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High-risk BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) is a condition that is typically treated with Bacillus Calmette-Guérin (BCG) therapy. Unfortunately, NMIBC is characterized by high recurrence, with a significant percentage of BCG patients ultimately requiring radical cystectomy. As a consequence, the development of effective new therapies to avoid RC has become a rapidly evolving field to address this unmet clinical need. To date, three biologics-Keytruda, Adstiladrin, and Anktiva-have been approved by the FDA, and multiple drug modalities, particularly gene therapies, have shown promising results in clinical trials. Advances in drug delivery strategies, such as targeted delivery, sustained release, and permeabilization of protective layers, are critical in overcoming the challenges posed by therapeutic intervention in bladder cancer. This review focuses on high-risk BCG-unresponsive NMIBC therapies that have been or are currently being investigated in clinical trials, offering a broad overview of the delivery system designs and up-to-date clinical outcomes that have been reported as of July 2024. It aims to inform the development of future drug delivery systems for second-line therapies in high-risk BCG-unresponsive NMIBC.
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http://dx.doi.org/10.3390/pharmaceutics16091154 | DOI Listing |
Curr Opin Urol
August 2025
S.H. Ho Urology Centre, Department of Surgery, The Chinese University of Hong Kong, Hong Kong; Division of Urology, Prince of Wales Hospital, Hong kong.
Purpose Of Review: Antibody-drug conjugates (ADCs) have recently emerged as a promising targeted therapeutic strategy in urothelial carcinoma, and their application in nonmuscle invasive bladder cancer (NMIBC) is an evolving frontier. This review is timely as it synthesizes recent advances in ADC development for NMIBC, addressing critical unmet needs among both Bacillus Calmette-Guérin (BCG) naïve high-risk and BCG-unresponsive patients.
Recent Findings: The literature reveals that ADCs that target HER2, Trop-2, Nectin-4 are under active investigation.
Purpose: TAR-200 is a first-in-class intravesical drug-releasing system designed to provide sustained delivery of gemcitabine in the bladder. TAR-200 alone or in combination with cetrelimab (PD-1 inhibitor) could improve outcomes in patients with bacillus Calmette-Guérin (BCG)-unresponsive high-risk non-muscle-invasive bladder cancer (NMIBC) ineligible for or refusing radical cystectomy.
Methods: In this phase IIb parallel cohort study, patients with BCG-unresponsive carcinoma in situ (CIS) with/without papillary disease received TAR-200 monotherapy (Cohort 2 [C2]), TAR-200 plus cetrelimab (C1), or cetrelimab monotherapy (C3).
Front Pharmacol
July 2025
Department of Urology, Kunshan Hospital of Traditional Chinese Medicine, Kunshan, Jiangsu, China.
Recent advances in bladder cancer immunotherapy have shown promise, particularly in addressing limitations of the current gold standard, Calmette-Guérin (BCG). Novel combinations, such as sasanlimab (a PD-1 monoclonal antibody) with BCG, have improved event-free survival in high-risk non-muscle-invasive bladder cancer (NMIBC). Intravesical anti-PD-1/PD-L1 agents like pembrolizumab and nadofaragene firadenovec have demonstrated efficacy and safety in BCG-unresponsive NMIBC, leading to regulatory approval.
View Article and Find Full Text PDFCurr Opin Urol
July 2025
Department of Urology UROSUD, La Croix du Sud Hospital, Quint Fonsegrives.
Purpose Of Review: Nonmuscle invasive bladder cancer (NMIBC) represents approximately 75% of bladder cancer cases at diagnosis and poses a significant management challenge due to high recurrence rates and risk for progression. Conventional intravesical therapies face limitations including suboptimal drug delivery, mucosal exposure time and significant adverse events. This review provides a timely assessment of novel intravesical delivery systems developed to overcome these limitations and improve oncological outcomes for patients with NMIBC.
View Article and Find Full Text PDFCurr Opin Urol
July 2025
Department of Urology, Hospital Universitario Ramón y Cajal, IRYCIS, Universidad de Alcala, Madrid.
Purpose Of Review: Bacillus Calmette-Guérin (BCG) remains the standard of care for high-risk non-muscle-invasive bladder cancer (NMIBC), yet up to 40-50% of patients experience treatment failure, leaving limited alternatives to avoid radical cystectomy. This narrative review critically examines both traditional and emerging BCG-based strategies - including repeat induction and modern combination regimens - for patients with BCG-unresponsive NMIBC.
Recent Findings: BCG monotherapy after BCG failure has shown limited effectiveness, with recent studies reporting 12-month disease-free survival (DFS) rates of 60-70%.