Chad Reichard, MD, and Eugene Cone, MD
Urology of Indiana, US Urology Partners, Indianapolis
KEYWORDS:
non–muscle invasive bladder neoplasms; BCG vaccine; immunotherapy
Abstract
Background: The treatment landscape for non–muscle invasive bladder cancer (NMIBC) has expanded recently and is poised to continue with new therapy options across stages of disease. Studies of newer treatments for NMIBC, however, have been limited by lack of consensus on trial end points, among other aspects of clinical trial design. Additional alignment and clarification are needed across trials for standardization in measuring treatment effects.
Methods: Previous and current studies of treatments across stages of NMIBC, including BCG-naive disease, BCG-exposed/experienced disease, and BCG-unresponsive carcinoma in situ, were assessed for this review, with a focus on efficacy end points and their definitions.
Results: Early NMIBC trials primarily used complete response at any time as an efficacy measure in response to efforts by various organizations to standardize and streamline clinical trial design. More recent studies report disease-free survival and event-free survival as primary efficacy metrics. Whether trial end points are defining meaningfully different metrics or simply representing different nomenclatures with similar clinical significance is an important distinction.
Conclusions: Although clinical trial end points have become better defined recently, further clarification is still needed, and differences remain in the use of end points in clinical trials. Awareness of details and definitions of trial end points are important for the urologic community to accurately interpret results and effectively counsel patients.
Bladder cancer is the sixth-most common cancer in the United States. It poses a substantial burden to patients and the health care system, with an estimated 84 870 new cases and 17 420 deaths in 2025.1 Most bladder cancer, approximately 75%, is non–muscle-invasive bladder cancer (NMIBC) at diagnosis.2,3 Many patients with NMIBC may respond well to initial treatment, then experience disease progression or recurrence, necessitating further surgical and intravesical therapies, leading to complications and reduced quality of life.4,5 Some data suggest that patients with newly diagnosed NMIBC that advances to muscle invasion may have a worse prognosis than patients who present initially with muscle-invasive disease.6-8
Among patients with NMIBC, the risk of progression to muscle-invasive disease is approximately 10% to 20% over 5 years, with estimated cancer-specific mortality of 6.5%, 10%, and 12% at 2 years, 5 years, and 10 years, respectively.9,10
Several expert panels have stratified NMIBC into low-risk, intermediate-risk, and high-risk categories, based on clinical and pathologic factors indicative of disease severity and prognosis.11-14 Although no single risk classification system for NMIBC is internationally accepted, several have been suggested and published (Table 1).11,13,15 Generally, low-risk NMIBC is characterized by a single tumor 3 cm or smaller in diameter that is a papillary neoplasm of low malignant potential.11,13,14 Intermediate-risk NMIBC is usually classified as non–carcinoma in situ (CIS); it may include a single low-grade tumor larger than 3 cm in diameter and low-risk NMIBC that has recurred within 12 months of the last tumor.11,13,14 High-risk NMIBC is defined as any high-grade tumor, CIS, or BCG failure and aggressive variants of urothelial carcinoma.11,13,14
Carcinoma in situ is a stage of high-grade NMIBC along the lining of the urothelium that confers an increased risk of recurrence (≤78% in 5 years), progression (≤50% in 5 years), and death.16-19 It accounts for approximately 10% of NMIBC cases.20 Carcinoma in situ at diagnosis is more favorable than CIS with progression because rates are more than doubled in patients with secondary disease.21,22
Although types of NMIBC are well defined, studies of new treatments for NMIBC have been hampered by lack of consensus on trial end points, among other aspects of clinical trial design.23 Multiple new therapies have emerged in recent years for various stages of NMIBC, but additional alignment and clarification are needed across trials to standardize the measure of treatment effects. This review discusses the current treatment landscape for NMIBC, the use of various clinical trial end points in NMIBC studies, and implications for urology practice.
Standard-of-care treatment for NMIBC typically includes transurethral resection of the bladder tumor and intravesical BCG therapy.11,14,24 Despite adequate BCG therapy, however, approximately 30% of patients do not respond, with up to 40% of cancers recurring within a year and approximately 20% progressing to muscle-invasive disease.24
Up to 78% of patients with high-risk NMIBC experience recurrence after BCG treatment, and additional BCG therapy is not recommended for early recurrences (within 1 year) because of the therapy’s limited efficacy.25 Radical cystectomy is currently considered the standard of care for early BCG-unresponsive recurrence of papillary disease, although it is limited by clinically significant morbidity, mortality, and impairment of quality of life. Therefore, many patients who are ineligible for or refuse radical cystectomy have few approved treatment options; most treatments approved for high-risk NMIBC are restricted to patients with CIS.25
The SunRISe-5 trial (ClinicalTrials.gov identifier NCT06211764) is evaluating TAR-200 (an intravesical system designed for sustained delivery of gemcitabine in the bladder) vs intravesical chemotherapy in patients with papillary disease–only high-risk NMIBC recurrent after BCG therapy who refuse or are unfit for radical cystectomy.26 In addition, the MoonRISe-3 trial (ClinicalTrials.gov identifier NCT06919965) is evaluating TAR-210 (an intravesical system designed for sustained delivery of the fibroblast growth factor receptor inhibitor erdafitinib in the bladder) vs intravesical chemotherapy in patients with papillary disease–only high-risk NMIBC recurrent after BCG therapy who refuse or are not good candidates for radical cystectomy.27 Both SunRISe-5 and MoonRISe-3 seek to address the need for additional bladder-sparing therapies.
