Evolving landscape for BCG-naïve NMIBC

The treatment of BCG-naïve and unresponsive non-muscle-invasive bladder cancer (NMIBC) is set for significant change, according to Dr Max Kates, Director of the Division of Urologic Oncology, Johns Hopkins Memorial Hospital, US. Speaking at the 2026 John Fitzpatrick Irish Genitourinary Cancer Conference, Dr Kates predicted a change in practice as a result of important clinical trial data published in the last year.

He pointed out that a number of drugs have been approved in the US in recent years for this patient population, with pembrolizumab receiving Food and Drug Administration approval in 2019, followed by approval for adstiladrin in 2022, nogapendekin-alfa-inbakicept-pmln (NAI) in 2024, and TAR-200 (Inlexzo) in 2025. Several other potential therapies are in development, including EV-70, TARA-002, Fidia, Oncofid, and NanoDoce.

Based on these approvals and newly published trial data, treatment strategies for NMIBC are evolving. In the past, the strategy was to treat with BCG, then move on to a second-line therapy or enter a clinical trial, before ultimately progressing to radical cystectomy. Today, patients are likely to receive several lines of therapy before reaching the clinical trial point.

“Our evolving strategy is quite confusing and quite problematic,” Dr Kates said. “Patients undergo BCG, then they may go on to a second-line therapy, maybe a third-line therapy, and who knows, maybe a fourth-line therapy, depending on the approval pathways, and then radical cystectomy. But that’s a very dangerous strategy. We’re giving our patients more bladder toxicity and more financial toxicity to the healthcare system, with really unclear long-term benefits.”

Several recent trials have focused on this issue. In his presentation, Dr Kates highlighted three phase 3 randomised, open-label trials in particular – Alban, Potomac, and Crest.

Potomac evaluated whether the addition of durvalumab to BCG induction and maintenance therapy improved outcomes versus BCG induction and maintenance alone. At median follow-up of 60.7 months, there was a 32 per cent reduction in the risk of recurrence of high-risk disease or death by any cause for durvalumab plus BCG versus BCG alone (HR 0.68; 95% CI 0.50-0.93; log-rank P = 0.0154), and 24-month disease free survival  rates were 86.5 per cent (95% CI 82.2-89.8) and 81.6 per cent, respectively.

The three-arm CREST trial evaluated subcutaneous sasanlimab in combination with BCG versus BCG monotherapy in patients with high-risk NMIBC (HR-NMIBC). At a median follow-up of 36.3 months, the rate of recurrence of high-grade disease was reduced by more than 50 per cent with sasanlimab plus BCG induction and maintenance compared to BCG induction and maintenance alone.

However, not all findings have been positive. The Alban trial looked at intravenous atezolizumab and intravesical BCG versus BCG alone in BCG-naïve HR-NMIBC. At a median follow-up of 35.3 months, there was no statistically significant difference in event-free survival between the arms (HR 0.98; 95% CI 0.71-1.36; P=0.9106).

In all three trials, the addition of immune checkpoint inhibitors to BCG significantly increased grade ≥3 treatment-related adverse events compared to BCG alone, ranging from 20 per cent to over 40 per cent in combination arms. Common toxicities included urinary frequency, haematuria, and immune-related adverse events like fatigue and rash.

Despite differences in methodology and protocols, all three trials were similar in the finding that one out of 10 patients recur at the three-month time point. It took another two years for another one out of 10 patients to recur. Dr Kates said this shows that “disease persistence is perhaps our biggest problem”.

“All these trials showed us that basically, if you have recurrences over a three-year period, half of them will be at the three-month time point. It will take the other half three years to show up,” he told the meeting.

“The evolving strategy of multiple lines of therapy is quite simply not going to work in this disease space,” he said. “Relying on second-line therapies is a difficult task, extraordinarily expensive, and impacts a fraction of total NMIBC patients. Second-line is already behind the eight ball. Marginal gains to BCG-naïve NMIBC will impact many patients, but we really need to do it safely without increasing toxicity.”

“Maximising long-term cancer control for NMIBC patients starts with improved treatment strategies for BCG-naïve NMIBC, rather than relying on second- and third-line therapies as salvage treatments,” Dr Kates said.

“The future paradigm is really going be a personalised approach based on biomarkers and other factors, in which we have multiple options up front and don’t rely so heavily on salvage lines of therapy,” he said.

“The biggest thing I’ve learned from these trials is that we have a problem with our three-month recurrence rates and we need to understand how to improve outcomes for this group of patients.”