Global clinical trial landscape and therapeutic trends in bladder cancer: a systematic analysis

Abstract

Bladder cancer (BCa) remains a major oncological challenge worldwide, characterized by high recurrence rate, treatment resistance and variable clinical outcomes. As of 25 April 2025, the assessment of 2899 clinical trials registered in the INFORMA database revealed the main trends affecting this field. Since 2014, the number of BCa trials has increased sharply, and since 2018, it has tended to stabilize. The United States leads the world in research with over 1000 trials. Immunotherapy, especially PD-1/PD-L1 checkpoint blockade and cytotoxic chemotherapy, dominate the treatment field, while targeted therapy has also accelerated its follow-up. Antibody-drug conjugates (ADCs) and Bladder preservation therapy (BPT) have become increasingly prominent, reflecting a shift towards patient-centeredness and individualized and organ-preserving strategies. Driven by regulatory innovation and technological progress, the trial cycle has been accelerated, indicating a transformation in the clinical development process. These findings emphasize the importance of precise oncology and multidisciplinary team management in contemporary BCa treatment paradigms.

Bladder cancer (BCa) ranks as the ninth most common malignancy worldwide, posing a significant threat to human health^[1]. Based on the degree of invasion, BCa is classified into non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC), which differ markedly in clinical features and therapeutic strategies^[2,3]. NMIBC is characterized by a high recurrence rate and is typically managed with transurethral resection of bladder tumor (TURBT) combined with intravesical instillation therapy^[2]. MIBC exhibits aggressive behavior and is primarily treated with radical cystectomy, often supplemented by chemotherapy, radiotherapy, immunotherapy, or targeted therapy^[3]. In recent years, substantial advances have been made in BCa treatment, such as ADCs and BPT^[4,5]. ADCs are a systemic treatment method that precisely delivers cytotoxic drugs to tumor cells through antibody targeting; while BPT is a comprehensive treatment strategy aimed at curing BCa while maximizing the preservation of the anatomical structure and function of the bladder, avoiding the decline in quality of life caused by total bladder removal. These innovations align with the trend toward personalized therapy, emphasizing patient-centered care and offering expanded therapeutic options. Nevertheless, challenges persist, including difficulties in early diagnosis, shortages or resistance to Bacillus Calmette–Guérin (BCG), limited efficacy of chemoradiotherapy, high rates of recurrence and metastasis, difficulty in bladder preservation, and substantial treatment-related adverse effects^[6]. This study systematically analyzes global clinical trial data to elucidate therapeutic trends and research priorities, providing evidence to inform clinical practice and guide future investigations. In alignment with the 2025 TITAN guideline on transparent reporting of artificial intelligence in scholarly work, this study explicitly declares that no generative AI tools were used in the processes of data acquisition, analysis, or manuscript drafting^[7].

HIGHLIGHTS

• Systematic analysis of 2899 clinical trials in bladder cancer globally.

• Immunotherapy and chemotherapy dominate bladder cancer treatment trials.

• Clinical trial timelines shortened significantly after the rise of precision medicine.

• Academic institutions are leading clinical trial sponsorship in bladder cancer.

• Future research focuses on personalized therapy and bladder preservation strategies.

We conducted a systematic analysis of BCa clinical trials registered in the INFORMA database (https://pharma.id.informa.com). This database integrates multiple international platforms such as ClinicalTrials.gov, WHO ICTRP, EudraCT, PMDA, and ChiCTR, which has the advantages of clear mechanism classification, wide coverage, and high degree of data structuring. It is suitable for analyzing the global trends and development paths of bladder cancer treatment. We fully recognize that this database has certain biases in terms of geography and time dimensions. For instance, developed countries have more complete registration systems and thus more complete data, while information in the early years of the database is relatively lacking. To reduce the interference of these biases on the research conclusions, we focused on analyzing the macro trends of mechanisms and development stages in recent years, avoided using absolute quantities for regional comparisons, and adopted cross-regional universal indicators to control the influence of regional differences. Therefore, these potential biases have a limited impact on the core conclusions of the study. At the same time, we remain cautious in interpreting the results and can further improve the research by combining regional databases in the future. As of 25 April 2025, a total of 2899 relevant trials were identified using the standardized search term “Disease is Oncology: Bladder.”

