TARA-002 Showcases Early Clinical Activity in BCG-Naive and -Unresponsive High-Risk NMIBC

Image Credit: © Sebastian Kaulitzki – stock.adobe.com

TARA-002 elicited responses that appeared to be durable in BCG-naive and -unresponsive patients with high-risk non–muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) ± Ta/T1 disease, according to updated data from the phase 2 ADVANCED-2 study (NCT05951179) presented during the 2025 American Urological Association Annual Meeting.1

In patients with BCG-unresponsive disease, TARA-002 induced high-grade complete response (CR) rates of 100% (n = 5/5), 100% (n = 5/5), 80% (n = 4/5), and 66.7% (n = 2/3) at any time, month 6, month 9, and month 12, respectively. In the patients who did not initially achieve CR and received re-induction (n = 3), all converted to CR by month 6 and response was maintained at month 9 for all patients.

In those with BCG-naive disease, rates of high-grade CR at any time, month 6, month 9, and month 12 were 76.2% (n = 16/21), 62.5% (n = 10/16), 62.5% (n = 5/8), and 42.9% (n = 3/7). Notably, 86% of those who had a CR at month 3 and remained on study (n = 7), maintained their response through month 6. Of those who were evaluable at later time points, 75% and 100% of patients maintained their response through month 9 (n = 3/4) and at month 12 (n = 2/2), respectively. Of the patients who did not initially achieve CR and received re-induction (n = 5), 80% converted to CR by month 6.

“This was a phase 2 trial, [which included patients with] BCG-unresponsive and -naive [disease]. They followed them for [approximately] 12 months, and you see a 100% CR rate in the BCG-unresponsive group. It’s a small number of patients, but that’s really good. And you see a 76% CR [rate] in the BCG-naive group. That’s interesting, because usually…we see that the naive group responds better than the unresponsive group,” Gautam Jayram, MD, of Urology Associates PC, in Nashville, Tennessee, told OncLive®. “To that point, there could be a priming effect of this treatment where if you have received previous BCG, you actually may do better with this drug because your immune system has already been primed; that’s the hypothesis. This is something that’s hypothesis generating and something that should be studied because it’s interesting.”

The Promise of TARA-002

TARA-002 is a unique formulation comprised of inactivated cells of Streptococcus pyogenes Su strain that are administered intravesically; the product induces a TH1 proinflammatory cytokine response.

“This is a very hot space, BCG-naive and BCG-unresponsive disease,” Jayram told OncLive. “What we’re starting to really look at is novel mechanisms of action. You have broad classes of gene therapy, cytotoxic therapies. This is kind of unique because it is its own broad spectrum immune potentiator. I [believe] this is probably most similar to BCG, but it has a broader spectrum approach, where it turns on a bigger cascade of cytokines. Some talk about immune exhaustion; if you’re just stimulating the same cytokines in the same pathway over and over again, that may limit your efficacy. So, this is something that may have some interesting mechanistic approaches, where maybe you involve more of the immune system and get a better response.”

Shining a Light on ADVANCED-2: Design, Treatment, Key Objectives

The open-label ADVANCED-2 study is enrolling patients aged 18 years or older with high-grade NMIBC with CIS (± Ta/T1) and active disease.2 Enrollment is complete for those with BCG-naive disease, which was defined as those who have not been exposed and those who have not received intravesical BCG for at least 24 months.1 Enrollment is ongoing for participants with BCG-unresponsive disease.

In the BCG-unresponsive (n = 100) and -naive (n = 31) groups, patients underwent induction treatment comprised of 6 weekly instillations of TARA-002. For months 3 to 18, those with CR received maintenance treatment comprised of 3 weekly instillations every 3 months. Those with residual CIS and/or recurrence of high-grade Ta received re-induction comprised of 6 weekly instillations of the product followed by maintenance treatment for months 6 to 18 comprised of 3 weekly instillations every 3 months. Patients then went into follow-up.

The primary end point of the study is high-grade CR at any time up to month 6, and a key secondary end point was durability of response at month 12. The data cutoff for the analysis was April 16, 2025.

In the BCG-unresponsive group, the median patient age was 80.0 years (range, 47-92); 78.9% of patients were male, 84.2% were White, all were non-Hispanic, and 86.7% had an ECOG performance status of 0. Most patients (94.1%) had CIS-only disease at baseline, and 5.9% had CIS+Ta disease. In the BCG-naive group, the median patient age was 71.0 years (range, 45-89); 80.6% of patients were male, 93.5% were White, 90.3% were non-Hispanic, and 83.3% had an ECOG performance status of 0. In this group, 58.1% of patients had CIS-only disease at diagnosis, 29.0% had CIS+Ta disease, and 12.9% had CIS+T1 disease.

Safety Spotlight

Treatment-emergent adverse effects (TEAEs) were reported in 74% of patients; 60% were grade 1, 30% were grade 2, and 19% were grade 3. Related TEAEs occurred in 30% of patients (grade 1, 28%; grade 2, 2%). Serious TEAEs were reported in 14% of patients (grade 2, 5%; grade 3, 14%). No related TEAEs resulted in study drug withdrawal.

“The majority of TEAEs were grade 1 and transient,” the study authors wrote in a poster. “Common urinary adverse effects [AEs] reflect urinary tract instrumentation effects, such as bladder spasm, burning sensation, and urinary tract infection. Systemic AEs were consistent with the known safety profile of an immune-potentiating drug, such as flu-like symptoms.”

Disclosures: The study was funded by Protara Therapeutics, Inc.

References

1. Jayram G, Kramolowsky E, Doronina M, et al. Preliminary efficacy and safety results from ADVANCED-2: a phase-2 open-label study of intravesical TARA-002 in adults with high-grade non-muscle invasive bladder cancer. J Urol. Published online April 27, 2025. doi:10.1097/01.JU.0001109740.05294.af.40
2. Safety and efficacy study of intravesical instillation of TARA-002 in adults with high-grade non-muscle invasive bladder cancer (ADVANCED-2). ClinicalTrials.gov. Updated March 21, 2025. Accessed April 27, 2025. https://clinicaltrials.gov/study/NCT05951179