TAR-200 Is Poised to Become a Targeted, Tolerable Addition to BCG-Unresponsive NMIBC Treatment Arsenal

The intravesical gemcitabine delivery system TAR-200 sits on the precipice of widening the treatment armamentarium for patients with Bacillus Calmette-Guérin (BCG)–unresponsive, high-risk non–muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) as a highly targeted, effective, and tolerable therapy, according to Sia Daneshmand, MD, who added that the agent could have a particularly vital role as salvage therapy or an alternative to radical cystectomy for many patients.

On January 15, 2025, an NDA was submitted to the FDA seeking the approval of TAR-200 for the treatment of patients with BCG-unresponsive high-risk NMIBC with CIS, regardless of the presence of papillary tumors.1 This NDA submission was backed by data from the TAR-200 monotherapy cohort of the phase 2b SunRISE-1 trial (NCT04640623). At a data cutoff date of May 13, 2024, the complete response (CR) rate among patients with high-risk NMIBC with CIS with or without papillary disease who received TAR-200 monotherapy (n = 85) was 83.5% (95% CI, 73.9%-90.7%).2 The estimated 12-month CR rate was 57.4% (95% CI, 40.6%-71.0%), and the estimated 12-month duration of response (DOR) rate was 65.7% (95% CI, 45.2%-80.1%). Notably, at a median follow-up of 9.2 months (range, 3.7-36.6), response was ongoing in 81.6% of responders.

“There are few drugs currently available in this setting, and TAR-200 will be a welcome addition to the armamentarium for the treatment of these patients who have limited options,” Daneshmand said in an interview with OncLive®.

In the interview, Daneshmand discussed key efficacy and safety findings with TAR-200 from SunRISE-1, how this therapy addresses an unmet need for patients with BCG-unresponsive, high-risk NMIBC, and directions for future research with TAR-200, including reinduction and therapeutic sequencing.

Daneshmand is a professor of urology with clinical scholar designation, the director of Clinical Research, and the urologic oncology fellowship director at Keck Medicine of the University of Southern California in Los Angeles.

OncLive: What is the mechanism of action of TAR-200?

Daneshmand: TAR-200 is a targeted releasing system that provides sustained intravesical delivery of gemcitabine, an active drug in bladder cancer. This device is placed in the bladder and has pellets of gemcitabine that are dissolved over many days within the bladder, providing a sustained release of gemcitabine.

How might TAR-200 uniquely address existing unmet needs for patients with BCG-unresponsive, high-risk NMIBC with CIS?

For the past 2 decades, few drugs have been available for patients who don’t respond to BCG. Fortunately, there’s been a lot of recent activity in this area, and more drugs are becoming available for use. Although BCG has been effective, there is a significant number of patients who don’t respond and need additional therapies. Several trials are addressing this, and there have been many FDA-approved therapies over the past few years, but TAR-200 fills in this [treatment gap] nicely for BCG-unresponsive disease.

Usually, we start these trials [in patients] with CIS to see if the drug is active [in that setting]. CIS is [a condition that] we can’t necessarily get rid of surgically. So, the efficacy [of any agent against CIS] is that of the drug and not the surgical resection of the tumor, as it is in papillary disease.

[TAR-200 is] the only drug/device combination that releases the drug over a few days. All the other drugs we have are intravesical therapies that are placed in the bladder for 1 hour at a time, the same way BCG is placed. [Instead, TAR-200 has] sustained delivery. We know gemcitabine, and we use gemcitabine as an intravesical therapy in its aqueous form, but its sustained delivery over many days allows further penetration of the drug, and we can measure that.

Some elegant animal studies have shown that active metabolites of TAR-200 are still present in the bladder several days after installation. The idea is that there’s increased dwell time for the drug, which hopefully increases its efficacy. [TAR-200 may] also penetrate the deeper layers of the bladder and treat a bit more invasive disease, particularly T1 disease, although we haven’t proven that yet.

What was the design of the SunRISE-1 trial?

[This trial had an] interesting design. It was evaluating whether TAR-200 either alone or in combination with a checkpoint inhibitor would improve outcomes. There were 3 cohorts: cetrelimab—a PD-1 inhibitor—alone, cetrelimab plus TAR-200, and TAR-200 alone. [These 3 arms were intended to tease] out the components of each of the drugs to see the efficacy.

In the cetrelimab alone arm, there was a limited number of patients [n = 28]. [In this arm], we saw the same effect as we have seen with other checkpoint inhibitors, and did not see high activity. Therefore, in this trial, we concentrated on TAR-200 alone, because we’d seen high preliminary CR rates [in this arm]. Cetrelimab didn’t seem to add much [benefit] to TAR-200, so that arm was dropped.

An additional arm opened later for papillary-only disease. That’s now the subject of another trial, the phase 3 SunRISE-5 trial [NCT06211764]. We know [TAR-200] works in CIS, [so we want to know whether it works] in papillary disease as well. However, for [SunRISE-1], the concentration was on the CIS population.

What were some of the key efficacy findings from the TAR-200 monotherapy cohort of SunRISE-1?

[We saw] exciting results. In the monotherapy arm, we saw [a CR rate of 83.5%]. We have not seen CR rates this high with any other drug that’s been tested this early. These are very high rates of CR. We want to consider DOR as well, and [the evaluation of that is] ongoing, so we’ll be seeing more data coming out.

[Overall, it is] encouraging that most patients are responding to this therapy. The device is placed in the bladder once every 3 weeks for the first 6 months [of treatment]. After that, it is placed quarterly for up to 2 years, as long as the patient remains disease free. We have disease assessments at prespecified time points. These are exciting results. We also have ongoing follow-up of the patients, and ongoing results will be presented and published soon.

