Bladder cancer is one of the most common malignancies of the urinary system, posing a serious threat to public health in China. For patients with localized disease, repeated intravesical treatments and follow-up procedures require frequent hospital visits, while those who undergo surgery often face the lifelong challenge of urinary diversion. Patients with inoperable advanced bladder cancer also have limited treatment options, as traditional chemotherapy provides only modest benefits. These significant unmet medical needs—affecting both survival and quality of life—have driven continuous innovation in the field of bladder cancer treatment.

As we close out 2024, Oncology Frontier has invited Dr. Qiang Wei from West China Hospital of Sichuan University to review this year’s key advancements in bladder cancer treatment. These breakthroughs are expected to extend survival and improve quality of life, offering patients a dual-benefit treatment approach.

NMIBC: A Dual Focus on Local and Systemic Therapy

Non-muscle invasive bladder cancer (NMIBC) is the most common form of bladder cancer, accounting for approximately 75% of newly diagnosed cases. Transurethral resection of bladder tumor (TURBt) remains the standard first-line treatment, yet nearly half of NMIBC patients experience recurrence within one year.

International guidelines categorize NMIBC into low-, intermediate-, high-, and very-high-risk groups, based on recurrence and progression risk. For patients with intermediate- to high-risk disease, intravesical Bacillus Calmette-Guérin (BCG) immunotherapy is commonly used. However, some patients fail to respond to BCG, develop BCG resistance, or cannot tolerate BCG-related adverse effects, such as cystitis, hematuria, infection, and fever. Additionally, BCG shortages remain a challenge in certain regions.

To address BCG-refractory NMIBC and reduce recurrence and progression risks, recent research has explored novel local and systemic treatments, including chemotherapy, immunotherapy, and innovative drug delivery methods for intravesical and systemic administration.

TAR-200 Intravesical Therapy

TAR-200 is an innovative intravesical drug delivery system composed of a semi-permeable silicone tube that continuously releases gemcitabine into the bladder over several weeks. The SunRISe study series has been investigating TAR-200 in different clinical settings. The SunRISe-1 and SunRISe-5 trials evaluated TAR-200 alone or in combination with Cetrelimab, a PD-1 inhibitor, for high-risk BCG-refractory NMIBC in Phase II and III trials. SunRISe-2 and SunRISe-4 focused on muscle-invasive bladder cancer (MIBC), assessing TAR-200 plus Cetrelimab versus chemotherapy and radiotherapy in a Phase III trial, and as a neoadjuvant treatment in a Phase II trial. SunRISe-3 compared TAR-200 with BCG as first-line therapy for high-risk NMIBC in a Phase III trial.

At ESMO 2024, results from SunRISe-1 were presented for high-risk BCG-refractory NMIBC patients. The confirmed complete response (CR) rate in patients receiving TAR-200 plus Cetrelimab was 67.9%, compared to 83.5% in the TAR-200 monotherapy group and 46.4% in the Cetrelimab monotherapy group. The one-year CR rates were 56.7% for the combination therapy, 57.4% for TAR-200 alone, and 22.8% for Cetrelimab alone. Treatment-related discontinuation rates were low for TAR-200 and Cetrelimab alone, at 6% and 7% respectively, but were higher when used in combination, with discontinuation rates of 26% for TAR-200 and 23% for Cetrelimab. No treatment-related deaths occurred. These preliminary results highlight that TAR-200 intravesical therapy offers a high CR rate with manageable safety, positioning it as a promising alternative for BCG-refractory NMIBC.

ADC-Based Systemic Therapy

Antibody-drug conjugates (ADCs) such as Disitamab vedotin (RC48) and Enfortumab vedotin (EV), which target HER2 and Nectin-4, have made breakthrough advancements in the first-line immunotherapy combination for metastatic urothelial carcinoma (mUC). These “targeted chemotherapy” agents enhance efficacy while reducing toxicity compared to traditional chemotherapy.

In recent years, ADC therapy has been expanding into localized bladder cancer, including systemic therapy and intravesical treatment for NMIBC. At ASCO 2023, preliminary results from the EV-104 trial were reported. This open-label, multicenter, dose-escalation Phase I trial evaluated intravenous EV in BCG-unresponsive high-risk NMIBC patients. The findings showed that EV was well tolerated, and at a 125 mg dose, three out of four patients achieved a CR, indicating early antitumor activity.

At ASCO 2024, another study investigated RC48 in high-risk NMIBC. Among 27 enrolled patients, 10 received Disitamab vedotin (RC48), while 17 received BCG. The study revealed that HER2 overexpression significantly influenced the tumor immune response. Additionally, RC48 demonstrated a superior one-year recurrence-free survival (RFS) rate compared to BCG, with rates of 100% versus 58.8%.

At AUA 2024, findings from the TRUCE04 trial were presented, which evaluated RC48 in HER2-expressing NMIBC patients who either had unresectable tumors or were unable to tolerate surgery. Among 24 patients with HER2 IHC 2+ or 3+ expression, 8 received RC48 monotherapy, while 16 received RC48 combined with the PD-1 inhibitor toripalimab. The results showed that 16 patients achieved complete response (CR), while 8 patients had stable disease (SD).

