Sia Daneshmand MD, is a professor of urology, clinical scholar designation; director of Clinical Research in the urologic oncology fellowship at Keck School of Medicine, University of Southern California.

Dr Daneshmand on Using TAR-200 to Address Unmet Needs in BCG-Unresponsive NMIBC

“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.”

Sia Daneshmand MD, professor, urology, clinical scholar designation; director, Clinical Research, urologic oncology fellowship, Keck School of Medicine, University of Southern California, discusses how the incorporation of TAR-200 into the bladder cancer treatment armamentarium could uniquely address existing unmet needs for patients with high-risk, Bacillus Calmette-Guérin (BCG)–unresponsive non–muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS).

Treatment options for BCG-unresponsive NMIBC have remained limited for the past 2 decades, but the recent introduction of multiple new therapies into the treatment paradigm reflects an increasing focus on therapeutic development for this population, Daneshmand begins. Although BCG remains an effective treatment, a significant proportion of patients do not respond and require additional therapeutic strategies, he says. TAR-200 represents a potential advancement in this setting; it uses a novel drug delivery mechanism designed to enhance treatment efficacy, Daneshmand states.

Unlike conventional intravesical therapies that require drug instillation for 1 hour per session, TAR-200 is a drug/device combination that provides sustained intravesical delivery of gemcitabine over multiple days, Daneshmand explains. This prolonged exposure enhances drug penetration into the bladder tissue, potentially improving its effectiveness, he says. Preclinical studies have also demonstrated that active drug metabolites remain detectable in the bladder several days after administration, suggesting an extended dwell time that could contribute to increased efficacy, Daneshmand notes.

The initial focus of TAR-200 development has been in patients with CIS, a disease state that typically cannot be managed surgically, he continues, adding that demonstrating efficacy in this setting provides a clear assessment of the drug’s antitumor activity without confounding effects from surgical resection. Beyond CIS, TAR-200’s sustained drug release may also offer benefits in more invasive disease, such as T1 tumors, although this has not yet been established in clinical trials, Daneshmand notes.

Future research is needed to define TAR-200’s role in the broader NMIBC treatment paradigm, particularly in comparison with other emerging therapies and in combination with existing agents, he emphasizes. The potential for deeper tissue penetration and longer drug exposure could position TAR-200 as an important addition to the therapeutic paradigm for BCG-unresponsive disease, Daneshmand concludes.

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Sia Daneshmand MD, discusses how the intravesical therapy TAR-200 could address unmet needs for patients with high-risk, BCG-unresponsive NMIBC with CIS.

Dr Daneshmand on Findings From the SunRISE-1 Trial of TAR-200 in BCG-Unresponsive NMIBC

“These are exciting results. We also have ongoing follow-up of the patients, and ongoing results will be presented and published soon.”

Sia Daneshmand MD, professor, urology, clinical scholar designation; director, Clinical Research, urologic oncology fellowship, Keck School of Medicine, University of Southern California, discusses key efficacy findings from the phase 2b SunRISE-1 trial (NCT04640623) that may support the FDA approval of TAR-200, an intravesical gemcitabine delivery system, for the treatment of patients with Bacillus Calmette-Guérin (BCG)–unresponsive, high-risk non–muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS), regardless of the presence of papillary tumors.

Results from the TAR-200 monotherapy arm of SunRISE-1 (n = 85) show that, at a data cutoff date of May 13, 2024, the complete response (CR) rate among patients with BCG-unresponsive, high-risk NMIBC with CIS with or without papillary disease was 83.5% (95% CI, 73.9%-90.7%). Additionally, 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, responses were ongoing in 81.6% of responders at a median follow-up of 9.2 months (range, 3.7-36.6).

Daneshmand begins by stating that this CR rate with TAR-200 has been unprecedented among other bladder cancer treatments that have been examined in earlier-phase trials. The ongoing evaluation of additional end points, including DOR, will provide further insights into the efficacy of this therapy, he says.

During the first 6 months of treatment, TAR-200 is placed in the bladder once every 3 weeks, according to Daneshmand. Thereafter, the treatment is placed in the bladder once every 3 months for a maximum of 2 years or for as long as the patient is disease free, he explains. Prespecified disease assessments and ongoing follow-up of patients on the study will be shared in the future, he concludes.

