1.1

Unmet need in bladder cancer

Globally, bladder cancer is the ninth most common cancer, with an estimated 614, 298 new diagnoses and 220, 596 cancer-specific deaths in 2022 [ ]. The estimated 1-year prevalence for bladder cancer was 491, 243 in 2022—the seventh highest across cancers worldwide [ ]. The burden of bladder cancer is also significant, with 54 disability-adjusted life years lost per 100, 000 individuals, making bladder cancer the fifteenth most burdensome cancer globally in 2019 [ ]. Despite this global disease burden, the current standard of care for recurrent high-risk non–muscle-invasive bladder cancer (HR NMIBC) and muscle-invasive bladder cancer (MIBC) offers patients few treatment options. This is due to multiple factors, including varying drug toxicity, quality of life detriments, or inadequate clinical outcomes, thus highlighting a need for clinically effective, accessible, and better-tolerated alternatives. Additionally, bladder cancer is among the most expensive tumors for healthcare systems, as evidenced by the cost of MIBC treatments (e.g., the 5-year median costs for trimodal therapy and radical cystectomy [RC] are approximately US $400, 000 and US $225, 000, respectively) [ , ].

1.2

Contemporary management of HR NMIBC

Treatment options for HR NMIBC include transurethral resection of bladder tumor (TURBT) and subsequent induction and maintenance with intravesical bacillus Calmette-Guérin (BCG), which was approved for bladder cancer by the US Food and Drug Administration (FDA) in the 1990s [ , ]. Compared with BCG as standard induction therapy alone, BCG maintenance therapy was shown to significantly increase recurrence-free survival [ ]. Response rates approach 85 % for HR NMIBC [ ]; however, more than 50 % of the individuals experience recurrence within 4 years after BCG treatment [ ]. Many patients do not complete the maintenance regimen per guideline recommendations due to significant treatment-associated toxicity: approximately two thirds of patients experience local toxicity, and approximately one third suffer systemic toxicity [ , ]. Furthermore, given variable yet substantial challenges with respect to global BCG manufacture shortages, limited supplies for some geographical regions necessitate strategies to provide patients with optimal treatment, including prioritizing high-risk patients for induction or giving split (i.e., 1/3 or 1/2) doses [ ]. For patients with disease that recurs following treatment with adequate BCG, RC is the standard of care recommended by the American Urological Association/Society of Urologic Oncology (AUA/SUO) and European Association of Urology (EAU) guidelines [ , ]; however, in the real-world setting, this treatment option is utilized at variable rates owing to patient preference in this older population with a high burden of frailty and comorbidity [ ].

1.3

Current treatment of MIBC

Treatment options for MIBC include RC with neoadjuvant cisplatin-based therapy for eligible patients [ ]. Approximately 50 % of patients are cisplatin ineligible due to age- and/or disease-related comorbidities [ , , ]. Trimodal therapy, including “maximal” TURBT, radiotherapy, and chemotherapy, is a bladder-sparing option that may be offered to select patients with MIBC, and its use varies by region [ ].

1.4

RC in HR NMIBC and MIBC

Although it is a treatment option for patients with recurrent HR NMIBC following adequate BCG exposure and for patients with MIBC [ , ], RC may be associated with significant complication rates, morbidity, hospital readmissions, and perioperative mortality [ ]. The weighted overall complication rate for the initial hospitalization is approximately 35 %, with postsurgical rates increasing to 39 % at 30 days and 60 % (ranging to >80 %) at 90 days [ ]. Based on recent prospective studies, the 90-day mortality rate from RC ranges between 4.4 % and 6.5 % [ ]. In older patients, 90-day mortality rates of 9 % to 15 % have been reported [ , ]. Patients selecting RC also require urinary diversion and thus will often have other comorbidities, which may impact their health-related quality of life and further affect the morbidity and mortality rates among this population [ ].

2.1

Design features of TAR-200

To address the challenge of delivering sustained local therapy within the bladder lumen to treat bladder cancer, also known as intravesical therapy, the TAR-200 gemcitabine intravesical system is composed of a silicone dual lumen tube with gemcitabine placed within the larger lumen, creating a solid drug core ( Fig. 2 ) [ ].

