The first real-world outcomes data for nadofaragene firadenovec (Adstiladrin, Ferring Pharmaceuticals) in patients with Bacillus Calmette-GuÉrin (BCG)-unresponsive non–muscle-invasive bladder cancer (NMIBC) support the gene therapy’s efficacy and safety, with promising clinical response (CR) rates and a tolerable adverse event (AE) profile.
NMIBC is the most common type of bladder cancer, affecting about 3 in 4 people with the malignancy. BCG, an intravesical immunotherapy using a mycobacterium that has immunomodulating effects when applied to the bladder, is typically used as an adjuvant therapy following surgery for early-stage NMIBC, but recurrence happens in approximately 40% of patients (Int J Mol Sci 2023;24[16]:12596).
Originally approved by the FDA in 2022, for NMIBC with carcinoma in situ (CIS) with or without papillary tumors, nadofaragene is a non-replicating adenoviral vector-based gene therapy and is the only FDA-approved intravesical bladder-sparing monotherapy for this indication. Previously, however, real-world post-marketing efficacy or safety data were lacking.
The new real-world outcomes study is a retrospective analysis of patients with BCG-unresponsive NMIBC who received treatment with nadofaragene firadenovec at three Mayo Clinic sites between November 2023 and December 2024. Of 24 evaluable patients with CIS with or without papillary disease, 79% had a CR at three months; the median duration of response had not yet been reached. At a median follow-up of 7.3 months, 84% (16/19) of responders still showed CR. Of patients with papillary-only disease, 68% (13) were recurrence-free at three months; 10 of those 13 (77%) remained recurrence-free at a median follow-up of 8.9 months.
At an overall median follow-up of 8.2 months for the entire efficacy-evaluable cohort, cystectomy-free survival and overall survival (OS) were 95% and 100%, respectively.
“In the trial that led to FDA approval, CR was 51%,” said study co-author Jacob Moyer, BS, a graduate research assistant at Mayo Clinic in Scottsdale, Ariz. “While this CR of 79% appears to be higher, this is very early data in a small group, so we are hesitant to say it is performing better in the real-world setting. We prefer to say that it is no worse than the clinical trial data, which is definitely reassuring. We are very excited to look at further real-world follow-up.”
In terms of safety, Mr. Moyer noted, there were no grade 4 or 5 AEs, or AEs that led to treatment discontinuation. “Most patients experienced low-grade, transient local AEs,” he said, including bladder spasm (61%), failure to retain the medication for the full target dwell time (33%), urinary urgency (20%), fatigue (13%) and dysuria (13%).
Asked to comment on the safety and efficacy data, Lisa Holle, PharmD, BCOP, FHOPA, FISOPP, offered some perspectives on the bladder spasm outcomes, given oncology pharmacy’s role in supportive care. “Whenever you instill anything into the bladder, including BCG and chemotherapy as well, it can be painful and cause bladder spasms,” said Dr. Holle, a clinical professor of pharmacy practice at the University of Connecticut (UConn) School of Pharmacy and UConn Health Carole & Ray Neag Comprehensive Cancer Center, in Storrs. That’s particularly the case with nadofaragene, “which patients have to keep in their bladder for a full hour,” she said.
To help keep the drug in the bladder, “we can premedicate patients with an anticholinergic agent,” added Dr. Holle, who is on the advisory board for Pharmacy Practice News. “Some institutions use diazepam instead, either orally or through a rectal suppository right before instillation.”
Adenoviruses Warrant PPE, Decontamination and Other Safe Handling Precautions
Because nadofaragene has a non-replicating adenovirus component, it requires careful biosafety handling, noted Lisa Holle, PharmD, BCOP, FHOPA, FISOPP, a clinical professor of pharmacy practice at the University of Connecticut (UConn) School of Pharmacy and UConn Health Carole & Ray Neag Comprehensive Cancer Center, in Storrs.
“Anyone on the clinical staff who is immunosuppressed or immune-deficient should not be involved in handling or administering this drug, which can sometimes be tricky when you have a small staff,” she said. “Individuals who are involved with handling and administering nadofaragene should also be using personal protective equipment to minimize viral shedding of the product onto their body, so they don’t inadvertently transmit that to someone else as well.”
Nadofaragene does not require preparation in a negative-pressure hood or biological safety cabinet because it is not made from a live virus such as BCG, Dr. Holle said. “Most institutions will prepare nadofaragene in a positive-pressure hood where they prepare nonhazardous medications, but often will decontaminate the hood following preparation and before preparation of other medications to minimize any viral spread.”
Storage of nadofaragene also includes some unique requirements. It is shipped at 60° C or colder, and ideally should be stored in a freezer at that temperature until its expiration date. “If you do not have a deep freezer, it is permitted to store it in a –25° to –15° C freezer for up to three months, as long as that is within the expiration date; but in order to do that, you have to mark the packaging as to the discard date,” advised Dr. Holle, who is on the advisory board for Pharmacy Practice News.
Preparation presents its own challenges. “It has to be thawed from frozen and brought to room temperature on its own,” Dr. Holle said. “You cannot use any sort of heating device. The time frame to thaw varies, depending on whether you do it at room temperature or whether you bring it up inside a refrigerator; there are a number of parameters involved. This requires proactive planning and coordination of care with the healthcare team and patient, because you can’t just pull the drug out of the freezer and prepare it right then and there when the patient arrives.”
Once thawing has started, “you can keep the vials at room temperature for 24 hours or refrigerated for up to seven days,” Dr. Holle added. “But if you have a small center with not many patients receiving this, you might waste the drug if the patient cannot come in due to unforeseen issues, such as transportation problems or getting sick.”
Pharmacist involvement in patient education is critical for nadofaragene use. For two days after instillation of the drug, patients must put a virucidal solution into the toilet every time they urinate or void, and let it sit for 15 minutes. “You have to teach them to make the solution or provide them with it, and then explain how it’s used,” Dr. Holle said. “They should be sitting down while using the toilet, and ideally they will be the only person using that toilet for that two-day period, to minimize transmission of the virus to anyone else. And after each instillation, patient education should be reinforced.”
New Data Provide ‘Reassurance’ Of Drug Activity
Mark D. Tyson II, MD, MPH, an associate professor of urology at Mayo Clinic in Arizona, in Scottsdale, and the study’s lead author, commented on the clinical relevance of the new data. “For those who wonder if the drug is just as effective in the real-world population compared to the highly selected population that we see in clinical trials, these data provide some reassurance that the drug maintains its activity,” he said. “The top-line numbers on complete response rates as well as the data on durability are at least as good as what we saw in the trial, as is the safety profile.”
For Mr. Moyer, convenience is another important factor that needs to be considered when evaluating nadofaragene firadenovec. He noted that the gene therapy’s “favorable administration schedule of once every three months” is a key benefit. “Most of the other treatments for these patients, including BCG as well as sequential gemcitabine/docetaxel, require patients to come in once a week for six weeks,” he said. “That can be a very demanding treatment schedule, especially for patients who do not live near their medical center.”
Dr. Holle and Mr. Moyer reported no relevant financial disclosures. Dr. Tyson reported relationships with AstraZeneca, enGene and Immunity Bio.
This article is from the May 2025 print issue.