Middleton, Claire

776 Background: There continues to be a significant unmet need for safe, effective, and bladder sparing treatment options for patients with non-muscle invasive bladder cancer (NMIBC). TARA-002 is a lyophilized biological preparation for intravesical instillation containing inactivated cells of Streptococcus pyogenes (Group A, type 3) Su strain. TARA-002 rapidly enters cancer cells, activating TLR2 and NOD2 to trigger innate immunity, inflammation, and potential immunogenic cell death. ADVANCED-2 (NCT05951179) is an ongoing Phase 2, open-label study to evaluate the safety and efficacy of intravesical TARA-002 in adults ≥ 18 years with high-grade (HG)-NMIBC CIS (± Ta/T1). Preliminary results showed promising complete response (CR) rates and durable responses in patients with HG NMIBC treated with TARA-002 (Jayram et al. AUA 2025). This abstract presents pooled safety data of TARA-002 from the BCG-naïve cohort and BCG-unresponsive cohort of the ADVANCED-2 study. Methods: The ADVANCED-2 study includes 2 cohorts of BCG-naïve (Cohort A) and BCG-unresponsive (Cohort B) participants. Key exclusion criteria include penicillin allergy; history of ≥ T2 bladder cancer, nodal, or metastatic disease; and concomitant prostatic or upper tract urothelial involvement. Each participant is treated with TARA-002 to receive induction (6 weekly doses), reinduction (if persistent disease at 3 months), and maintenance (through 24 months). Response is assessed every 3 months for 2 years. Long-term follow-up is conducted up to 60 months. Safety is monitored throughout the study. Results: As of 07-October-2025, 60 participants (median age: 74; range: 45 to 92), have been enrolled and exposed to TARA-002: 31 BCG-naïve (Cohort A) and 29 BCG-unresponsive (Cohort B). In both cohorts, 18/60 (30.0 %) participants reported drug-related treatment emergent adverse events (TEAEs). Related TEAEs were Grade 1 (18/60; 30.0%) and Grade 2 (3/60; 5.0%), with no reported Grade 3-5 related TEAEs. Commonly reported related TEAEs (≥ 5%) included bladder spasm (10.0%), dysuria (13.3%), fatigue (6.7%), and micturition urgency (6.7%). Most TEAEs were mild and transient. In both cohorts, 10/60 (16.7%) experienced serious AEs (SAEs); 4/60 (6.7%) were Grade 2 and 9/60 (15.0%) were Grade 3. No participants experienced drug-related SAEs or drug-related TEAEs leading to withdrawal or death. Conclusions: TARA-002 monotherapy was well tolerated, thus demonstrating a favorable tolerability profile to date for the treatment of BCG-naïve and BCG-unresponsive HG NMIBC with CIS (±Ta/T1). TARA-002 has a promising safety profile as a bladder-sparing treatment in HG NMIBC across BCG exposure status. Updated safety data will be provided based on evaluable time points at the time of the presentation. Clinical trial information: NCT05951179 .

743 Background: Although patients with Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) have several emerging therapeutic options, there remains a clinical unmet need to improve efficacy, durability of response, and tolerability while obviating the need for radical cystectomy. TARA-002 is a lyophilized biological preparation for intravesical instillation containing inactivated cells of Streptococcus pyogenes (Group A, type 3) Su strain. TARA-002 rapidly enters cancer cells, activating TLR2 and NOD2 to trigger the innate immune response, inflammation, and potential immunogenic cell death. Herein we present interim safety and efficacy data of TARA-002 from the BCG-unresponsive cohort of the ongoing ADVANCED-2 study (NCT05951179). Methods: ADVANCED-2 (Cohort B) is a Phase 2, open-label study to evaluate the safety and efficacy of intravesical TARA-002 in BCG-unresponsive adults ≥ 18 years with high-grade NMIBC CIS (± Ta/T1). Key exclusion criteria include penicillin allergy; history of ≥ T2 bladder cancer, nodal, or metastatic disease; or concomitant prostatic or upper tract urothelial involvement. TARA-002 is delivered intravesically for 2 hours and includes induction (6 weekly doses), reinduction (if persistent disease at 3 months), and maintenance (through 24 months). Response is assessed every 3 months for 2 years. Biopsy is mandated at Month 3. Long-term follow-up is conducted up to 60 months. Safety is monitored throughout the study. The primary endpoint is complete response (CR) at any time defined by the absence of any high-grade recurrence. The key secondary endpoint is duration of response. Results: As of 07-October-2025, 32 BCG-unresponsive participants have been enrolled. Majority of participants were White (84.4%, 27 of 32), non-Hispanic (93.8%, 30 of 32), and male (68.8%, 22 of 32). The median age was 74 years (range: 47 to 92). The majority of participants had a baseline diagnosis of CIS only ie, without concomitant Ta/T1 (75.0%, 24 of 32). TARA-002 demonstrated a 68.4% (13 of 19) CR at any time in evaluable participants. The 6-month CR was 75.0% (9 of 12), the 9-month CR was 50.0% (4 of 8), and the 12-month CR was 37.5% (3 of 8). The salvage rate was 75.0% (6 of 8) with reinduction therapy. Most treatment-emergent adverse events (TEAEs) were mild (CTCAE Grades 1-2) and transient; no participants experienced higher than Grade 3 TEAEs. No participants experienced drug-related serious adverse events (SAEs) or drug-related TEAEs leading to withdrawal or death. Conclusions: In participants with BCG-unresponsive high-risk NMIBC with CIS ± Ta/T1, TARA-002 appears to be well tolerated and demonstrated encouraging efficacy, supporting ongoing accrual of the ADVANCED-2 study. Further follow-up will inform durability of response, and data will be updated based on evaluable time points at the time of the presentation. Clinical trial information: NCT05951179 .