These studies reinforce the growing potential of ADCs in localized bladder cancer, particularly for patients with HER2-overexpressing NMIBC. As research continues, ADC therapy may emerge as a viable alternative to BCG and other intravesical treatments.

Intravesical ICI Therapy

As discussed earlier, the SunRISe study series explored TAR-200 intravesical therapy, both alone and in combination with systemic immune checkpoint inhibitors (ICIs). Most current research focuses on ICI as a systemic treatment. Theoretically, ICI therapy, which blocks the PD-1/PD-L1 immune escape mechanism, shares an immunoactivation effect similar to BCG. However, it remains unclear whether the two therapies have a synergistic effect when used together.

A Phase II, open-label, single-arm, multicenter clinical trial conducted by the Hellenic Cooperative Oncology Group enrolled 30 patients with high-risk NMIBC who received intravesical durvalumab. At one year after treatment, seven of the 19 evaluable patients had not experienced high-grade recurrence, with a one-year high-grade recurrence-free rate (HG-RFR) of 38.5%. At one, three, and six months post-treatment, the HG-RFR was 70%, 55%, and 38.5%, respectively. Aside from local irritation, no serious adverse events were observed. This study demonstrated the preliminary antitumor activity of intravesical ICI therapy. However, several questions remain for further exploration, such as whether ICIs and BCG should be administered sequentially or in combination, and if given sequentially, which therapy should be initiated first.

MIBC: A Diversified Approach to Perioperative Treatment

Radical cystectomy remains the standard treatment for muscle-invasive bladder cancer (MIBC). However, many patients struggle with the impact of urinary diversion on their quality of life, while others still face the risk of postoperative recurrence or disease progression. Perioperative therapy for MIBC primarily focuses on preoperative and/or postoperative treatment strategies aimed at tumor downstaging, prolonging bladder-preserving survival, and reducing the risk of recurrence.

ICI in Adjuvant and Neoadjuvant Therapy

The CheckMate-274 study marked the beginning of the era of adjuvant immunotherapy for MIBC. Previously published results in NEJM showed that for high-risk MIBC patients—defined as pT3, pT4a, or pN+ patients who had not received or were ineligible for neoadjuvant platinum-based chemotherapy, as well as ypT2-ypT4a or ypN+ patients who had received neoadjuvant chemotherapy—nivolumab significantly improved disease-free survival (DFS), with a median DFS of 20.8 months compared to 10.8 months in the placebo group (HR 0.70; 98.22% CI: 0.55–0.90; P<0.001). The eagerly awaited overall survival (OS) data were presented at the 2024 EAU Congress, showing a median OS of 69.5 months in the nivolumab group versus 50.1 months in the placebo group, representing a 24% reduction in the risk of death (HR 0.76; 95% CI: 0.61–0.96). Among patients with PD-L1 expression ≥1%, the nivolumab group experienced a 44% reduction in mortality risk (HR 0.56; 95% CI: 0.36–0.86).

The AMBASSADOR study is another Phase III trial investigating adjuvant ICI therapy for MIBC. It enrolled patients with ≥pT2 and/or pN+ or positive surgical margins after neoadjuvant chemotherapy, as well as patients with ≥pT3 and/or pN+ or positive surgical margins who were ineligible for or refused neoadjuvant chemotherapy. Participants received one year of adjuvant pembrolizumab or placebo. Results presented at the 2024 ASCO-GU Congress showed that pembrolizumab significantly improved DFS, with a median DFS of 29.0 months compared to 14.0 months in the control group (HR 0.69; 95% CI: 0.54–0.87; P=0.001). However, OS differences were not yet significant (50.9 vs. 55.8 months; HR 0.98; 95% CI: 0.76–1.26; P=0.883).

The NIAGARA study incorporated immunotherapy into both preoperative neoadjuvant and postoperative adjuvant treatment. The trial enrolled cisplatin-eligible patients with MIBC (cT2-T4aN0/1M0) scheduled for radical cystectomy. The experimental group received four cycles of neoadjuvant durvalumab combined with gemcitabine-cisplatin (GC) chemotherapy, followed by eight cycles of adjuvant durvalumab after surgery. The control group received neoadjuvant chemotherapy only. Results published at ESMO 2024 and in NEJM showed that median DFS was 29.6 months in the durvalumab group versus 14.2 months in the control group (HR 0.73; 95% CI: 0.59–0.90; P=0.003), with a pathologic complete response (pCR) rate of 37.3% versus 27.4%. However, OS differences were not yet significant (HR 0.98; 95% CI: 0.17–1.26).

ADC in Neoadjuvant Therapy

The multi-cohort Phase II SURE-01 study enrolled 21 patients with cT2-T4N0M0 MIBC who were ineligible for or refused cisplatin-based neoadjuvant chemotherapy. These patients received four cycles of the TROP2 ADC sacituzumab govitecan (SG) as neoadjuvant therapy. Results presented at ASCO 2024 showed that among the 11 patients who underwent radical cystectomy, four (36.4%) achieved pCR.