For BCG-unresponsive CIS, additional bladdersparing treatment approaches have become clinically available in the ongoing effort to improve clinical outcomes because of the high rates of recurrence, lack of treatment response, and limited value of repeat BCG treatment.28 The current National Comprehensive Cancer Network guidelines recommend gemcitabine intravesical system, nadofaragene firadenovec-vncg, nogapendekin alfa inbakicept-pmln plus BCG, and pembrolizumab for certain patients with BCG-unresponsive or BCG-intolerant disease (Table 2).29
Various organizations, including the American Urological Association, US Food and Drug Administration (FDA), and European Association of Urology, have proposed trial designs to support development of new treatments for NMIBC.23 Most recommendations are based on expert commentary rather than formal consensus or literature review, and not all experts have agreed on these trial designs.23 In 2016, the International Bladder Cancer Group proposed recommendations for definitions, end points, and trial designs for NMIBC based on formal consensus.23 The International Bladder Cancer Group end point recommendations are summarized in Table 3.
Although these recommendations are intended to align clinical trial end points for NMIBC, there still exists some heterogeneity among trials, and it is important for the urologic community to clearly understand potential variations in trial end points and how they can affect patient counseling. For example, when interpreting data from trials, clinicians should determine whether complete response (CR) was measured at any time or was measured at prespecified time points (ie, 12 or 24 months). It is also important to note whether biopsy was required—and, if required, when it was performed—which differs across studies. Event-free survival (EFS) can include 4 events—discontinuation due to toxicity, disease recurrence, progression, and death—but nuances can vary between studies. This information is also helpful when evaluating treatments in a neoadjuvant setting that could have complications that would preclude surgical intervention. Furthermore, disease-free survival (DFS) or recurrence-free survival includes only recurrence and death and can exclude progression, and the terms are often used interchangeably. Cystectomy-free survival and outcomes of eventual cystectomies are also important to characterize; it can be challenging to compare between studies, but doing so is important because these end points are important to patients. In addition, overall survival is rarely used in early NMIBC because of the disease’s early favorable prognosis.
End points for early BCG-unresponsive CIS trials were guided by recommendations from the International Bladder Cancer Group and emphasized CR at any time.23 More recently, studies have reported DFS or EFS as additional primary end points. Agents studied earlier or later are noted here:
Early:
– Pembrolizumab (FDA approved January 8, 2020)
– Nadofaragene firadenovec (FDA approved December 16, 2022)
– Nogapendekin alfa inbakicept (FDA approved April 22, 2024)
Later:
– Gemcitabine intravesical system (FDA approved September 9, 2025)
– Cretostimogene grenadenorepvec (investigational, BOND-00330 [ClinicalTrials.gov identifier NCT04452591])
– Detalimogene voraplasmid (EG-70) (investigational, LEGEND31 [ClinicalTrials.gov identifier NCT04752722])
– Photodynamic therapy (investigational, phase 2 trials32)
Whether clinical trial end points are actually defining meaningfully different metrics or simply representing different nomenclatures with similar clinical significance or applications is an important distinction. Clarity in end point definitions remains critical for studies evaluating new and emerging therapies,33,34 several of which are summarized here and detailed in Table 4.
A few trials evaluating immuno-oncology therapy in BCG-naive disease have been completed, including ALBAN (atezolizumab [ClinicalTrials.gov identifier NCT03799835]), POTOMAC (durvalumab [ClinicalTrials.gov identifier NCT03528694]), and CREST (sasanlimab [ClinicalTrials.gov identifier NCT04165317]).35-37 Arguably, end points in immunooncology therapy trials are more important given the addition of immunotherapy and the potential for immune-mediated adverse events, some of which can be life changing. Clinicians will need to determine whether the potential for increased toxicity is worth the potential additional efficacy of these regimens compared with intravesical-only regimens. Qualityof-life end points are needed and may vary between studies, which points to implications for discussing safety data with patients.
