While bacillus Calmette-Guérin (BCG) remains the most effective treatment for high-grade nonmuscle invasive bladder cancer (NMIBC), up to 20% to 30% of patients do not respond to BCG monotherapy, and ∼50% of initial responders will relapse within 5 years of treatment.¹ A number of new therapeutic approaches have recently been approved by the US Food and Drug Administration (FDA) for BCG-unresponsive NMIBC. Results from KEYNOTE-057 led to approval in 2020 of the intravenous PD1/PDL1 inhibitor pembrolizumab for treatment of BCG-unresponsive carcinoma in situ (CIS) in patients ineligible for, or who declined, radical cystectomy,² although the oncological efficacy of pembrolizumab was modest. Another PD1/PDL1 inhibitor, atezolizumab, was evaluated in SWOG S1605 and had similar oncologic outcomes but failed to achieve the prespecified futility threshold.³ Nadofaragene firadenovec, an intravesical vector-based gene therapy, and nogapendekin alfa inbakicept, an interleukin-15 superagonist administered with BCG, are now approved for BCG-unresponsive CIS with/without papillary tumors, but durable efficacy is still lacking. Cretostimogene grenadenorepvec, a conditionally replicating oncolytic adenovirus, received FDA Fast Track and Breakthrough Therapy designation for BCG-unresponsive disease based on preliminary results from the phase 1 BOND-003 study (NCT04452591). Intravesical cretostimogene monotherapy resulted in a 75% complete response rate at “any time,” with 83% retaining an ongoing response at 12 months.⁴

FDA Breakthrough Therapy designation was also given to TAR-200, a novel osmotically driven intravesical drug delivery system. TAR-200 delivers sustained local release of gemcitabine into the bladder without detectable concentration in plasma. Several trials are underway to evaluate TAR-200 alone and in combination with immune checkpoint blockade (ICB). The SunRISe-1 trial (NCT04640623) randomized patients with BCG-unresponsive NMIBC CIS to 3 cohorts: TAR-200 alone, TAR-200 with cetrelimab (anti-PD1), and cetrelimab alone. Preliminary data demonstrated that TAR-200 monotherapy resulted in an 83% complete response rate at “any time” and an estimated 1-year duration of response rate of 75%.⁵

Notably, these have been single-arm, nonrandomized clinical trials with varying methodology and heterogeneous patient populations, limiting cross-trial comparisons. Randomized trials to determine the relative efficacy of these treatments should be prioritized by the urologic oncology community, although they will be challenging to conduct because pharmaceutical companies lack the incentive to participate when their drugs have already been FDA approved.

With the ongoing BCG shortage (since 2012), investigators have focused on identifying alternative formulations and intravesical treatment options, such as using strains other than TICE BCG (the only strain currently available in the United States). SWOG S1602 PRIME (NCT03091660) is a phase 3 trial randomizing patients to TICE BCG vs Tokyo-172 BCG with/without intradermal T-cell priming with the Tokyo-172 strain prior to intravesical therapy. While the trial’s findings are still pending, results showing noninferiority of the Tokyo-172 strain may mean a new strain of BCG will be allowed into the United States. Among the most important studies investigating alternatives to BCG is the BRIDGE trial (ECOG-ACRIN EA8212/NCT05538663), which is randomizing 870 patients with newly diagnosed high-grade NMIBC to either BCG or gemcitabine with docetaxel (GemDoce).⁶ A investigator-initiated phase 2 trial of GemDoce in the BCG-naïve setting found the combination was well tolerated and had a complete response rate of 100% (25/25) at 3 months and 92% recurrence-free survival at 12 months.⁷

Even if Tokyo-172 BCG does not get FDA approval, the shortage is expected to be resolved in 2026 with the opening of a new Merck TICE BCG manufacturing facility. In anticipation of the crisis being resolved, developing strategies to enhance the effectiveness of BCG is of the utmost importance.

Preclinical studies suggest that PD1/PDL1 overexpression may be a mechanism for BCG resistance. Three large industry-sponsored trials (KEYNOTE-676 cohort B [NCT03711032], CREST [NCT04165317], and POTOMAC [NCT03528694]) are testing whether the addition of ICB can enhance the effectiveness of BCG for patients with BCG-naïve NMIBC. The results of these trials are of great interest but need to be carefully analyzed to determine which patients with NMIBC represent justifiable risk/benefit trade-offs, given the 12% to 15% risk of developing immune-related major adverse events after ICB.^2,3 Additional data for identifying which patients with NMIBC are most likely to benefit from ICB will likely be provided by an ongoing investigator-initiated phase 2 trial testing the combination of pembrolizumab with BCG in 37 patients with BCG-naïve “very high risk T1” for whom the AUA and NCCN guidelines typically recommend immediate radical cystectomy (NCT03504163).

Another promising approach for NMIBC is combination chemoimmunotherapy regimens using BCG and intravesical chemotherapy. ANZUP 1301 (NCT02948543) is an international open-label phase 3 trial of standard BCG therapy vs BCG and passive instillation of mitomycin C (MMC) in 500 patients with high-risk BCG-naïve NMIBC. This trial builds upon a prior successful randomized clinical trial demonstrating the superiority of combination BCG+MMC, where MMC is delivered via electromotive drug administration.⁸ Gemcitabine, a better tolerated, more effective, and less costly intravesical option, is also under investigation in combination with BCG. In a phase 1 trial (NCT04179162) of BCG-exposed high-grade NMIBC, 25 patients with BCG-exposed NMIBC (high-grade recurrence within 24 months of last BCG, but not meeting BCG-unresponsive criteria) received combination intravesical gemcitabine and BCG (GemBCG). Complete response at 6 and 12 months was 96% and 92%, respectively; no patient progressed to muscle-invasive disease or underwent cystectomy.⁹ The phase 2 portion of this trial recently completed enrollment (n = 44) with promising preliminary results. A phase 3 trial (Alliance A032303; GAIN) set to open in May 2025 will randomize 330 patients with BCG-exposed NMIBC to receive gemcitabine and BCG or re-treatment with BCG alone.

Ongoing investigations also include combinatorial strategies of novel intravesical therapies with/without ICB. For example, the phase 2 CORE-001 trial demonstrated 83% and 57% complete response rates at 3 and 12 months, respectively, in 35 patients with BCG-unresponsive CIS treated with intravesical cretostimogene and pembrolizumab.¹⁰ Ultimately, randomized trials are needed to understand the additive benefits of component treatments, but trials adding ICB will need to be thoughtfully designed to enrich for NMIBC patients for whom the added toxicity is most justified. Efforts should also focus on conducting randomized comparisons of novel agents that were approved based on single-arm, nonrandomized studies, and concerted efforts should be made to develop predictive biomarkers to help select patients for these treatment approaches.

Funding/Support: This work was supported in part by the National Institutes of Health/National Cancer Institute with a Cancer Center Support Grant to Memorial Sloan Kettering Cancer Center (P30 CA008748).