Purpose: Half of patients with muscle-invasive bladder cancer worldwide may not receive curative-intent therapy. Elderly or frail patients are most affected by this unmet need. TAR-200 is a novel, intravesical drug delivery system that provides sustained, local release of gemcitabine into the bladder over a 21-day dosing cycle. The phase 1 TAR-200-103 study evaluated the safety, tolerability, and preliminary efficacy of TAR-200 in patients with muscle-invasive bladder cancer who either refused or were unfit for curative-intent therapy.

Materials and methods: Eligible patients had cT2-cT3bN0M0 urothelial carcinoma of the bladder. TAR-200 was inserted for 4 consecutive 21-day cycles over 84 days. The primary end points were safety and tolerability at 84 days. Secondary end points included rates of clinical complete response and partial response as determined by cystoscopy, biopsy, and imaging; duration of response; and overall survival.

Results: Median age of the 35 enrolled patients was 84 years, and most were male (24/35, 68.6%). Treatment-emergent adverse events related to TAR-200 occurred in 15 patients. Two patients experienced treatment-emergent adverse events leading to removal of TAR-200. At 3 months, complete response and partial response rates were 31.4% (11/35) and 8.6% (3/35), respectively, yielding an overall response rate of 40.0% (14/35; 95% CI 23.9-57.9). Median overall survival and duration of response were 27.3 months (95% CI 10.1-not estimable) and 14 months (95% CI 10.6-22.7), respectively. Progression-free rate at 12 months was 70.5%.

Conclusions: TAR-200 was generally safe, well tolerated, and had beneficial preliminary efficacy in this elderly and frail cohort with limited treatment options.

Purpose of review

To provide expert recommendations for side effect management in patients with bladder cancer receiving intravesical-drug releasing system (iDRS) treatment and for optimizing iDRS insertion procedure success.

Recent findings

Indwelling iDRS are designed to provide sustained local exposure to therapy. In clinical trials, frequent side effects of iDRS treatment were lower urinary tract symptoms (LUTS) (e.g., dysuria, pollakiuria, micturition urgency), urinary tract infections (UTIs), and hematuria. These side effects are generally low grade, but if not properly managed, may lead to treatment interruptions or discontinuations. As data are limited, practical recommendations based on expert opinion for the management of common side effects and best practices for iDRS insertion procedures may improve treatment adherence and optimize outcomes in patients with bladder cancer receiving iDRS.

Summary

Two separate expert panels were convened to develop recommendations for side effect management with iDRS and optimizing iDRS insertion procedure success. Stepwise treatment-specific management strategies for LUTS, UTIs, and hematuria in patients receiving iDRS treatment that are familiar to practicing urologists are presented, including considerations for continuation or discontinuation of iDRS treatment. Several advanced techniques can be considered to improve iDRS insertions based on variations in patient anatomy.

Objectives: Neoadjuvant chemotherapy and radical cystectomy (RC) are underutilized standards of care for the treatment of muscle-invasive bladder cancer (MIBC) due to high patient burden from systemic toxicities and postoperative complications, respectively. TAR-200 is a novel intravesical drug delivery system developed to release gemcitabine into the bladder urine continuously, resulting in distribution of drug into stromal layers of the bladder. The primary aim of the TAR-200-101 study was to evaluate the safety of TAR-200 in patients with MIBC prior to RC (NCT02722538).

Methods and materials: This phase I, open-label study was conducted across 6 US and European sites. Eligible patients were aged ≥18 years with histologically confirmed T2a-T3b N0-N1 M0 urothelial cancer and had refusal or were ineligible to receive cisplatin-based combination chemotherapy. Two arms were enrolled serially. Patients in Arm 1 had residual tumor >3 cm after transurethral resection of bladder tumor (TURBT); those in Arm 2 had undergone maximal TURBT (residual tumor <3 cm). Patients received two 7-day cycles of intravesical gemcitabine delivery via TAR-200 before undergoing RC. Primary outcome was safety; secondary outcomes were tolerability, pharmacokinetics, and preliminary efficacy.

Results: Of 23 patients in the intention-to-treat population (11 in Arm 1, 12 in Arm 2), 20 completed both dosing cycles of TAR-200. No patients were classified as intolerant to TAR-200. Ten patients (4 in Arm 1, 6 in Arm 2) experienced ≥1 treatment-emergent adverse events (TEAEs). The most common TAR-200-related TEAEs were pollakiuria (n = 3) and urinary incontinence (n = 2). All TEAEs prior to RC were grade ≤2; 1 patient in Arm 2 experienced a grade 3 non-treatment-related TEAE. Plasma gemcitabine levels were undetectable. In Arm 1, those with residual tumor, 4 of 10 patients exhibited pathologic downstaging; 1 experienced a complete response (CR) and 3 a partial response (PR). In Arm 2, those undergoing maximal TURBT, 6 of 10 patients exhibited downstaging; 3 experienced a CR and 3 a PR.

Conclusion: Controlled intravesical gemcitabine release via TAR-200 was safe and well tolerated in patients with MIBC.