2. UroToday Home
  3. Conference Highlights
  4. ASCO GU 2025
  5. ASCO GU 2025 Bladder Cancer

ASCO GU 2025

ASCO GU 2025: The Changing World of Non-Muscle-Invasive Bladder Cancer

(UroToday.com) The 2025 American Society of Clinical Oncology Genitourinary (ASCO GU) cancers symposium held in San Francisco, CA between February 13th and 15th 2025, was host to the Case-Based Session: Non-Muscle Invasive Bladder Cancer: Exploring Therapies Beyond Bacillus Calmette-Guérin Session. Dr. Bogdana Schmidt in her presentation titled The Changing World of Non-Muscle-Invasive Bladder Cancer (NMIBC) discussed new treatment paradigms for NMIBC.

Dr. Bogdana Schmidt began her presentation by highlighting that, from a medical oncology perspective, the focus is often on metastatic or locally advanced bladder cancer. This is largely because bladder cancer is the sixth most common cancer in the United States, with NMIBC accounting for approximately 70-75% of all newly diagnosed cases. Bladder tumors are typically identified through imaging and cystoscopy, with staging performed using TURBT. The first-line treatment for high-risk NMIBC remains BCG-based immunotherapy, a standard that has remained unchanged for decades.

Staging plays a crucial role in risk stratification for NMIBC, with the AUA risk stratification system outlined below. Notably, there are differences between the risk classification systems proposed by the AUA, EAU, and IBCG. For example, in the AUA system, intermediate-risk NMIBC includes only HG Ta solitary tumors <3 cm.1 However, in the European (EAU) and IBCG definitions, all HG Ta tumors are considered high-risk NMIBC.2
  
Dr Schmidt highlighted that according to the IBCG risk-stratification system, treatment is guided depending on how many of the following risk factors the patient has:

  • Multiple tumors
  • Early recurrence (<1 yr)
  • Frequent recurrence (>1/yr)
  • Tumor size (>3 cm)
  • Failure of previous intravesical treatment
Notably, if the patient has 1-2 risk factors could be treated with intravesical chemotherapy induction or BCG for up to a year. If the patient had 3 or more risk factors should receive BCG.

 

Dr. Schmidt highlighted that we have been using BCG for over 50 years. This medication stimulates NK cells, cytotoxic T cells, and activated macrophages to attack tumor cells. BCG triggers a strong immune response in the bladder, driving a Th1-predominant activation that leads to the release of cytokines like IFN-γ, TNF-α, and IL-2. This creates an inflammatory environment that enhances tumor cell destruction.

However, the BCG journey involves induction (6 weekly instillations), maintenance, and serial cystoscopies, adding a significant burden to both healthcare systems and patients' lives.


What's wrong with BCG? For one, the treatments are intense and non-selective, meaning some patients are undertreated while others are overtreated. General side effects can be challenging, and despite its effectiveness, approximately 30–40% of patients still experience recurrence or progression after treatment. Adding to the problem, ongoing BCG shortages make it difficult to administer treatments on schedule, disrupting standard protocols and patient care. 

Dr. Schmidt highlighted that an expert-based definition of BCG unresponsive NMIBC has been proposed, this definition includes:

  • Patients with HGT1 at the first evaluation following induction BCG (at least 5 of 6 doses)
  • Persistent/recurrent high-grade Ta/T1 within 6
months of adequate BCG
  • Persistent/recurrent CIS within 12 months of adequate BCG
    • Adequate BCG defined as at least 5 of 6 induction plus 2 of 3 maintenance or 2 of 6 for another induction course 

A European study on BCG-unresponsive NMIBC, patients were given a choice task as illustrated below. Notably, the investigators found that only 11% of patients chose radical cystectomy (RC) as their preferred treatment option. Among the 107 participants, the vast majority (89%) never selected RC. The strongest factors influencing treatment preferences were time to RC (RAI 55%), risk of progression to MIBC (RAI 25%), and medication administration (RAI 12%). The risk of serious side effects was also a consideration, though the specific relative attribute importance (RAI) was not provided.3