In the ALBAN trial, atezolizumab plus BCG showed no statistically significant improvement in EFS vs BCG alone, with higher rates of treatment-related adverse events in the combination arm than in the BCG-only arm.35 In the POTOMAC trial, 1 year of durvalumab combined with BCG induction and maintenance therapy showed improved DFS compared with BCG induction and maintenance alone, and safety profiles were consistent with those of the individual agents.37 In the CREST trial, patients who received sasanlimab combined with BCG induction and maintenance experienced greater prolongation of EFS compared with BCG induction and maintenance alone, with treatment-related adverse events consistent with known profiles of individual agents.36 On the surface, the end points appear different, with ALBAN and CREST reporting EFS and POTOMAC reporting DFS; however, when the nuances of the definitions are considered, there appears to be no clinically meaningful difference. In addition, the favorable outcomes of the control arms with BCG induction plus maintenance in these studies should be highlighted. They had roughly 25% risk of recurrence at 3 years, which is remarkably high compared with published real-world data, despite the fact that roughly two-thirds of the patients had pT1 disease. This finding indicates how effective BCG is when disease is managed in a highly controlled clinical trial environment, where repeat resection for T1 tumors is mandated by protocol and large percentages of patients complete the prescribed course of maintenance BCG therapy.35-37
Additional trials evaluating immuno-oncology therapies in BCG-naive disease are expected to have results soon or are ongoing, such as KEYNOTE-676 (pembrolizumab [ClinicalTrials.gov identifier NCT03711032]), SunRISe-3 (TAR-200 with or without cetrelimab), and PATAPSCO (durvalumab [ClinicalTrials.gov identifier NCT05943106]).38-40 In KEYNOTE-676, patients received pembrolizumab plus BCG or BCG alone; end points include CR, duration of response, EFS, recurrence-free survival, time to cystectomy, overall survival, DFS, safety, tolerability, and patient-reported outcomes; results are expected shortly.38,41 SunRISe-3 is evaluating TAR-200 (gemcitabine intravesical delivery system) with or without cetrelimab compared with BCG; the primary outcome of EFS is defined as time from random assignment to either the time of the first recurrence of high-risk disease, progression, or death from any cause, whichever occurs first; study completion is estimated in 2029.39 The PATAPSCO trial is assessing the efficacy, tolerability, and safety of durvalumab plus BCG induction and maintenance as an open-label, single-arm study; the primary outcome is safety related, but the efficacy measure of DFS is defined as the time from the date of first dose of study intervention until the date of first recurrence of high-risk disease or death; results are expected in the near future.40
The BRIDGE trial (ECOG-ACRIN EA8212 [ClinicalTrials.gov identifier NCT05538663]) is a phase 3 randomized trial evaluating intravesical BCG compared with intravesical gemcitabine and docetaxel, with the objective of determining whether EFS for gemcitabine and docetaxel is noninferior to that for BCG; the study is ongoing.42
Trials in patients with BCG-exposed/experienced disease include SunRISe-5 (TAR-200, gemcitabine intravesical system), described earlier, and LEGEND (EG-70, detalimogene voraplasmid).26,31 In the phase 2 portion of the LEGEND trial, patients with BCG-unresponsive NMIBC with CIS with or without resected coexisting papillary tumors who were ineligible for or elected not to undergo cystectomy received intravesical administration of detalimogene voraplasmid; the trial is ongoing.31 The primary efficacy end point in LEGEND is CR at week 48; in contrast, SunRISe-5 is measuring DFS as the primary efficacy outcome, defined as the time from random assignment to the time of the first recurrence of high-risk NMIBC, progression, or death from any cause, whichever occurs first.26,31
End points in trials for BCG-unresponsive papillaryonly disease are more challenging to evaluate because the quality of transurethral resection of the bladder tumor is paramount to outcomes. Trials include SunRISe-1 (TAR-200, gemcitabine intravesical system), a phase 3 trial for nadofaragene firadenovec, QUILT-3.032 (nogapendekin alfa inbakicept [ClinicalTrials.gov identifier NCT03022825]), KEYNOTE-057 (pembrolizumab [ClinicalTrials. gov identifier NCT02625961]), and BOND-003 (cretostimogene grenadenorepvec).30,43-46 Of note, these studies had multiple cohorts, which included papillary-only cohorts, but results in the CIS-containing cohorts are what led to FDA-approved indications for these therapies. Therefore, although papillary-only cohorts were enrolled in QUILT-3.032 and KEYNOTE-057, these treatments are not FDA approved for this population, probably in part because the quality of transurethral resection of the bladder tumor is heavily influential on outcomes.
