Nadofaragene Firadenovec

This intravesical gene therapy uses a nonreplicating adenovirus vector to deliver the interferon alfa-2b gene into bladder urothelium.¹ FDA approval in 2022 followed a phase 3 trial in bacillus Calmette-Guérin (BCG)–unresponsive high-risk (HR) NMIBC with carcinoma in situ (CIS) ± papillary disease.¹ Among patients with CIS, the complete response (CR) rate at any time was 55%. Median CR duration was 9.7 months; 24% remained recurrence-free at 12 months. In papillary-only patients, CR was 72.9%, with 12.3 months’ median duration. High-grade (HG) recurrence-free survival (RFS) at 12 months was 43.8%. Of those recurrence-free at 3 months, 60% remained so at 12 months. Of note, unlike in other trials discussed in this article, patients who did not demonstrate initial response were not offered reinduction.

Long-term data showed HG RFS at 24, 36, 48, and 57 months as 36.4%, 25.5%, 20.0%, and 10.9%, respectively.² Five-year cystectomy-free survival was 43.2% (CIS) and 58.7% (papillary). Ongoing studies include ABLE-22 (combining with chemo-/immunotherapy in HG BCG-unresponsive disease) and ABLE-32 (nadofaragene vs observation in intermediate-risk [IR] disease).

Nogapendekin Alfa-Inbakicept + BCG

Nogapendekin alfa-inbakicept is an IL-15 receptor agonist that activates natural killer and CD8+ T cells given concurrently with BCG to augment the immune response.³ The QUILT 3.032 trial led to FDA approval in April 2024.³ Cohort A (CIS ± papillary disease) CR rates were 55%, 56%, 45%, and 33% at 3, 6, 12, and 18 months, respectively. Median CR duration was 26.6 months. CR rates by baseline disease were 68% (CIS only), 81% (CIS + Ta), 67% (CIS + T1). Of those reinduced after no CR at 3 months, 54% achieved delayed CR. At 24 months, cystectomy-free survival was 89.2% in responders and 63.2% in nonresponders.

In cohort B (papillary only), median disease-free survival (DFS) was 19.3 months, with 24-month DFS of 48.3%. Cohort C (monotherapy) was closed for futility.

Cretostimogene Grenadenorepvec

Cretostimogene grenadenorepvec (CG0070) is an oncolytic adenovirus targeting Rb pathway–defective tumor cells, also expressing granulocyte-macrophage colony-stimulating factor.⁴ BOND-003 cohort C for BCG-refractory disease (CIS ± Ta/T1) was recently updated at AUA2025, demonstrating an overall 75.5% CR rate, with 50% of repeat induction patients converting to CR.⁴ This included a 46.4% and 33.7% 12- and 24-month CR rate. Median duration of response is 27.9 months and ongoing. It was well tolerated, with no grade 3 or greater treatment-related adverse events (AEs), and 95% of patients received all protocol treatments with no treatment-related discontinuations.

Cohort P includes patients with HG Ta/T1 disease only, and early data show 90.5% HG RFS at 3 and 9 months.⁴

PIVOT-006 is a phase 3, randomized study of CG0070 vs surveillance for IR NMIBC. CORE-008 is a phase 2 trial investigating CG0070 in BCG-naïve and BCG-exposed HG patients.

TAR-200

TAR-200 is a gemcitabine-eluting device placed intravesically via urethral catheter, with sustained gemcitabine release over weeks.

In SunRISe-1:

• Cohort 1 (TAR-200 + cetrelimab): CR rate of 67.9%, with 26% discontinuation.
• Cohort 2 (TAR-200 alone): 82.8% CR at 12 weeks; estimated 6- and 12-month CR rates were 75.7% and 61.9%. Most responses (85%) were ongoing at median 30-week follow-up.⁵
• Cohort 3 (cetrelimab alone): CR 46.4%, with 23% discontinuation.
• Cohort 4 (papillary only, ∼40% T1): DFS at 6 and 9 months was 85.3% and 81.1%, respectively; only 7.7% discontinued due to AEs.⁶

Ongoing trials:

• SunRISe-3 compares TAR-200 ± cetrelimab vs BCG in BCG-naïve HR NMIBC.
• SunRISe-5 compares TAR-200 to investigator’s choice chemotherapy in BCG-unresponsive papillary-only NMIBC.