A European study on BCG-unresponsive NMIBC, patients were given a choice task as illustrated below. Notably, the investigators found that only 11% of patients chose radical cystectomy (RC) as their preferred treatment option. Among the 107 participants, the vast majority (89%) never selected RC. The strongest factors influencing treatment preferences were time to RC (RAI 55%), risk of progression to MIBC (RAI 25%), and medication administration (RAI 12%). The risk of serious side effects was also a consideration, though the specific relative attribute importance (RAI) was not provided.3
Furthermore, patients were willing to accept significant risks to delay the time to RC. To extend the time to RC from 1 year to 6 years, they accepted a 43.8% increase in the risk of progression and a 66.1% increase in the risk of serious side effects.3 This highlights a strong preference for bladder-sparing options, emphasizing that patients value alternatives that preserve their bladder despite the associated risks.
Furthermore, patients were willing to accept significant risks to delay the time to RC. To extend the time to RC from 1 year to 6 years, they accepted a 43.8% increase in the risk of progression and a 66.1% increase in the risk of serious side effects.3 This highlights a strong preference for bladder-sparing options, emphasizing that patients value alternatives that preserve their bladder despite the associated risks.
Novel treatment options like the TARIS delivery system and UGN-102 offer promising alternatives for patients with BCG-unresponsive NMIBC, providing bladder-sparing approaches that could delay or even eliminate the need for radical cystectomy. These therapies are designed to improve drug delivery and efficacy while reducing treatment burden. Importantly, we should not focus solely on achieving a complete response (CR) at three months but also consider other key factors, including efficacy (both CR and durability of response), treatment schedule intensity, route of administration, side effects, cost, and overall quality of life. This highlights the need for patient-centered approaches that balance efficacy with tolerability, convenience, and individualized patient priorities.
Novel treatment options like the TARIS delivery system and UGN-102 offer promising alternatives for patients with BCG-unresponsive NMIBC, providing bladder-sparing approaches that could delay or even eliminate the need for radical cystectomy. These therapies are designed to improve drug delivery and efficacy while reducing treatment burden. Importantly, we should not focus solely on achieving a complete response (CR) at three months but also consider other key factors, including efficacy (both CR and durability of response), treatment schedule intensity, route of administration, side effects, cost, and overall quality of life. This highlights the need for patient-centered approaches that balance efficacy with tolerability, convenience, and individualized patient priorities.
Patients who undergo radical cystectomy after BCG-unresponsive NMIBC often have muscle-invasive disease by the time of surgery, highlighting the risks of delaying definitive treatment. Many patients move from one salvage therapy to another, which may not be ideal. Instead, we should focus on identifying the appropriate timing for radical cystectomy while ensuring that patients are well-informed about the efficacy, risks, and alternative treatment options. Below is a proposed algorithm for managing patients with BCG-unresponsive NMIBC, balancing the need for bladder preservation with timely intervention to prevent disease progression.
Patients who undergo radical cystectomy after BCG-unresponsive NMIBC often have muscle-invasive disease by the time of surgery, highlighting the risks of delaying definitive treatment. Many patients move from one salvage therapy to another, which may not be ideal. Instead, we should focus on identifying the appropriate timing for radical cystectomy while ensuring that patients are well-informed about the efficacy, risks, and alternative treatment options. Below is a proposed algorithm for managing patients with BCG-unresponsive NMIBC, balancing the need for bladder preservation with timely intervention to prevent disease progression.
In the past, treatment decisions for NMIBC were largely based on risk factors, with most patients receiving either chemotherapy or BCG. However, this approach is no longer the way forward. The future lies in biomarker-driven treatment selection, allowing for more precise and personalized therapies. Dr. Schmidt emphasizes that monotherapy is unlikely to be the ultimate solution. Instead, combination approaches—such as combination chemotherapy, combination immunotherapy, or a mix of intravesical and systemic therapies—are gaining traction. Additionally, a one-size-fits-all strategy is no longer viable. Disease-specific selection, incorporating targeted agents and predictive models, will be key to optimizing treatment and improving patient outcomes.

