgroup analysis, which suggested that in high-risk patient populations, the addition of mitomycin may offer further improvement in disease-free survival (DFS). In short, BCG combined with mitomycin is a strong alternative to BCG alone.
Right now, we are facing a global shortage of BCG, with estimates indicating that supply falls short by 30% to 50%. Broad adoption of the BCG plus mitomycin regimen could be a practical solution to help alleviate this worldwide BCG shortage.
Oncology Frontier: In clinical practice, combination therapies often come with increased toxicity. Why did this study observe better tolerability with the combination of BCG and mitomycin?
Professor Dickon Hayne: I think one reason is that although other studies have also looked at combining mitomycin with BCG, the toxicity has generally been more pronounced. In our study, the adverse events observed in the combination group were comparable to those in the BCG monotherapy group, and there was no statistically significant difference.
What stood out, however, was that the treatment completion rate was higher in the combination group—78% compared to 68%, with a P value of 0.02. This suggests that the combination therapy may actually be better tolerated than BCG alone. Given past data, that may seem a little unexpected, but I believe it reflects the design and practicality of the regimen itself. It’s a well-tolerated treatment approach.
Oncology Frontier: Looking ahead, what areas of NMIBC research will you and your team continue to explore?
Professor Dickon Hayne: We recently completed a phase I clinical trial involving durvalumab, not as a systemic immunotherapy, but delivered via suburothelial injection, directly into the bladder wall. The study, called the SUBDUE-1 trial, was a dose-escalation, proof-of-concept study. In this small study, we found that durvalumab was very safe, with no immune-related adverse events reported. Importantly, we also observed local immune responses within the bladder. I would like to see more large-scale studies on locally administered immunotherapies, which could potentially deliver the benefits of immunotherapy while avoiding systemic side effects. That is certainly a direction we’re eager to pursue in the future.
Of course, there are also several new agents already approved in the United States but not yet available in Australia, such as N-803 (Anktiva) and nadofaragene firadenovec (Adstiladrin). Both are commercially available in the U.S. and appear to have activity in BCG-unresponsive disease. Whether these therapies could be used earlier in combination with other agents for high-risk NMIBC is a very interesting question.
Additionally, we have recently been involved in three trials using systemic immune checkpoint inhibitors. For example, the CREST trial is studying the PD-1 inhibitor sasanlimab combined with BCG as maintenance therapy. The POTOMAC trial is evaluating durvalumab, and while the full results haven’t been published yet, a press release indicates that it was a positive study. There are also upcoming trials investigating systemic pembrolizumab in combination with BCG and mitomycin, but in my view, these regimens are unlikely to see widespread adoption due to concerns over cost and toxicity, which need to be carefully weighed.