What is the safety profile of TAR-200?

With any new therapy, we want to assess tolerability, especially when it’s intravesical, and especially when it’s a device that’s placed in the bladder. We learned early in the phase 1 part of the study that [TAR-200] is well tolerated. This device is not sitting in 1 place in the bladder. It’s moving around in the bladder, so it’s not irritating the bladder in one place as stents do. That’s part of [the reason for its tolerability].

[Additionally, we wanted] to know [whether] the sustained release of gemcitabine [created] additional problems or adverse effects [AEs] for patients. Fortunately, we did not see this. Most of the AEs were grade 1 and 2 [and were AEs] we’re used to [seeing] with intravesical therapy with BCG, mitomycin, and gemcitabine in the aqueous form. These are irritative voiding symptoms, dysuria, and occasional frequent and urgent urinary tract infections.

Few patients discontinued therapy. Of the 85 patients who were on [the TAR-200 monotherapy arm of] the trial, only 4 patients discontinued therapy due to AEs. It’s well tolerated. I’ve had many patients on this [therapy] for many years. I was [an investigator on] the phase 1 trial, so I’m aware of its tolerability. [Tolerability is] important, especially because this is an ongoing therapy for up to 2 years.

What are the next steps for evaluating TAR-200 in NMIBC?

We have ongoing disease assessments and ongoing follow-up for the patients [in SunRISE-1]. We’d like to know whether [TAR-200 a treatment] we can revisit if a patient experiences recurrence once they come off therapy. We don’t have those data. Reinduction is not part of [SunRISE-1], so I look forward to seeing reinduction in these patients. If they remain disease free for 2 years, for instance, and have a recurrence at that point, can we go back to this device, knowing that it worked earlier and was well tolerated? I have a couple patients who have completed their 2-year follow-up, so I’m thinking of those patients particularly.

Additionally, the sequencing of drugs [is a consideration]. When is this the most appropriate therapy? If the patient has received prior gemcitabine as immediate intravesical therapy, [will they] respond just as well to [TAR-200]?

There are a lot more data to come. SunRISE-5 is concentrating on [TAR-200] as an adjuvant therapy in [patients with] papillary-only disease to see whether [the agent] would reduce recurrence rates. There are exciting times ahead to work out these newer therapies and see where [TAR-200] fits in trials where there is sometimes limited enrollment. We’d like to see it used in other settings as well. We look forward to hearing more results from the other SunRISE studies and seeing whether there’s efficacy in patients with muscle-invasive disease with the phase 3 SunRISE-2 trial [NCT04658862] and some [other planned] trials, so I’m excited about the future.

If TAR-200 were to become approved for patients with BCG-unresponsive, high-risk NMIBC, how would this agent affect the treatment paradigm?

We would have 1 more drug available to us. This is exciting. This is what we need, because all the newer therapies are associated with significantly high recurrence rates. Pembrolizumab [Keytruda], nadofaragene firadenovec [Adstiladrin], and nogapendekin alfa inbakicept-pmln [Anktiva]—the newest drug to be approved in this setting—all have failure rates. We’ll be looking to use [TAR-200], if it becomes available, as a salvage treatment or in the sequencing of treatments. We’re going to have a lot of use for this product when it becomes available.

It’s well tolerated. It’s easily placed in the bladder and removed from the bladder. Urologists are familiar with these types of insertions and removal. It’s going to be a welcome addition to the armamentarium of the available therapies for bladder cancer.

Could TAR-200 serve as an alternative to surgery for certain patients?

Certainly. In the past, we always said the gold standard treatment for BCG-unresponsive disease was radical cystectomy, but that’s not feasible or acceptable for many patients. [With the use of TAR-200], we’ll be avoiding surgery in a lot of patients. In every trial [investigating TAR-200], the number of patients who underwent cystectomy during follow-up is low. We’re decreasing the number of cystectomies we perform for BCG-unresponsive NMIBC.

We need to be careful, though. High-grade T1 [disease is categorized at] a special stage now, in between the more superficial bladder tumors and the muscle-invasive tumors. Those are at high risk of progression. We have to be careful when enrolling those patients onto [TAR-200] trials and [considering them for TAR-200 therapy, if] it becomes available, to not miss the opportunity for a curative operation. [TAR-200] will help alleviate the lack of therapies we have for treating these patients and reduce the number of radical surgeries that are done, which are associated with a lot of morbidity.

References

1. New drug application initiated with US FDA for TAR-200, the first and only intravesical drug releasing system for patients with BCG-unresponsive high-risk non-muscle-invasive bladder cancer. News release. Johnson & Johnson. January 15, 2025. Accessed February 24, 2025. https://www.investor.jnj.com/news/news-details/2025/New-Drug-Application-initiated-with-U.S.-FDA-for-TAR-200-the-first-and-only-intravesical-drug-releasing-system-for-patients-with-BCG-unresponsive-high-risk-non-muscle-invasive-bladder-cancer/default.aspx
2. van der Heijden MS, Simone G, Boegemann M, et al. TAR-200 +/- cetrelimab (CET) and CET alone in patients (pts) with bacillus Calmette-Guérin-unresponsive (BCG UR) high-risk non-muscle-invasive bladder cancer (HR NMIBC): updated results from SunRISe-1 (SR-1). Ann Oncol. 2024;35(suppl 2): S1272-S1273. doi:10.1016/j.annonc.2024.08.2329