AUA 2023: First Results from SunRISe-1 in Patients with BCG Unresponsive High-Risk Non–muscle-Invasive Bladder Cancer Receiving TAR-200 in Combination With Cetrelimab, TAR-200, or Cetrelimab Alone

(UroToday.com) The 2023 American Urological Association (AUA) annual meeting held in Chicago, IL between April 28 and May 1st, 2023, was host to a late-breaking oncology abstract session. Dr. Siamak Daneshmand presented the first results from SunRISe-1 in patients with BCG-unresponsive high-risk non–muscle-Invasive bladder cancer (NMIBC) receiving TAR-200 in combination with Cetrelimab, TAR-200 alone, or Cetrelimab alone.

Most patients with HR NMIBC treated with intravesical BCG do not maintain sustained remissions, with up to 60% and 80% experiencing recurrence or progression within 1 and 5 years, respectively.^1,2 For patients with BCG-unresponsive HR NMIBC, standard-of-care treatment remains radical cystectomy. However, many patients are either unable or unwilling to undergo radical cystectomy, with options for such patients remaining limited. As such, there remains a high unmet need in the BCG-unresponsive HR NMIBC population.

TAR-200 is a novel drug delivery system for the sustained local release of gemcitabine in the bladder, relying on an osmotic system for sustained release as illustrated below.

Evaluation of urine and plasma gemcitabine concentrations over a 7-day period demonstrated the ability of TAR-200 to provide sustained, local delivery of gemcitabine while limiting systemic toxicity. As demonstrated in the figure below, intravesical instillation of gemcitabine (green curve) is associated with a sharp increase/decrease in the gemcitabine urine concentration, which is non-sustained beyond day 1. Conversely, we see an increase in the urine gemcitabine concentration between days 1 and 3 with TAR-200 (blue curve), followed by a gradual decline with measurable levels detected until at least day 7. Conversely, no gemcitabine was detected in the plasma of patients receiving TAR-200.

SunRISe-1 is a randomized trial of BCG-unresponsive HR NMIBC CIS patients (+/- papillary disease) who did not receive a radical cystectomy. Patients underwent stratified randomization (by presence or absence of concomitant papillary disease) in a 2:1:1 fashion to either:

• Cohort 1: TAR-200 + cetrelimab (PD-1 inhibitor)
• Cohort 2: TAR-200 alone (target sample size 50, currently enrolled: 23)
• Cohort 3: Cetrelimab alone (target sample size 50, currently enrolled: 24)

Patients received TAR-200 every 3 weeks for the first 24 weeks, followed by every 12 weeks through week 96. Patients in the cetrelimab group received the drug through week 78. The primary endpoint was overall complete response (CR) rate, with key secondary endpoints of duration of response (DoR), OS, pharmacokinetics (PK), HRQoL, and safety/tolerability.

In this report, Dr. Daneshmand presented the first results from the monotherapy arms of TAR-200 alone and cetrelimab alone groups of SunRISe-1 from a planned futility analysis (n=47 patients). The clinical cut-off date of April 4, 2023.

Baseline patient characteristics were well-balanced between the two monotherapy arms. Median age was 70-72 years, and the majority of patients were males (~80%). CIS only disease was present in 70% and 65% of patients in the TAR-200 and cetrelimab groups, respectively. The median total doses of prior BCG were 12 in each arm. The majority of patients in this analysis had declined RC (96-100%).

From an efficacy standpoint, 73% of patients in the TAR-200 arm achieved a complete response, defined based on the results of cystoscopy, centrally assessed urine cytology, and mandated biopsy at weeks 24 and 48. The CR rate in the cetrelimab arm was 38%.

The median DoR with TAR-200 has not been reached yet after a median follow-up of ~11 months.

Overall, most AEs in the TAR-200 group were grade ≤2. AEs reported in the cetrelimab group were similar to that expected and observed with other PD-1 agents. 9% and 4% of patients discontinued TAR-200 and cetrelimab due to treatment-related AEs. In each arm, 1 patient had treatment-related serious AEs and 2 patients had treatment-related grade ≥3 AEs. No deaths were observed in the study.

Dr. Daneshmand concluded his presentation as follows:

• TAR-200 monotherapy showed a promising overall CR rate of 73% in patients with HR NMIBC unresponsive to BCG
  • After a median follow-up of 11 months, 15 of 16 responses are ongoing (median DoR was not reached)
  • 6 complete responders maintained their response beyond 12 months
  • None of the complete responders have documented recurrence or progression
• TAR-200 was well-tolerated
  • TAR-200-related SAEs, grade ≥3 AEs, and discontinuations were infrequent.
• Cetrelimab monotherapy safety and efficacy profiles were consistent with other anti-PD-L1 treatments in this disease setting
• First efficacy and safety data from SunRISe-1 support the ongoing investigation of TAR-200 with or without cetrelimab in patients with BCG-unresponsive HR NMIBC

Presented by: Siamak Daneshmand, MD, Professor of Urology, Department of Urology, University of Southern California, Los Angeles, CA

Written by: Rashid K. Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2023 American Urological Association (AUA) Annual Meeting, Chicago, IL, April 27 – May 1, 2023

1. Sylvester RJ et al. Predicting Recurrence and Progression in Individual Patients with Stage Ta T1 Bladder Cancer Using EORTC Risk Tables: A Combined Analysis of 2596 Patients from Seven EORTC Trials. Eur Urol, 2006.
2. Ritch CR et al. Use and Validation of the AUA/SUO Risk Grouping for Nonmuscle Invasive Bladder Cancer in a Contemporary Cohort. J Urol, 2020.