Sia Daneshmand MD, discusses key efficacy findings from the SunRISE-1 trial of TAR-200 in patients with BCG-unresponsive, high-risk NMIBC with CIS.

Sia Daneshmand MD, professor of Urology, Keck School of Medicine, University of Southern California, discusses preliminary results from the phase 2 SunRISe-1 trial (NCT04640623) in patients with non–muscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guérin (BCG).

TAR-200 is a novel intravesical drug delivery system that leads to sustained local release of gemcitabine into the bladder, and cetrelimab is a PD-1 inhibitor. When combined, these agents may display synergistic activity, thereby improving outcomes in patients with high-risk NMIBC unresponsive to intravesical BCG.

In the trial, TAR-200 was administered every 3 weeks for 24 weeks, then every 12 weeks until week 96. Cetrelimab was administered through week 78. Cystoscopy, urine cytology, CT/MRI, and transurethral resection of bladder tumor were done at baseline and prespecified time points to evaluate response. The primary end point of the study is complete response (CR) rate at any time point. Secondary end points include duration of response, overall survival, pharmacokinetics, quality of life, safety, and tolerability.

The study enrolled patients who are ineligible for or decline radical cystectomy. Data from cohorts 2 and 3, which were presented at the 2023 AUA Annual Meeting, were encouraging, according to Daneschmand. The combination arm (cohort 1) did not have enough evaluable patients for analysis, Daneschmand says. In total, 22 patients received TAR-200 in cohort 2; 73% of these patients achieved CR. Among the patients who received cetrelimab, the CR rate was 38%, which is in line with expectations of response for single-agent checkpoint inhibition in this setting, Daneschmand says, citing the phase 2 KEYNOTE-057 trial (NCT02625961), which demonstrated a CR rate of 41% with pembrolizumab (Keytruda) in patients with BCG-unresponsive, high-risk, NMIBC with carcinoma in situ. 

Regarding safety, 11 patients (85%) in cohort 2 and 8 (62%) in cohort 3 had treatment-emergent adverse effects (TEAEs), most of which were grade 1/2. The most common TEAEs were pollakiuria (39%), micturition urgency (39%), and noninfective cystitis (39%) in cohort 2, and fatigue (23%) and lipase increased (23%) in cohort 3. One patient (8%) in cohort 2 and 2 patients (15%) in cohort 3 had grade 3 treatment-related, TEAEs. One serious TEAE of myocarditis occurred in cohort 3.

Sia Daneshmand MD, discusses preliminary results from the phase 2 SunRISe-1 trial (NCT04640623) in patients with non–muscle invasive bladder cancer unresponsive to Bacillus Calmette-Guérin.

Dr Daneschmand on Data From SunRISe-1 With TAR-200 and Cetrelimab in BCG-Unresponsive NMIBC

Siamak Daneshmand, MD, professor of Urology with Clinical Scholar designation, director, Clinical Research, fellowship director, Urologic Oncology, the University of Southern California, discusses the rationale for investigating erdafitinib (Balversa) in patients with recurrent, intermediate-risk non–muscle invasive bladder cancer (NMIBC) harboring 

Erdafitinib, a selective pan-FGFR TKI, is being evaluated in the multicohort phase 2 THOR-2 trial (NCT04172675). Data from an interim analysis of cohort 3 presented at the 2023 Genitourinary Cancers Symposium showed that at a median follow-up of 5.7 months from first erdafitinib dose, responses were observed in 7 of 10 evaluable patients responded, including 6 who achieved a complete response and 1 who had a partial response.

THOR-2 is an ongoing study with 3 cohorts, including cohort 3, which consists of patients at an intermediate risk with recurrent, low-grade tumors. Oral erdafitinib is a different approach to most other studies in patients with high-risk NMIBC, and the agent was 

 in April 2019 for the treatment of adult patients with locally advanced or metastatic bladder cancer with an 

 alteration that has progressed on platinum-containing chemotherapy.

 alterations are strong targets in NMIBC, and with the response rates observed with erdafitinib for patients with metastatic disease, moving these drugs into the early-stage disease setting could beneficial, Daneshmand says. However, investigators are still learning what the response rate is in the early-stage disease, and more research with further follow-up is needed, Daneshmand concludes.

