A phase III trial, SunRISe-5 (NCT06211764), is underway to evaluate TAR-200, a novel drug delivery system for gemcitabine, against intravesical chemotherapy in patients with high-risk non-muscle invasive bladder cancer (NMIBC) who have recurrent disease following Bacillus Calmette-Guerin (BCG) treatment. The trial targets patients with papillary-only NMIBC who are ineligible for or decline radical cystectomy, addressing a critical unmet need for bladder-sparing treatments.
The Challenge of BCG-Unresponsive NMIBC
Recurrence rates after intravesical BCG therapy for high-risk NMIBC range from 20% to 46%. Subsequent BCG treatments are often ineffective for early recurrences (within one year), leaving radical cystectomy as the standard of care. However, there is a strong push to develop localized therapies that can preserve the bladder, especially for patients with papillary-only recurrent high-risk NMIBC.
TAR-200: Sustained Gemcitabine Delivery
TAR-200 is designed for sustained local release of gemcitabine in the bladder. Unlike intravesical instillation of gemcitabine, which results in a sharp spike and rapid decline in urine concentration, TAR-200 maintains measurable levels of gemcitabine in the urine for at least seven days, while limiting systemic toxicity. Phase II trial SunRISe-1 (NCT04640623) demonstrated a 73% complete response rate at 48 weeks with TAR-200 monotherapy in BCG-unresponsive, high-risk NMIBC with or without papillary disease.
SunRISe-5 Trial Design
The SunRISe-5 trial is randomizing 250 eligible patients (1:1) to either TAR-200 monotherapy or investigator’s choice of intravesical gemcitabine or mitomycin. TAR-200 is administered every three weeks during induction and every 12 weeks during maintenance. Intravesical chemotherapy is given weekly during induction and monthly during maintenance. Eligible patients are those aged ≥18 years with an ECOG performance status of 0-2, diagnosed ≤90 days before informed consent with histologically confirmed recurrent, papillary-only high-risk NMIBC (high-grade Ta, any T1, without carcinoma in situ) with last dose of BCG ≤12 months, and who are ineligible for or decline radical cystectomy.
The primary endpoint is disease-free survival, defined as the time from randomization to first recurrence of high-risk NMIBC (high grade Ta, any T1, or CIS). Secondary endpoints include recurrence-free survival, time to next intervention, time to progression, time to disease worsening, overall survival, safety and tolerability, patient-reported outcomes, and health-related quality of life. The trial is actively recruiting across multiple countries, with 25 patients randomized as of August 1, 2024, at 106 sites.
Gemcitabine and BCG Combination Shows Promise
Initial results of a multicenter phase II trial of intravesical gemcitabine plus BCG for patients with BCG-exposed NMIBC were also presented at the 2024 Society of Urologic Oncology (SUO) annual meeting. The study hypothesized that the combination would lead to improved response rates compared to historic outcomes with BCG re-treatment. Patients received gemcitabine 200 mg twice weekly on weeks 1, 4, 7, and 10 and BCG 50 mg TICE strain weekly on weeks 2, 3, 5, 6, 8, and 9. Patients without high-grade recurrences were continued on SWOG maintenance BCG.
At 6 months, the complete response rate was 94% (34/36), and at 12 months, it was 81% (21/26). In the CIS +/- papillary cohort, the 3-, 6-, and 12-month complete response rates were 100%, 97%, and 80%, respectively. The high-grade recurrence-free survival rates at 6, 12, and 18 months were 97%, 85%, and 76%, respectively. The 12-month cystectomy-free survival rate was 100%. Only two patients (5%) experienced a grade 3 treatment-related adverse event. Based on these data, a phase III randomized trial, the GAIN trial, is opening in May 2025 to further evaluate this combination.
