Emerging therapies for BCG unresponsive non-muscle-invasive bladder cancer: an overview

Nadofaragene firadenovec is a replication-deficient adenoviral vector encoding interferon-α2b, designed for local immune activation within the bladder. In the pivotal single arm phase III trial, the 3‑month complete response (CR) rate was 53%, and 45% of patients remained disease-free at 12 months, with only 4% grade ≥ 3 adverse events (AE) [4]. FDA approval was granted in 2022, and EMA review is ongoing. It is the first intravesical gene therapy to demonstrate durable efficacy in BCG-unresponsive NMIBC, preserving the familiar catheter-based administration route of BCG.

N‑803 is an IL-15 superagonist that enhances NK-cell and CD8⁺ T‑cell proliferation in the bladder microenvironment. In the phase III QUILT 3.032 trial, combination BCG + N-803 achieved a 71% CR at 3 months with 24.1 months median duration of response and low rates of grade ≥ 3 immune-related toxicity [5]. FDA approval followed in 2024. As of December 2025, the Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion supporting conditional marketing authorisation for N‑803 + BCG, pending a European Commission decision. This combination maintains the procedural simplicity of standard BCG while significantly improving durable response rates.

TAR-200 is a novel intravesical drug delivery system releasing gemcitabine continuously over three months. The device maintains sustained local exposure with negligible systemic absorption. In SunRISe‑1, TAR-200 monotherapy achieved a centrally reviewed CR of 82.4% in CIS, with grade ≥ 3 AEs in 12.9%; adding cetrelimab increased toxicity without clear added benefit [6]. Combination with intravenous cetrelimab (anti-PD-1) did not enhance efficacy but increased toxicity, supporting TAR-200 monotherapy. FDA approval has been granted in September 2025 for treating patients with BCG-unresponsive NMIBC with CIS, with or without papillary tumors. The ongoing SunRISe‑3 phase III trial (n = 1050) compares TAR-200 ± cetrelimab versus BCG in high-risk, BCG-naïve NMIBC; results are expected by 2029. If confirmed, TAR-200 could become the first purely intravesical alternative to systemic immunotherapy, combining efficacy, tolerability, and practicality.

Before the approval of dedicated intravesical agents, sequential gemcitabine-docetaxel (Gem/Doce) had become the most widely used off-label salvage regimen for BCG-unresponsive NMIBC, particularly in North America. Retrospective series reported 1‑year recurrence-free survival (RFS) rates around 50–60% with low toxicity [7]. Although no prospective randomized trials exist, Gem/Doce provides a cost-efficient benchmark against which the aforementioned newer agents can be contextualized. Its use remains relevant in settings with delayed access to approved therapies or as a bridge to RC.

Pembrolizumab, a systemic PD‑1 inhibitor, was the first systemic agent approved by the FDA (2020) for BCG-unresponsive CIS in patients ineligible for or declining cystectomy. This indication has not been authorised by the EMA (as of December 2025). In KEYNOTE-057, the 3‑month CR rate was 41%, with a median duration of 16 months; grade ≥ 3 adverse events occurred in 13% of patients [8]. Although effective, pembrolizumab requires intravenous administration and careful toxicity monitoring. In clinical practice, it is generally reserved for patients unfit for intravesical therapy.

In the phase II SWOG S1605 study, intravenous atezolizumab achieved a 27% CR with a median duration of 17 months [9]. Grade 3–5 treatment-related adverse effects occurred in 16% of patients, including three treatment-related deaths.

The ADAPT-BLADDER phase I trial combined durvalumab with intravesical BCG, yielding a 85% 3‑month CR and 73% at 12 months [10]. This suggests a possible synergistic effect between systemic checkpoint inhibition and local immune stimulation.

Erdafitinib, an oral FGFR3 inhibitor, demonstrated 77% 12-month recurrence-free survival in FGFR3-altered, BCG-unresponsive NMIBC [11]. The THOR‑2 phase III trial is ongoing to confirm whether targeted precision therapy can replace or complement intravesical strategies in this molecular subset.

Collectively, these systemic approaches expand options for patients in whom intravesical therapy is contraindicated or has failed, while underscoring the growing importance of molecular profiling and multidisciplinary management in NMIBC.

CG0070 selectively replicates in tumor cells with a defective retinoblastoma pathway, inducing GM-CSF-mediated immune activation. The phase III BOND-003 trial reported overall CR of ~75% in BCG-unresponsive CIS, with no grade ≥ 3 toxicities [12]. Combination with pembrolizumab in the CORE‑1 study achieved an exceptional 92% CR rate in early data (24 evaluable patients) [13]. The synergy between viral lysis and checkpoint inhibition represents a promising direction, though monotherapy remains attractive due to its safety profile and urologist-controlled administration.

Oncofid-P‑B enhances paclitaxel solubility and bladder adhesion via a hyaluronic acid conjugate, improving drug retention. In a phase I single-arm trial of 20 BCG-unresponsive patients, CR was 75% after induction and 40% at 12 months, with only mild local side effects [14]. A phase III study (NCT05024773) is ongoing, expected to conclude in 2027. Its simplicity and local tolerability make it particularly suitable for elderly or comorbid patients.

Designed for FGFR3-altered NMIBC, TAR-210 delivers erdafitinib intravesically through a sustained-release device. Early results from the ErdaRIS phase I trial (cohort 1) showed an 82% 3‑month recurrence-free rate in BCG-unresponsive papillary tumors (with no CIS) [15]. Systemic absorption was negligible. This represents the first true precision-medicine approach for NMIBC.

Enfortumab vedotin (EV-104) is an antibody-drug conjugate targeting Nectin‑4 administered intravesically. Preliminary data (n = 6) showed a 75% CR rate with no significant toxicity [16].

TARA-002, a Streptococcus pyogenes-derived biologic immunotherapy, has shown acceptable safety and local immune activation in ADVANCED‑1 (phase I/II) [17], with further evaluation ongoing.

Nanoparticle-based formulations of paclitaxel (NCT06173349) are under exploration to improve urothelial penetration and retention [18], while hyperthermic intravesical chemotherapy (HIVEC) with mitomycin C offers an established device-assisted approach that enhances cytotoxicity and recurrence-free survival in post-BCG settings [19].

Together, these innovations signal a renewed era of locally delivered, bladder-preserving therapy, reinforcing the central role of the urologist in the management of BCG-unresponsive NMIBC.