Siamak Daneshmand, MD, discusses the rationale for investigating erdafitinib in patients with recurrent, intermediate-risk non–muscle invasive bladder cancer harboring FGFR3 or FGFR2 alterations.

Dr Daneshmand on the Investigation of Erdafitinib in NMIBC With FGFR2/3 Alterations

Siamak Daneshmand, MD, professor, Urology with Clinical Scholar designation, director, Clinical Research, fellowship director, Urologic Oncology, the University of Southern California, discusses findings from the interim analysis of cohort 3 of the multicohort phase 2 THOR-2 trial (NCT04172675).

Cohort 3 is evaluating erdafitinib (Balversa), a selective pan-FGFR TKI, in 20 patients with recurrent, intermediate-risk non–muscle invasive bladder cancer (NMIBC) with grade 1 or 2 tumors that have 

 alterations. Patients needed to have less than a 5% risk of progression in the 2 years following enrollment and a risk of recurrence over 50% to be eligible for this cohort. Patients who achieved a partial response (PR) or complete response (CR) within 3 months of starting erdafitinib could continue erdafitinib for up to 2 years, until progressive disease, intolerable toxicity, withdrawal of consent, treatment discontinuation per investigator decision, or trial closure.

Cohort 3 has an exploratory end point of CR rate, with safety as a key secondary end point. At a data cutoff of September 2022, 11 patients have been enrolled and 10 have received erdafitinib. This interim analysis reported findings from the first 8 evaluable patients.

Patients in cohort 3 underwent transurethral resection of their bladder tumors that left a single untouched 5- to 10-mm marker lesion. After their initial marker lesions were photographed, patients in cohort 3 received 6 mg of oral erdafitinib once daily without uptitration in 28-day cycles, Daneshmand says. When assessed at 6 weeks for safety, some patients’ marker lesions showed partial or complete responses, Daneshmand notes.

Patients received erdafitinib for a median duration of 2.9 months. At a median follow-up of 5.7 months from first erdafitinib dose, 7 patients had responded, with 6 achieving CRs, for a CR rate of 75.0%, and 1 achieving a PR, Daneshmand emphasizes. Additional results from all 20 patients in the cohort are still immature, Daneshmand concludes.

Siamak Daneshmand, MD, discusses findings from the interim analysis of cohort 3 of the multicohort phase 2 THOR-2 trial. 

Dr. Daneshmand on Erdafitinib in NMIBC

Sia Daneshmand MD, professor of Urology, Keck School of Medicine, University of Southern California, discusses emerging treatments in bladder cancer.

For patients with low-grade, non-muscle invasive bladder cancer, surveillance is an acceptable approach, and for patients with advanced disease, systemic therapies have a role, Daneshmand says. Though the practice of surveillance is not new, more data have emerged on how to perform it, the safety involved, and the rates of progression for patients with low-grade, non-muscle invasive bladder cancer, Daneshmand adds. Combination therapies have started to find a place in advanced bladder cancer, and ongoing trials continue to investigate these regimens, Daneshmand explains.

Regarding currently available therapies, retrospective studies have shown the benefits of gemcitabine plus docetaxel, and more long-term data have been seen regarding the regimen, Daneshmand concludes.

Sia Daneshmand MD, discusses emerging treatments in bladder cancer.


Dr. Daneshmand on Emerging Treatments in Bladder Cancer

 Siamak Daneshmand, MD, associate professor of Urology, Director of Clinical Research, Keck School of Medicine of USC, discusses blue light cystoscopy compared with white light cystoscopy for patients with bladder cancer. 

This phase III study involved 304 patients at 17 leading institutions in the United States, explains Daneshmand. The objective was to determine if blue light cystoscopy increased the detection of bladder tumors.  

Patients first underwent white light cystoscopy and then would have blue light cystoscopy done, states Daneschmand. The number and character of lesions were determined and compared with the number seen in the operating room.  