BCG/ICI combinations offer potential paradigm shift in BCG-naïve NMIBC

BCG has been the standard of care for patients with high-risk, BCG-naïve non–muscle invasive bladder cancer (NMIBC) for more than 30 years. Yet a significant challenge remains: a subset of patients eventually fail BCG therapy, leaving them with limited treatment options.

In the following interview, Tom Jayram, MD, a urologic oncologist at Urology Associates in Nashville, Tennessee, discusses the evolving treatment landscape for BCG-naïve NMIBC, which is offering hope in overcoming BCG resistance.

The current approach involves combining BCG with immune checkpoint inhibitors (ICIs). By targeting the PD-1/PD-L1 pathway, these regimens aim to overcome the mechanisms of resistance with BCG monotherapy. Several of these regimens are currently in phase 3 development.

The first data readout on one such of these combinations was from the phase 3 CREST trial. Preliminary findings from the CREST trial (NCT04165317) were presented at the 2025 American Urological Association (AUA) Annual Meeting in Las Vegas, Nevada, showing that the combination of BCG plus sasanlimab significantly improved event-free survival vs BCG alone (HR, 0.68; 95% CI, 0.49 to 0.94; P = .019).¹

In the near future, we can also expect to see data from the POTOMAC (NCT03528694) and PATAPSCO (NCT05943106) trials, evaluating the combination of durvalumab plus BCG in this setting, as well as from the ALBAN trial (NCT03799835), evaluating the combination of atezolizumab plus BCG.

These regimens have the potential to redefine the treatment landscape for BCG-naïve NMIBC. While the data is still maturing, one thing is clear: We are on the cusp of a transformational shift in the management of BCG-naïve NMIBC, with BCG/ICI combinations leading the charge.

Urology Times: What are the current unmet needs for patients with high-risk BCG-naïve non–muscle invasive bladder cancer?

Jayram: It's an interesting time in the BCG-naïve space, predominantly driven by some questions we have about the future of BCG. We're currently in an era where there is a shortage, but we're also in an era where there is a lot of novel therapies and new mechanisms of action that are hitting the stage. What I think about when I think of the spaces is trying to understand who is going to benefit from what, and how do we get those patients towards the right treatment?

BCG, as we know, is still extremely effective. We have seen that from some of the trials in the BCG-naïve space. The complete response rates at 1 year, 2 years, and 3 years is still very high. However, we know that a percentage of patients will eventually become BCG-unresponsive. For that group of patients, trying to understand if we can change their initial treatment, or if we can try to develop some sort of biomarkers that may predict if they will be better off with another treatment, I think is going to be the primary concern.

Urology Times: From your perspective, how important is it to expand bladder sparing treatment options?

Jayram: Bladder preservation is a hot topic right now, and we're seeing a lot of conceptually different things happening in muscle-invasive disease. We're not jumping immediately to the thought of radical surgery in the non–muscle invasive setting, even in BCG-unresponsive disease, because we have such new, effective therapies.

Bladder preservation is very important. It's what patients want. We know that from a quality-of-life standpoint, patients do very well and are very happy preserving their bladder. The thing that I always tell my patients is that we have to match the intensity of the disease with the intensity of the treatments, and radical cystectomy is a very aggressive treatment. It's very necessary for some patients, but the key is, are there patients [in whom] we could potentially avoid a cystectomy and still get a very good outcome?

Urology Times: There are several investigational regimens exploring the combination of BCG with immune checkpoint inhibitors such as sasanlimab, atezolizumab, and durvalumab. What is the rationale for combining BCG with these PD-1/PD-L1 inhibitors in this space?

Jayram: The thought is that when patients fail BCG or they're not responding to it optimally, there might be some immune escape mechanism that's happening, which may be mediated through the PD-1/PD-L1 pathway. By reinvigorating that pathway with a checkpoint inhibitor, we may be able to augment the response to BCG. Ultimately, the hope is that it makes the immune therapy better and it avoids or bypasses that immune escape phenomenon that we see where some patients don't respond to BCG in an optimal manner.

Urology Times: What do you see as potential strengths or limitations of these agents?

Jayram: It's all going to come down to patient selection and trying to understand which patients are going to be best intensified. The checkpoint inhibitors have shown a tremendous amount of activity in urothelial carcinoma, but they also have systemic [adverse] effects. For a group of patients that have non–muscle invasive disease, you want to maximize your ability to treat patients without introducing a whole lot of serious [adverse] effects. That comes down to patient selection and potentially developing biomarkers to help us understand which patients may need to be intensified, or which patients would be best intensified.

Obviously, it's going to come down to a discussion with the patient. Some patients may do very well with checkpoint inhibitors and not develop [adverse] effects. Some patients may have permanent [adverse] effects. Giving the patient that education and helping them decide is going to be a big part of our jobs going forward.

Urology Times: Pending FDA approval, how will agents such as sasanlimab fit into clinical practice? How accessible do you think these agents will be, particularly in community practice?

Jayram: It's a great question. The results of the CREST trial, which were presented at the AUA, opened a lot of people's eyes, and a lot of people are talking about this. We're going to have PATAPSCO and POTOMAC results unveiled here in the next 3 to 4 months in a similar space.

About 20% to 30% of community practices are already giving their own checkpoint inhibitors. The question becomes, now with the subcutaneous checkpoint inhibitor, is that going to change a lot? My feeling is that because the primary issue is still going to be managing the adverse events, I don't know that a lot more practices are going to start giving it right away, but it may make people more interested in trying to adopt a program and treat their own patients. [This may be] especially [true] in the BCG- naïve setting, [where] you're looking at treating a much larger group of patients than you would be in the BCG-unresponsive setting. I do think there's going to be interest in operationalizing a program for more community groups. Certainly, the groups that are already doing it are going to switch over to the subcutaneous form.

I think that a lot of us are very well positioned to do this. We have programs with a team-based approach where we're already managing the [adverse] effects of checkpoint inhibitors quite well. I think the community is excited for this, and many groups are very capable of doing this. Certainly not everybody needs to be doing this or should be doing this if you don't have the infrastructure or the expertise in your group, but it's definitely going to be something that people are going to be more aware of.

Urology Times: What are the next steps for these combination approaches in terms of determining sequencing strategies, patient selection, identifying biomarkers, etc?

Jayram: CREST was already published, and that data is out there. There's going to be some critical evaluation of that data and trying to understand who benefits the most. POTOMAC is going to come out, which is the BCG and durvalumab combination. That's going to re-enforce where this combination needs to be used. Ultimately, I think we're heading towards an area where we need biomarkers to help us understand patient sensitivity and response to BCG.

We're starting to see some of those markers, both genomic markers, as well as maybe artificial intelligence-driven markers, that can help us understand if patients will respond to BCG optimally. That will help us drive this decision. [For example, a patient may] have a tumor type or a genomic profile that is not optimally suited for BCG. In that situation, those patients probably will need to be intensified, or maybe would benefit from another treatment, even such as intravesical chemotherapy. Biomarkers are going to be important, as well as understanding all the composite sets of data that come out to help us start building that patient profile for which patient will benefit the best.

REFERENCE

1. Shore ND, Powles T, Bedke J, et al. Sasanlimab in combination with Bacillus Calmette-Guérin improves event-free survival versus Bacillus Calmette Guérin as standard of care in high-risk non-muscle invasive bladder cancer: Phase 3 CREST study results. J Urol. 2025;213(5S)