The multi-cohort Phase II EV-103 study reported data from Cohort H, which included cisplatin-ineligible MIBC patients (T2-T4aN0M0) who received three cycles of enfortumab vedotin (EV) as neoadjuvant therapy. Among evaluable patients, the pCR rate was 36.4%, the pathologic downstaging (pDS) rate was 50.0%, and the two-year event-free survival (EFS) rate was 62.0%.

The Phase II RC48-C017 study enrolled treatment-naïve MIBC patients (cT2-T4aN0-1M0), who received six cycles of neoadjuvant RC48 combined with toripalimab. The study reported a pCR rate of 61.3% (19/31). These studies highlight the promising tumor downstaging effects of ADC therapy in MIBC neoadjuvant treatment.

TAR-200 in Neoadjuvant Therapy

At ESMO 2024, the TAR-200-based neoadjuvant therapy for MIBC was presented in the SUNRISE-4 study. Patients received four cycles of TAR-200 intravesical therapy combined with intravenous Cetrelimab or Cetrelimab monotherapy before undergoing radical cystectomy, followed by postoperative follow-up. Results showed that the pCR rate was 42% in the TAR-200 plus Cetrelimab group compared to 23% in the Cetrelimab monotherapy group, while the overall pathologic response (pOR, ≤ypT1N0) rates were 60% and 36%, respectively. Treatment-related adverse events (TRAEs) were observed in 72% of patients in the TAR-200 plus Cetrelimab group and 44% in the Cetrelimab group, with most events classified as Grade 1–2.

mUC: Emerging “Immunotherapy Plus” Combinations

In metastatic urothelial carcinoma (mUC), the negative results from the IMvigor130 and KEYNOTE-361 trials initially cast doubt on the role of ICI plus chemotherapy. However, further research has explored additional combination strategies, including chemotherapy, ADCs, and FGFR-targeted therapies.

The EV-302 trial was the first global Phase III study to confirm the efficacy of ADC plus immunotherapy as a first-line treatment for mUC. Previously published results in NEJM showed that enfortumab vedotin plus pembrolizumab nearly doubled both median PFS (12.5 vs. 6.3 months; HR 0.45; P<0.001) and median OS (31.5 vs. 16.1 months; HR 0.47; P<0.001) compared to chemotherapy alone.

At ASCO 2024, patient-reported outcomes (PROs) from EV-302 confirmed that the combination therapy did not negatively impact quality of life or physical function, reinforcing its clinical value in mUC. At ESMO Asia 2024, the pan-Asian subgroup analysis showed that enfortumab vedotin plus pembrolizumab reduced PFS event risk by 70% and decreased mortality risk by 66%.

Conclusion

Advancements in bladder cancer research and treatment have led to a more diverse and personalized approach, spanning NMIBC, MIBC, and mUC. Innovations in intravesical therapies like TAR-200 are driving transformative changes in localized treatment. In MIBC, perioperative strategies—including neoadjuvant and adjuvant therapy—are improving outcomes with ADCs and ICIs. For metastatic disease, novel combination therapies, particularly immunotherapy plus ADC regimens, are offering new hope for extended survival. These developments are rapidly reshaping clinical practice and the future of bladder cancer treatment.

About Dr. Qiang Wei

Qiang Wei, MD, PhD

• Director, Urological Disease Center, West China Hospital, Sichuan University
• Chair, Department of Urology, West China Hospital, Sichuan University
• Professor and Doctoral Supervisor
• Vice Chair, Chinese Urological Association (CUA)
• Vice President, Urology Branch, Chinese Medical Doctor Association
• Vice Chair, Prostate Cancer and Kidney Cancer Committee, Chinese Society of Clinical Oncology (CSCO)
• Vice Chair, Male Genital Tumors Committee, Chinese Anti-Cancer Association (CACA)
• Director, Sichuan Province Clinical Research Center for Kidney and Urological Diseases
• President, Surgical Robotics Branch, Sichuan Medical Doctor Association
• Chair, Urological and Male Reproductive Oncology Committee, Sichuan Anti-Cancer Association
• Chair, Urology Branch, Chengdu Medical Association
• Recipient of the CUA “Golden Cystoscope Award”, Wu Jieping Urology Medical Award, and the Global Chinese Urology Lifetime Achievement Award

Dr. Qiang Wei is a leading expert in urological oncology, specializing in prostate, kidney, and bladder cancer research and treatment. As a pioneer in robotic-assisted urological surgery in China, he has contributed significantly to minimally invasive techniques and personalized treatment strategies for urological malignancies.

With multiple leadership roles in national and regional medical associations, Professor Wei has been instrumental in advancing clinical research and shaping treatment guidelines for urological cancers. His work continues to drive innovations in surgical oncology, systemic therapies, and precision medicine, benefiting patients across China and beyond.