The phase 2b SunRISe-1 trial evaluated TAR-200 (gemcitabine intravesical system) alone or in combination with cetrelimab, a programmed cell death protein 1 inhibitor, in patients with BCG-unresponsive high-risk NMIBC who were ineligible for or refused radical cystectomy.43 Monotherapy with TAR-200 was well tolerated, with a CR rate of 82.4% and 25.8-month duration of response.43
Nadofaragene firadenovec is an intravesically administered replication-deficient recombinant adenovirus that delivers human interferon alpha 2b complementary DNA into the bladder epithelium. In an open-label phase 3 trial, patients with BCG-unresponsive NMIBC received nadofaragene firadenovec, with 55 of 103 (53.4%) achieving CR within 3 months of the first dose.46
Nogapendekin alfa inbakicept is an immune cell–activating interleukin 15 superagonist that may act synergistically with BCG to elicit durable CR in patients with BCG-unresponsive NMIBC.44 In the phase 2/3 single-arm QUILT-3.032 trial, patients with BCG-unresponsive CIS who received intravesical nogapendekin alfa inbakicept plus BCG (82 patients) achieved a 71% CR, with a median duration of 26.6 months (95% CI, 99 to not reached).44
In KEYNOTE-057, adults with histologically confirmed BCG-unresponsive CIS with or without papillary tumors who were ineligible for or declined radical cystectomy received pembrolizumab every 3 weeks for up to 24 months or until disease persistence, recurrence, progression, or intolerable adverse effects.45 Over a median follow-up of 36.4 months (IQR, 32.0-40.7), 39 of 96 (40.6%) patients had a CR at 3 months.45 At 12 months, 40% of 3-month responders were without recurrence.
BOND-003 enrolled 110 adults (efficacy analysis) with confirmed high-risk NMIBC and CIS that was BCG-unresponsive; treatment with cretostimogene grenadenorepvec was administered as 6 weekly doses during induction, followed by maintenance. At a median follow-up of 22.3 months, CR at any time was 75.5% (83 of 110 patients), with 12-month and 24-month estimated CR rates of 46.4% and 42.3%, respectively.30
Although it is exciting to have many new potential options for bladder-sparing treatment of NMIBC, there remains a need to raise awareness of various end points among urologists to increase accurate understanding of the implications of clinical trial results. A better understanding of end points can improve patient counseling about treatment options.47 In addition, there is a need for patient education tools to translate medical definitions of end points into patient-friendly language, including components such as CR, duration of response, progression rates, and toxicity rates (severity and duration). Costeffectiveness of various treatment strategies will also need to be considered as well as patient selection based on initial response to BCG for stratifying BCG-naive patients for clinical practice.48,49
Future directions for clinical trials might include sequencing of therapies and further clarification of safety. Sequencing of treatments is important, and further direct comparison of treatments or treatment combinations will probably be the next phase of disease management.50 The number of treatments that is safe to attempt with ongoing recurrence without progression will need to be clarified, while noting that it is important to keep progression avoidance as the primary goal of safely avoiding cystectomy.51
The treatment landscape for NMIBC has expanded in recent years and is poised to continue with new therapy options across stages of disease. Clinical trial end points have become better defined as a result of efforts by various organizations to standardize and streamline clinical trial design. Further clarification of trial end points is still needed, however, and differences remain in the use of end points in clinical trials. As treatments continue to be evaluated in clinical trials, urologists need to be aware of the details and definitions of trial end points to accurately interpret results and effectively counsel patients.
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Published: December 19, 2025.
Conflict of Interest Disclosures: E.C. is a speaker for ImmunityBio, Johnson & Johnson, and Merck and an advisor for enGene; he has received research funding from AstraZeneca, enGene, Ferring, ImmunityBio, Johnson & Johnson, Merck, Pfizer, Sumitomo, and Theralase. C.R. is a consultant/advisor for AstraZeneca, Bayer, Dendreon, Ferring, Johnson & Johnson, Merck, and Pfizer; has received research funding from CG Oncology, Dendreon, Ferring, ImmunityBio, Johnson & Johnson, Merck; and has been a member of the speakers bureau of AstraZeneca, Bayer, Ferring, Johnson & Johnson, and Merck.
Funding/Support: Funding for this article was provided by Pfizer.
Author Contributions: All authors had the final responsibility for the decision to submit for publication.
Data Availability Statement: The authors confirm that the data supporting the findings of this study are available within the article.
Acknowledgments: The authors thank Austin Ulrich, PharmD, BCACP, of Dragonfly Editorial for medical writing assistance in preparing the manuscript.
Citation: Reichard C, Cone E. The evolving end point definitions in bladder cancer clinical trials. Rev Urol. 2025;24(4):e51-e62.
Corresponding author: Chad Reichard, MD, 11380 Illinois St, Carmel, IN 46032 (creichard@urologyin.com)