A paradigm shift in early-stage bladder cancer treatment is imminent

The Ministry of Food and Drug Safety (MFDS) said it granted orphan drug and developmental orphan drug designations to two therapies for the treatment of BCG-refractory high-risk non-muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS), with or without papilloma, on June 12.

The designations include nadofaragene firadenovec (U.S. trade name Adstiladrin), the first gene therapy approved in the U.S. for bladder cancer, and TAR-200, an intravesical sustained-release drug delivery device under accelerated review in the U.S.

TAR-200, in particular, received the designation despite divided opinions within the Central Pharmaceutical Review Committee (CPRC) during its deliberations on orphan drug status.

The gene therapy drug nadofaragene firadenovec, which was first designated as an orphan drug, became the first Korean orphan drug following its FDA approval in the United States in December 2022. TAR-200, a device-type formulation that continuously releases gemcitabine, was designated as a development-stage orphan drug.

Non-muscle-invasive bladder cancer (NMIBC) is an early-stage bladder cancer confined to the bladder mucosa, accounting for approximately 70 to 80 percent of all bladder cancer cases. High-risk groups include patients with carcinoma in situ (CIS) or multiple high-grade tumors, which carry a high risk of recurrence and progression. Bacillus Calmette-Guérin (BCG) intravesical therapy is the standard first-line treatment; however, about 30 to 50 percent of patients eventually relapse or become refractory within a few months. While radical cystectomy remains the standard of care in such cases, it poses a significant burden on patients, highlighting the continued need for bladder-sparing therapeutic options.

Nadofaragene firadenovec is a non-replicating adenoviral vector that delivers the human interferon alfa-2b gene, inducing an immune response by enabling direct expression of the protein within the bladder epithelium.

The clinical trial (NCT02773849) that supported FDA approval demonstrated a complete response (CR) in 51 percent of 98 patients with BCG-refractory NMIBC, including those with carcinoma in situ (CIS). The median duration of response (mDOR) was 9.7 months, with a 12-month response maintenance rate of 46 percent.

TAR-200 is a drug delivery system that employs a silicone device inserted into the bladder to continuously release gemcitabine over several weeks. Unlike the traditional drip method, it provides sustained anti-cancer effects with a single procedure and has a relatively low impact on the patient’s daily life.

Results from the global phase 2b SunRISe-1 study, recently presented at the American Urological Association (AUA 2025), showed that in Cohort 2 -- comprising patients who were unable or refused radical cystectomy -- TAR-200 monotherapy achieved a complete response (CR) rate of 82.4 percent. Of these, 52.9 percent maintained their response without re-induction therapy through one year, with a bladder preservation rate of 86.6 percent at 12 months. These results demonstrate that TAR-200 is a viable treatment option for disease control without the need for radical cystectomy.

However, TAR-200’s path to orphan drug designation has not been smooth. According to the recently released minutes of the CPRC meeting by the MFDS, members were divided in their opinions.

Opposing opinions included that “simple formulation changes do not meet the criteria for designation” and that “clinical compliance is poor,” while proponents argued that “significant improvement in efficacy compared to existing treatments has been demonstrated” and that the therapy holds “clinical significance as an alternative to cystectomy.”

In the end, the MFDS granted its orphan drug designation in the development stage, recognizing its innovative delivery mechanism and clinical significance.

Meanwhile, Keytruda (pembrolizumab) is currently the only immuno-oncology drug approved for BCG-refractory NMIBC in Korea. However, its response rate is limited to approximately 41 percent, and immune-related adverse events require careful management.

On the other hand, nadofaragene firadenovec is a local immunoinduction therapy, while TAR-200 is a direct delivery anticancer drug; with their different treatment mechanisms, the potential for combination with Keytruda is also being explored.

Therefore, the introduction of these two therapies is expected to bring a major shift in the domestic treatment paradigm. In particular, they significantly expand treatment options by promoting bladder preservation strategies and improving patients’ quality of life. However, challenges remain, including the high cost of treatment, formulation-specific considerations, and the process of securing insurance coverage.