TAR-200 is a targeted releasing system designed to provide sustained intravesical delivery of gemcitabine.

The smaller lumen contains a flexible wire that allows for insertion into the urethra and intravesical coiling to enable successful deployment of the drug delivery system and retention within the bladder during the planned indwelling period [ ]. TAR-200 is uncurled and loaded into a lubricated urinary placement catheter (UPC), which is then inserted into the bladder lumen through the urethra, after which the product is pushed out of the UPC with a stylet. The system returns to its original bi-oval shape after emerging from the UPC. TAR-200 is designed to resist structural collapse and promote retention within the bladder as it is freely mobile and compressible. The size may be compared to a quarter or €2 coin ( Fig. 2 ) [ ]. It is retained within the bladder for an extended period, approximately 3 weeks, and is retrieved via cystoscopy using a grasping forceps [ ].

Intravesical gemcitabine instillations have established efficacy and safety in NMIBC and as standard chemotherapy in combination with cisplatin in the treatment of MIBC [ ]. As a sustained gemcitabine intravesical system, TAR-200 is loaded with one tenth of the usual intravesical gemcitabine dose (225 vs. 2, 000 mg) [ , ], with the goal of optimizing gemcitabine dwell time while minimizing both local and systemic adverse events (AEs) and maximizing efficacy.

Inside the bladder, osmotic pressure regulates gemcitabine release from the TAR-200 internal reservoir, allowing the system to act as an osmotic drug pump ( Fig. 2 ) [ ]. Urea serves as an osmotic agent [ ]. The system is designed to provide localized, sustained gemcitabine delivery into the bladder over an extended period, while minimizing systemic exposure [ ].

2.2

Pharmacokinetics of gemcitabine delivered via TAR-200

TAR-200 is designed to allow for sustained release of gemcitabine over an indwelling period of up to 21 days [ , ]. In animal models, TAR-200 delivered gemcitabine into the urine for at least 7 days at concentrations comparable to target levels ( Fig. 3 A) [ , ]. TAR-200 maintains the gemcitabine therapeutic dose in urine over time, with no gemcitabine detected in the plasma, and the maximum plasma 2′, 2′-difluorodeoxyuridine (dFdU) concentration at any time point is ≤0.35 µg/ml ( Fig. 3 B) [ , ].

TAR-200 is designed to provide sustained, local delivery of gemcitabine while limiting systemic toxicity. (A) Gemcitabine dwell time in the bladder over 7 days with TAR-200; TAR-200 delivery (unpublished results, TARIS Biomedical) vs. current intravesical methods [ , , ]. (B) Maintenance of gemcitabine therapeutic dose in urine over time with no detection in plasma [ ].

^a Estimated clinical concentrations based on miniature pig pharmacokinetics (unpublished results, TARIS Biomedical). Minimum target concentration (4–5 µg/ml) [ , , ].

^b Patients received instilled doses of 500 to 2,000 mg in 50 to 100 ml [ ], 2,000 mg in 50 ml [ ], or 2,000 mg in 50 to 100 ml [ ]. Patients received two 7-day dosing cycles of TAR-200, with a 14-day rest period between cycles.

^c Phase I study in patients with MIBC [ ]. Similar findings in phase I study of patients with IR NMIBC [ ].

^d dFdU is an inactive metabolite of gemcitabine.

In preclinical models, gemcitabine penetrated deep into bladder tissue following continuous local exposure (unpublished data, TARIS Biomedical). In a rodent model of MIBC, continuous, low-dose intravesical gemcitabine inhibited tumor growth in a concentration-dependent manner [ ]. As gemcitabine is a prodrug, prolonged exposure to a sufficient concentration of gemcitabine may enhance intracellular accumulation of its active tri-phosphorylated metabolite, which impairs DNA synthesis [ ]. In addition, preclinical studies provide evidence of gemcitabine augmentation of antitumor T-cell response [ ].