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Novel delivery systems for bladder cancer: advancing intravesical and systemic approaches

Bladder cancer remains a major therapeutic challenge, with high recurrence rates and a need for repeated interventions that impact patient quality of life. Standard treatments for high-risk non-muscle invasive bladder cancer (NMIBC) include bacillus Calmette-Guérin (BCG) and transurethral resection of bladder tumor (TURBT). However, limitations include high progression rates and the potential need for radical cystectomies. Intravesical systems offer the advantage of localized, sustained drug release within the bladder, maximizing therapeutic exposure while minimizing systemic side effects.1

TAR-200: sustained intravesical gemcitabine release

TAR-200 represents a significant step forward in the treatment of NMIBC, addressing some of the shortcomings of traditional intravesical therapy. The device is a small, flexible polymer system designed for intravesical placement, where it provides continuous local release of gemcitabine over several weeks. This slow, sustained drug delivery bypasses the challenges of rapid drug clearance from the bladder and allows for extended exposure of the urothelium to cytotoxic therapy.2

Cohort 2 of the Phase IIb SunRISe-1 trial (NCT04640623) evaluated the gemcitabine intravesical implant as monotherapy for individuals with BCG-unresponsive carcinoma in situ. Among the 83 participants in the cohort, the trial demonstrated a confirmed complete response rate of 82.4% (95% CI, 72.6-89.8). In terms of safety, 12.9% of patients experienced grade ≥3 treatment-related adverse events, while 5.9% had serious treatment-related events.3

Based on these findings, the U.S Food and Drug Administration (FDA) approved TAR-200 on 9th September 2025, marking it as the first intravesical drug delivery system of its kind to receive regulatory authorization.2 This approval represents an important advance for patients who are either unfit for or unwilling to undergo cystectomy, and highlights the potential of drug-eluting devices in bladder cancer management.

UGN-102: a chemoablation approach for low-grade NMIBC

Another important innovation in bladder cancer drug delivery is mitomycin intravesical solution (UGN-102), a reverse thermal gel formulation of mitomycin C. Unlike conventional instillations that are diluted and rapidly excreted, the solution transitions from liquid to gel upon exposure to body temperature, adhering to the bladder wall and enabling sustained drug release. This design effectively transforms mitomycin into a chemoablative therapy, capable of treating low-grade NMIBC tumors without the need for surgical resection.4

The FDA approved mitomycin intravesical solution on 12th June 2025 based on findings from the Phase III ENVISION trial (NCT05243550). This single-arm trial enrolled 240 patients with primary low-grade intermediate-risk NMIBC, and patients received weekly instillations of 75 mg mitomycin intravesical solution over six consecutive weeks. Out of the 228 patients who received all six doses, 191 (95% CI, 73.9-84.5) achieved complete response (CR) at three months, and an 82% (95% CI, 75.9-87.1) probability of response at 12 months was also reported. The treatment was generally well tolerated, with the most common adverse events being dysuria, fatigue, hematuria, pollakiuria, urinary tract infections, and urinary retention.4,5

The approval of UGN-102 addresses an unmet need in NMIBC, particularly for patients facing frequent recurrences and repeated transurethral resections. By offering a non-surgical chemoablative option, UGN-102 has the potential to significantly reduce reliance on operative interventions in this setting. Its success also reinforces the growing clinical value of intravesical drug delivery technologies, which are moving beyond conventional instillation approaches to achieve more reliable and durable outcomes.

Subcutaneous pembrolizumab: systemic innovation with clinical potential

While intravesical systems are transforming localized treatment, innovation in systemic therapy delivery is also advancing. Pembrolizumab, a PD-1 inhibitor with established efficacy across urothelial and multiple other solid tumors, has traditionally been administered intravenously.6 However, the development of a subcutaneous formulation combining pembrolizumab with the permeation enhancer hyaluronidase offers a more convenient and potentially patient-friendly route of administration.7

On 19th September 2025, the FDA approved subcutaneous pembrolizumab in all previously approved solid tumor indications, including patients with locally advanced or metastatic urothelial cancer. The approval was based on findings from the Phase III 3475A-D77 trial (NCT05722015), which assessed subcutaneous versus intravenous pembrolizumab with chemotherapy in patients with metastatic non-small-cell lung cancer.8

The dual primary endpoints of overall exposure and trough concentrations were met, where subcutaneous pembrolizumab achieved a geometric mean ratio for area under the curve (AUC) of 1.14 (96% CI, 1.06–1.22). The subcutaneous approach was additionally associated with shorter administration times and reduced resource utilization, which could be particularly advantageous in high-volume oncology clinics. Safety profiles were consistent with established intravenous pembrolizumab, with no new safety signals identified. 7

Although not bladder-specific, the subcutaneous formulation could improve patient experience, streamline healthcare delivery, and expand access to checkpoint inhibitors worldwide. Overall, these innovations illustrate how novel drug delivery technologies are reshaping treatment paradigms in bladder cancer and beyond, with the potential to improve efficacy, tolerability, and patient quality of life.

References

  1. Filon M, Schmidt B. New Treatment Options for Non-Muscle-Invasive Bladder Cancer. American Society of Clinical Oncology 2025 Jan;45(2):e471942
  2. ‌Center for Drug Evaluation and Research. FDA approves gemcitabine intravesical system for non-muscle invasive bladder cancer [Internet]. FDA; [cited 2025 Sep 19]. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancerhematologic-malignancies-approval-notifications
  3. Daneshmand S, Van, Jacob JM, Guerrero-Ramos F, Bögemann M, Simone G, et al. TAR-200 for Bacillus Calmette-Guérin–Unresponsive High-Risk Non–Muscle-Invasive Bladder Cancer: Results From the Phase IIb SunRISe-1 Study. Journal of Clinical Oncology. 2025 Jul 30
  4. Prasad SM, Shishkov D, Mihaylov NV, Khuskivadze A, Genov P, Terzi V, et al. Primary Chemoablation of Recurrent Low-Grade Intermediate-Risk Nonmuscle-Invasive Bladder Cancer With UGN-102: A Single-Arm, Open-Label, Phase 3 Trial (ENVISION). The Journal of urology [Internet]. 2025 Feb;213(2):205–16
  5. ‌Center for Drug Evaluation and Research. FDA approves mitomycin intravesical solution for recurrent low-grade [Internet]. U.S. Food and Drug Administration. 2025 [cited 2025 Sep 19]. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-mitomycin-intravesical-solution-recurrent-low-grade-intermediate-risk-non-muscle
  6. Balar AV, Castellano DE, Grivas P, Vaughn DJ, Powles T, Vuky J, et al. Efficacy and safety of pembrolizumab in metastatic urothelial carcinoma: results from KEYNOTE-045 and KEYNOTE-052 after up to 5 years of follow-up. Annals of Oncology. 2023 Mar;34(3):289–99.
  7. Felip E, Rojas CI, Schenker M, Kowalski DM, Casarini IA, Csöszi T, et al. Subcutaneous versus intravenous pembrolizumab, in combination with chemotherapy, for treatment of metastatic non-small-cell lung cancer: the phase III 3475A-D77 trial. Annals of Oncology. 2025 Mar 27
  8. ‌Center for Drug Evaluation and Research. FDA approves pembrolizumab and berahyaluronidase alfa-pmph for subcutaneous injection. 2025 [cited 2025 Sep 19]. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-and-berahyaluronidase-alfa-pmph-subcutaneous-injection