TAR-210

TAR-210 delivers erdafitinib—a pan-FGFR inhibitor—directly to the bladder in patients with FGFR3-mutant NMIBC, using the same platform as TAR-200.

MoonRISE-1, launched in April 2024, compares every-3-months TAR-210 to intravesical chemotherapy in IR NMIBC. Preliminary data show a 90% 3-month CR with 89% durable response at 9 months.⁷

Sasanlimab

Sasanlimab is an anti-PD-1 antibody that is given subcutaneously, providing systemic immune activation. The CREST III trial recently presented at AUA2025 compared BCG + sasanlimab vs BCG alone in BCG-naïve HR NMIBC.⁸ At 12 and 24 months, event-free survival (EFS) was 84.7% and 82.1%, respectively, vs 79.9% and 74.8% in the control group. The sasanlimab arm had a 32% reduction in 24-month EFS and a 50% reduction in HG recurrence. Of patients receiving BCG + sasanlimab 46.3% completed treatment vs 57.8% of those receiving BCG alone. In the CIS-only subgroup, 36-month EFS was 92%. This also demonstrated the importance of BCG maintenance in this population.

Detalimogene Voraplasmid

Unlike nadofaragene and CG0070, EG-70 (detalimogene voraplasmid) represents a nonviral, nonintegrating intravesical immunotherapy that was designed to elicit local antitumor immune response. It is being investigated in the phase 1/2 LEGEND study using EG-70 for treatment of BCG-refractory and exposed NMIBC with CIS. In the phase 2 data, patients had CR rates of 70% and 60% at 3 and 6 months, respectively.⁹ Reported treatment-related AEs are mostly grade 1 to 2 and consistent with catheterization and instillation.

TARA-002

Derived from OK-432 (inactivated Streptococcus pyogenes), TARA-002 is a novel immune-stimulatory agent under investigation for both BCG-unresponsive and BCG-naïve NMIBC. In phase 1, the 3-month CR was 43% overall and 63% in CIS-only patients. ADVANCED-2, a phase 2 trial, is evaluating induction followed by maintenance over 15 months. The agent demonstrated a favorable safety profile with no grade ≥ 3 treatment-related AEs.

Gemcitabine/Docetaxel

The combination of sequential intravesical gemcitabine/docetaxel (Gem/Doce) has gained prominence as an available alternative treatment for patients with BCG-unresponsive bladder cancer. Previous nonrandomized series have shown that patients with BCG-unresponsive CIS were found to have a 60% and 50% 1- and 2-year RFS with Gem/Doce, respectively. BCG-unresponsive patients were also found to have a 5-year 28% RFS.¹¹ Recent analysis found a 63%, 47%, and 38% at 1-, 2-, and 5-year HG RFS, respectively.¹² A small prospective study of BCG-naïve HR NIMBC patients demonstrated 100% CR at 3 months and 92% RFS at 12 months.¹³ Currently, the BRIDGE trial is a phase 3 randomized study comparing the efficacy of Gem/Doce vs BCG in BCG-naïve HG NMIBC patients.

Conclusions

The treatment landscape for NMIBC continues to evolve, with novel agents aimed at improving efficacy, durability, and patient experience while preserving the bladder. The next wave of therapies includes a long list of immunotherapies, some in combination with BCG, as well as treatment of BCG-naïve and IR disease. As data mature, it will become clearer if these therapies are truly effective in delaying disease progression and recurrence. Longer-term cystectomy-free data and adverse pathology at cystectomy will need to support the role of a multiagent stepwise approach.