Novel agents are rapidly transforming the treatment landscape for BGC-unresponsive non–muscle invasive bladder cancer (NMIBC). This new wave of therapies stems from over a decade of innovation, driven in part by the persistent unmet need caused by the global BCG shortage. As a result, there have been several notable approvals since 2020, which are offering patients options beyond standard-of-care BCG.
Agents in development include detalimogene voraplasmid, cretostimogene grenadenorepvec, and TAR-200.
The first breakthrough came in 2020 with the approval of pembrolizumab (Keytruda) for the treatment of patients with BCG-unresponsive, high-risk NMIBC with carcinoma in situ (CIS) with or without papillary tumors. This was followed by the regulatory approval of the adenoviral vector-based gene therapy nadofaragene firadenovec-vncg (Adstiladrin) in December 2022, and most recently, nogapendekin alfa inbakicept-pmln (Anktiva) in April 2024.
There are also several agents still in development, poised to offer urologists an expanded arsenal for the management of BCG-unresponsive NMIBC. These include the non-viral gene therapy detalimogene voraplasmid (formerly EG-70), the immunotherapy cretostimogene grenadenorepvec, and the intravesical drug delivery system TAR-200.
In recognition of the evolving landscape, we outlined the novel agents that are set to further redefine the treatment landscape for patients with high-risk BCG-unresponsive NMIBC.
Agent: Detalimogene voraplasmid
Company: enGene
Phase: 1/2
Detalimogene voraplasmid is a non-viral gene therapy that is currently in phase 2 development for high-risk BCG-unresponsive NMIBC with CIS. The agent was granted a Regenerative Medicine Advanced Therapy (RMAT) designation in June 2025, which is intended to expedite the development and review process for regenerative medicines that demonstrate promising preliminary data.
Initial data on the agent comes from the pivotal phase 1/2 LEGEND trial (NCT04752722), which is evaluating the safety and efficacy of the therapy across 4 patient cohorts. Cohort 1, which is intended to support the company’s biologics license application for detalimogene, is assessing the agent in approximately 100 patients with high-risk BCG-unresponsive NMIBC with CIS with or without papillary disease.
Preliminary data from cohort 1 of the phase 2 study were presented at the 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium in San Francisco, California.1 Data showed an overall complete response (CR) rate of 71% (15 of 21). CR rates at 3- and 6-months were 67% (14 of 21) and 47% (8 of 17), respectively. The estimated 6-month CR rate per Kaplan-Meier was 51%.
The findings also showed a favorable safety/tolerability profile across the 42 patients who had received a dose of detalimogene in the trial. Overall, 20 patients (47.6%) reported a treatment-related adverse event (TRAE), all of which were grade 1/2. The most common TRAEs included dysuria (21.4%), bladder spasm (19.0%), pollakiuria (11.9%), and fatigue (11.9%).
Primary completion of the study is anticipated for June 2026.2
Agent: Cretostimogene grenadenorepvec
Company: CG Oncology, Inc
Phase: 3
Cretostimogene grenadenorepvec is an oncoloytic immunotherapy for patients with high-risk BCG-unresponsive NMIBC with CIS with or without papillary tumors. The FDA granted breakthrough therapy and fast track designations to the agent in December 2023.
The immunotherapy is being assessed in the phase 3 BOND-003 trial (NCT04452591), which read out during the 2025 American Urological Association (AUA) Annual Meeting in Las Vegas, Nevada.3
In cohort C of the trial, which enrolled patients with high-risk, BCG-unresponsive NMIBC, treatment with cretostimogene yielded an overall CR rate of 75.5% (95% CI: 66.3%-83.2%). At the time of data report, the median duration of response was 27.9 months (95% CI, 14.3 to NE) and ongoing.
Treatment with cretostimogene was also well-tolerated, with the majority of AEs being grade 1 to 2. No treatment-related AEs of grade 3 or higher were reported.
Primary completion of the trial is expected in December 2027.4
Agent: TAR-200
Company: Johnson & Johnson
Phase: 3
TAR-200 is an investigational intravesical gemcitabine releasing system that is “designed to provide sustained local delivery of a cancer treatment into the bladder,” according to Johnson & Johnson. In July 2025, the FDA granted priority review to a new drug application (NDA) for the agent, intended to expedite a regulatory decision on market authorization.
The NDA for TAR-200 is supported by data from cohort 2 of the phase 2b SunRISe-1 trial (NCT04640623), which were presented at the AUA 2025 Annual.5 Cohort 2 in the trial assessed TAR-200 as a monotherapy in patients with BCG-unresponsive high-risk NMIBC with CIS with or without papillary tumors.
Overall, the CR rate among the 85 patients enrolled in cohort 2 was 82.4% (95% CI, 72.6% to 89.8%). The median duration of response (DOR) was 25.8 months (95% CI, 8.3 to NE), with 52.9% of responders (37 of 70) achieving a DOR of at least 12 months.
According to the authors, high CR rates were observed across all clinically relevant subgroups, including in those with and without concurrent papillary disease (82.1% to 82.5%, respectively).
Treatment-related adverse events (TRAEs) of any grade were reported in 83.5% of patients. The most common TRAEs included pollakiuria (43.5%), dysuria (40%), micturition urgency (24.7%), and urinary tract infection (21.2%).
Remaining Questions
These emerging therapies are introducing promising new strategies for managing BCG-unresponsive NMIBC. But with a growing range of options, urologists now face a new set of challenges.
One key issue is that most of these agents are being evaluated in single-arm trials, making it difficult to compare their efficacy directly or determine the best sequencing strategies. The absence of head-to-head data underscores the increasing importance of shared decision-making. Each treatment comes with its own advantages and trade-offs, and selecting the right option requires thoughtful discussion around factors like dosing schedules, modes of administration, and patient preferences.
As we await additional data on these emerging agents, these questions will remain top of mind for clinicians navigating this evolving landscape. What’s clear is that agents such as detalimogene, cretostimogene, and TAR-200 are at the forefront of the next wave of innovation—poised to further redefine care for patients with BCG-unresponsive NMIBC.
REFERENCES
1. Taylor JA, Joshi S, Satkunasivam R, et al. Preliminary results from LEGEND: A phase 2 study of detalimogene voraplasmid (EG-70), a novel, non-viral intravesical gene therapy for patients with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS). J Clin Oncol. 2025;43(5). doi:10.1200/JCO.2025.43.5_suppl.802
2. LEGEND study: EG-70 in NMIBC patients BCG-unresponsive and high-risk NMIBC incompletely treated with BCG or BCG-naïve. ClinicalTrials.gov. Last updated August 13, 2025. Accessed August 25, 2025. https://clinicaltrials.gov/study/NCT04752722
3. BOND-003 Cohort C- phase 3, single-arm study of intravesical cretostimogene grenadenorepvec for high-risk BCG-unresponsive non-muscle invasive bladder cancer with carcinoma in situ. J Urol. 2025;213(5S).
4. Study of cretostimogene given in patients with non-muscle invasive bladder cancer ,unresponsive to bacillus-calmette-guerin (BOND-003). ClinicalTrials.gov. Last updated July 3, 2025. Accessed August 25, 2025. https://clinicaltrials.gov/study/NCT04452591
5. Jacob JM, Guerrero-Ramos F, Necchi A, et al. TAR-200 monotherapy in patients with Bacillus Calmette-Guérin–unresponsive high-risk non–muscle-invasive bladder cancer carcinoma in situ: 1-year durability and patient-reported outcomes from SunRISe-1. J Urol. 2025;213(5S2):e2. doi:10.1097/01.JU.0001111604.90306.91.03