BCG-naïve

In a single-arm phase II trial, intravesical Gemcitabine + Docetaxel demonstrated promising short-term efficacy and was well-tolerated in patients with BCG-naïve high-risk NMIBC. Among the 25 patients, most of whom had papillary disease, the complete response (CR) rate was 100% at three months and 92% at 12 months. Notably, no patients were upstaged to T2, required cystectomy, or developed cN+ or cM+ disease. In terms of safety, over 80% of patients completed the induction regimen, with grade 1–2 adverse events being common. Grade 3 adverse events, including urinary tract infections and hematuria, occurred in 20% of patients, but no grade 4–5 toxicities were reported.4In a single-arm phase II trial, intravesical Gemcitabine + Docetaxel demonstrated promising short-term efficacy and was well-tolerated in patients with BCG-naïve high-risk NMIBC. Among the 25 patients, most of whom had papillary disease, the complete response (CR) rate was 100% at three months and 92% at 12 months. Notably, no patients were upstaged to T2, required cystectomy, or developed cN+ or cM+ disease. In terms of safety, over 80% of patients completed the induction regimen, with grade 1–2 adverse events being common. Grade 3 adverse events, including urinary tract infections and hematuria, occurred in 20% of patients, but no grade 4–5 toxicities were reported.4In a single-arm phase II trial, intravesical Gemcitabine + Docetaxel demonstrated promising short-term efficacy and was well-tolerated in patients with BCG-naïve high-risk NMIBC. Among the 25 patients, most of whom had papillary disease, the complete response (CR) rate was 100% at three months and 92% at 12 months. Notably, no patients were upstaged to T2, required cystectomy, or developed cN+ or cM+ disease. In terms of safety, over 80% of patients completed the induction regimen, with grade 1–2 adverse events being common. Grade 3 adverse events, including urinary tract infections and hematuria, occurred in 20% of patients, but no grade 4–5 toxicities were reported.4 2

BCG-exposed

In a study of BCG-exposed patients (75% with CIS ± papillary disease), treatment consisted of gemcitabine 2 g twice weekly alongside 50 mg BCG (TICE strain) weekly. Patients without recurrence continued on SWOG maintenance BCG. While this was an intense treatment schedule, it yielded impressive results, with 85% of patients achieving high-grade recurrence-free survival (HG RFS) at 12 months. Additionally, the regimen was well tolerated, with only 5% experiencing grade 3 adverse events and no grade 4 or 5 toxicities.5

In a study of BCG-exposed patients (75% with CIS ± papillary disease), treatment consisted of gemcitabine 2 g twice weekly alongside 50 mg BCG (TICE strain) weekly. Patients without recurrence continued on SWOG maintenance BCG. While this was an intense treatment schedule, it yielded impressive results, with 85% of patients achieving high-grade recurrence-free survival (HG RFS) at 12 months. Additionally, the regimen was well tolerated, with only 5% experiencing grade 3 adverse events and no grade 4 or 5 toxicities.5
BCG unresponsive

The THOR study (Cohort 1) evaluated 73 patients with BCG-unresponsive NMIBC who had papillary-only disease and FGFR alterations or fusions. Patients were randomized 2:1 to receive either erdafitinib (n = 49) or chemotherapy (n = 24). With a median follow-up of 13.4 months, median recurrence-free survival (RFS) was 11.6 months for the chemotherapy group and had not yet been reached for the erdafitinib group. Notably, erdafitinib demonstrated a 72% reduction in the risk of recurrence, highlighting its potential as a targeted therapy for this subset of patients.6

The THOR study (Cohort 1) evaluated 73 patients with BCG-unresponsive NMIBC who had papillary-only disease and FGFR alterations or fusions. Patients were randomized 2:1 to receive either erdafitinib (n = 49) or chemotherapy (n = 24). With a median follow-up of 13.4 months, median recurrence-free survival (RFS) was 11.6 months for the chemotherapy group and had not yet been reached for the erdafitinib group. Notably, erdafitinib demonstrated a 72% reduction in the risk of recurrence, highlighting its potential as a targeted therapy for this subset of patients.6
Dr. Schmidt briefly discussed AI-driven models, highlighting the Computational Histology AI (CHAI) biomarker, which is derived from the analysis of digitized H&E whole-slide images and is clinically available as Vesta (Valar Labs). This biomarker predicts response to BCG, with data suggesting that patients identified as non-responders may achieve better outcomes with Gem/Doce. Additionally, CHAI provides increased accuracy in predicting recurrence and helps guide treatment selection by distinguishing between patients more likely to benefit from BCG versus Gem/Doce.

