FDA Approval of Adstiladrin Expands Options for Patients With BCG-Unresponsive NMIBC

By Akhil Abraham Saji, MD - Last Updated: June 8, 2023

The National Cancer Institute estimates that more than 82,000 patients will be diagnosed with bladder cancer in 2023.1 Of those patients, an estimated 70% will be diagnosed with non-muscle-invasive bladder cancer (NMIBC), and approximately 10% of that patient population will have carcinoma in-situ (CIS).2 Adjuvant intravesical bacillus Calmette-Guérin (BCG) therapy is typically administered to patients with intermediate- or high-risk NMIBC based on American Urological Association risk stratification. Patients in the high-risk category are particularly difficult for urologists to manage, as nearly 80% of patients experience recurrence and 50% will experience progression at 5 years.3 The gold standard of management for such patients is radical cystectomy with urinary diversion; however, with an estimated overall complication rate of nearly 60%, cystectomy is not without its downsides.4 In terms of bladder-sparing therapy, options such as intravesical valrubicin and pembrolizumab exist for patients with CIS, but overall response rates are generally very low.5 Therefore, the research and continued development of more intravesical agents remains of paramount importance to give patients seeking bladder-sparing therapy more options.

The US Food and Drug Administration (FDA) defines BCG-unresponsive bladder cancer as “at least 5 of the 6 induction doses and 2 of the 3 maintenance treatments of BCG or at least 2 of 6 instillations of a second induction course in which maintenance BCG is not given.”6 The FDA’s definition also includes patients with “recurrences of high grade Ta or T1 non-muscle-invasive bladder cancer within 6 months, or CIS within 12 months of disease-free state after BCG.”6 These definitions were referred to as BCG-refractory and BCG-relapsed disease, respectively.

Adstiladrin (nadofaragene firadenovec gene therapy) is an intravesical agent produced by Ferring Pharmaceuticals. The mechanism of action involves a nonreplicating adenovirus gene therapy that stimulates an antitumor response by infecting bladder cells and producing cytokine interferon alfa-2b.6 Unlike prior attempts at intravesical adenovirus therapy, the Adstiladrin compound contains the adenovirus vector bound to Syn3, a “polyamide surfactant that enhances viral transduction into urothelium.”6 Stimulating production of interferon alfa-2b results in increased interferon alpha receptor binding on bladder cancer cells, which can ultimately restrict bladder cancer cell growth.7 Adstiladrin therapy is instilled into patients’ urinary bladders via catheter at a favorable dosing schedule of once every 3 months.6

Several clinical trials were conducted to evaluate the efficacy and safety of Adstiladrin in patients with NMIBC. Prior to the trial that led to FDA approval, phase 2 data provided by Shore et al demonstrated both safety and potential efficacy. Patients with high-grade (HG) BCG-refractory or BCG-relapsed disease were given Adstiladrin randomized 1:1 at a lower and higher dose based on data from the original phase 1 study.8 Overall, the phase 2 trial demonstrated that Adstiladrin was very well tolerated and safe. No grade 4 or 5 adverse events (AEs) were noted, and the most common AEs were organ localized (eg, dysuria, urgency). Furthermore, the primary end point of the trial, HG recurrence-free survival (RFS), was comparable at 33.3% in the low-dose group and 36.8% in the high-dose group at the 12-month mark.8 These data, along with the fact that the response was noted to be durable (patients remained disease-free for up to 24 months), suggested that Adstiladrin was a viable therapy for further study.

In December 2022, the FDA approved Adstiladrin for use in high-risk BCG-unresponsive bladder cancer with CIS, with or without papillary tumors present in the bladder.9 This landmark approval was based on the CS-003 trial and marked the first time that an adenovirus-based gene therapy was approved for the treatment of bladder cancer. CS-003, a phase 3, single-arm clinical trial, was run by Stephen Boorjian, MD, at the Mayo Clinic to evaluate the efficacy and safety of intravesical Adstiladrin in a larger series of patients.6 Enrollment took place at 33 hospitals and health systems across the United States, thereby ensuring a large and diverse pool of potential patients.

The authors enrolled a total of 157 patients between September 19, 2016, and May 24, 2019, from a pool of 198 patients.6 More than half the patient population had received at least 3 doses of BCG therapy.6 Unlike other intravesical agents such as pembrolizumab, which have only been approved for BCG-unresponsive CIS, CS-003 enrolled patients with isolated, high-grade Ta and T1 disease (32%), as well as those with CIS. The primary outcomes of interest were complete response rate and freedom from HG recurrence. Of the 48 patients enrolled in the HG Ta/T1 cohort, 43.8% of patients were HG recurrence-free at the 12-month mark. In the CIS cohort, 24.3% of patients were HG recurrence-free at 12 months. Adstiladrin was found to be overall very safe (consistent with phase 2 data), with no grade 4 or 5 AEs reported. More than half of patients (66%) reported transient treatment-related AEs such as peri-catheter discharge, fatigue, and lower urinary tract symptoms, which were all classified as grade 1 or 2.

Adstiladrin and its recent approval by the FDA for use in BCG-unresponsive NMIBC expands the armamentarium for treatment of high-risk NMIBC, the authors concluded. The inclusion of patients with isolated HG Ta/T1 tumors is unique and ensures that a wider range of patients will have access to this bladder-sparing therapy. The authors noted that future studies will focus on identifying mechanisms of nonresponse.6

Akhil Abraham Saji, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include urology education and machine learning applications in urologic care. He is a founding and current member of the EMPIRE Urology New York AUA section team.



  1. Cancer Stat Facts: bladder cancer. National Cancer Institute Surveillance, Epidemiology, and End Results Program. Accessed May 15, 2023. https://seer.cancer.gov/statfacts/html/urinb.html
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  3. Veeratterapillay R, Heer R, Johnson MI, Persad R, Bach C. High-risk non-muscle-invasive bladder cancer—therapy options during intravesical BCG shortage. Curr Urol Rep. 2016;17(9):68. doi:10.1007/s11934-016-0625-z
  4. Efstathiou JA, Ballas LK, Niemierko A, et al. Multi-institutional matched comparison of radical cystectomy to trimodality therapy for muscle invasive bladder cancer (MIBC). Int J Radiat Oncol Biol Phys. 2022;114(3):S74-S75. doi:10.1016/j.ijrobp.2022.07.472
  5. Balar AV, Kamat AM, Kulkarni GS, et al. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study. Lancet Oncol. 2021;22(7):919-930. doi:10.1016/S1470-2045(21)00147-9
  6. Boorjian SA, Alemozaffar M, Konety BR, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. Lancet Oncol. 2021;22(1):107-117. doi:10.1016/S1470-2045(20)30540-4
  7. Herzog RW, Suzuki M. Adenoviral gene therapy for bladder cancer. Cell. 2023;186(5):893. doi:10.1016/j.cell.2023.02.009
  8. Shore ND, Boorjian SA, Canter DJ, et al. Intravesical rAd–IFNα/Syn3 for patients with high-grade, bacillus Calmette-Guerin–refractory or relapsed non–muscle-invasive bladder cancer: a phase II randomized study. J Clin Oncol. 2017;35(30):3410-3416. doi: 10.1200/JCO.2017.72.3064
  9. FDA approves first adenoviral vector-based gene therapy for high-risk Bacillus Calmette-Guérin unresponsive non-muscle invasive bladder cancer. FDA. December 19, 2022. Accessed May 15, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-first-adenoviral-vector-based-gene-therapy-high-risk-bacillus-calmette-guerin