Dr. Schmidt concluded her presentation with the following key takeways:

  • NMIBC management is rapidly evolving beyond TURBT + BCG
  • New intravesical therapies (gene therapy, drug-delivery devices) and systemic options (checkpoint inhibitors, cytokine-based therapies) are expanding treatment choices
  • Oncologists should be aware of clinical trial opportunities for patients with NMIBC
  • Future approaches will likely be risk-adapted, biomarker-driven, and integrate systemic therapies to prevent progression and reduce recurrence
Presented by: Bogdana Schmidt, MD, MPH, Urologic Oncologist at The Huntsman Cancer Institute at the University of Utah, United States.

Written by: Julian Chavarriaga, MD – Urologic Oncologist at Cancer Treatment and Research Center (CTIC) via Society of Urologic Oncology (SUO) Fellow at The University of Toronto. @chavarriagaj on Twitter during the 2025 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, CA, Thurs, Feb 13 – Sat, Feb 15, 2025. 

Related content: Advances in Non-Muscle Invasive Bladder Cancer Treatment Options - Bogdana Schmidt

References:

 

  1. Holzbeierlein J, Bixler BR, Buckley DI, et al. Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO guideline: 2024 amendment. J Urol. 2024;10.1097/JU.0000000000003846.
  2. Tan WS, Steinberg G, Witjes JA, Li R, Shariat SF, Roupret M, Babjuk M, Bivalacqua TJ, Psutka SP, Williams SB, Cookson MS, Palou J, Kamat AM. Intermediate-risk Non-muscle-invasive Bladder Cancer: Updated Consensus Definition and Management Recommendations from the International Bladder Cancer Group. Eur Urol Oncol. 2022 Oct;5(5):505-516. doi: 10.1016/j.euo.2022.05.005. Epub 2022 Jun 17. PMID: 35718695.
  3. Collacott H, Krucien N, Heidenreich S, Catto JWF, Ghatnekar O. Patient Preferences for Treatment of Bacillus Calmette-Guérin-unresponsive Non-muscle-invasive Bladder Cancer: A Cross-country Choice Experiment. Eur Urol Open Sci. 2023 Jan 31;49:92-99. doi: 10.1016/j.euros.2022.12.016. PMID: 36874596; PMCID: PMC9974996.
  4. Patel SH, Gabrielson AT, Chan S, Schwartz D, Collins C, Singla N, Trock B, Bivalacqua TJ, Hahn N, Kates MR. A Phase 2 Trial of Intravesical Gemcitabine and Docetaxel in the Treatment of Bacillus Calmette-Guérin‒Naïve Nonmuscle-Invasive Urothelial Carcinoma of the Bladder. J Urol. 2024 Jul;212(1):95-103. doi: 10.1097/JU.0000000000003977. Epub 2024 Apr 23. PMID: 38653234.
  5. Christopher Gaffney et al. A phase II trial of intravesical chemoimmunotherapy with gemcitabine and bacillus Calmette-Guérin (BCG) for patients with BCG-exposed, high-grade, non-muscle–invasive bladder cancer.. JCO 41, TPS579-TPS579(2023)
  6. Loriot Y, Matsubara N, Park SH, Huddart RA, Burgess EF, Houede N, Banek S, Guadalupi V, Ku JH, Valderrama BP, Tran B, Triantos S, Kean Y, Akapame S, Deprince K, Mukhopadhyay S, Stone NL, Siefker-Radtke AO; THOR Cohort 1 Investigators. Erdafitinib or Chemotherapy in Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2023 Nov 23;389(21):1961-1971. doi: 10.1056/NEJMoa2308849. Epub 2023 Oct 21. PMID: 37870920.