The number of BCa clinical trials has shown an overall upward trend over the past four decades, with a marked surge in 2014 and stabilization after peaking in 2018 (Fig. 1A). The United States leads the world with 1521 trials, and the heat map shows the distribution of these trials in three major regions: North America, Europe, and East Asia (Fig. 1B). Phase I/II trials account for 86% of all studies, with a completion rate of 51% but a high termination rate of 18%, reflecting both the vibrancy of innovation and the rigorous selection pressure in the era of precision medicine (Fig. 1A). This termination rate is largely attributable to poor enrollment, business decisions, and early efficacy or safety signals, consistent with common causes reported in public trial databases (Supplement Figure 1, http://links.lww.com/JS9/E358). Approximately 73% of the trials focus on patients with stage III–IV tumors, and 74% target treatment from the second to fourth lines, indicating a research emphasis on advanced disease and multi-line therapeutic settings (Fig. 1C). Among the top 20 therapeutic mechanisms in BCa trials, immunotherapy and chemotherapy dominate, while targeted therapy remains relatively underrepresented. Immuno-oncology leads with 1058 trials, followed by immune checkpoint inhibition (725 trials), DNA synthesis inhibition (453 trials), DNA inhibition (417 trials), PD-1 antagonism (407 trials), and cell cycle inhibition (389 trials), whereas anti-angiogenesis targeting is limited to 183 trials or fewer (Fig. 1D). Principal therapeutic agents are similarly dominated by traditional chemotherapy drugs (e.g., gemcitabine, cisplatin) and immune checkpoint inhibitors (e.g., pembrolizumab, nivolumab), mainly targeting DNA crosslinking/synthesis inhibition and the PD-1/PD-L1 pathways, respectively. Radiotherapy and vaccines (such as BCG) also contribute a notable share, while novel agents like ADCs have achieved a promising position during the trial phase (Fig. 1E). Target distribution is primarily concentrated on receptor tyrosine kinases (RTKs) and immune checkpoints (PD-1, PD-L1), followed by DNA damage repair, microtubule/cytoskeleton dynamics, and nuclear metabolism pathways (Fig. 1F).

Figure 1.

Global characteristics of clinical trials for bladder cancer. (A) Annual number and status of trials. (B) Geographical distribution by country. (C) Patient stage and treatment lines. (D) Top therapeutic mechanisms. (E) Drug classes and molecular mechanisms. (F) Molecular targets by functional category.

The average development cycle for BCa clinical trials was prolonged (6–9 years) during the 1990s, shortened to 5–6 years after 2000, and further accelerated to 3–4 years following 2018, reflecting the substantial impact of immunotherapy and expedited regulatory pathways on improving research efficiency (Fig. 2A). Clinical trials predominantly focus on efficacy endpoints, such as clinical response and survival, and safety endpoints, including tolerability and adverse events, whereas pharmacokinetic/pharmacodynamic (PK/PD) assessments are relatively underrepresented (Fig. 2B). Academic medical institutions currently lead in trial sponsorship, followed by large- and small-sized pharmaceutical companies, with government-sponsored studies comprising a minority, highlighting a shift toward interdisciplinary collaboration and patient-centered clinical research (Fig. 2C).

Figure 2.

Other characteristics of clinical trials for bladder cancer. (A) Trial timelines from start to completion. (B) Distribution of efficacy, safety, and pharmacokinetic endpoints. (C) Major trial sponsors and sponsors type. “Industry, Top 20 Pharma” refers to the top 20 global pharmaceutical companies as classified by the INFORMA database, based on composite criteria including annual prescription drug sales, pipeline breadth, R&D activity level, and international market presence. “Industry, All Other Pharma” includes all remaining pharmaceutical or biotech companies not meeting the Top 20 criteria.

According to the latest literature, clinical research on novel therapeutics for BCa has primarily focused on cytotoxic agents and immune-modulating therapies, alongside active exploration of various molecular targets. Traditional chemotherapeutic agents, such as cisplatin and gemcitabine, remain fundamental to treatment^[8]. The new ADC demonstrates a significant advantage in enhancing therapeutic efficacy. For instance, the combined analysis of two Phase II clinical trials revealed that disitamab vedotin (DV) demonstrated promising efficacy and manageable safety in patients with HER2-positive locally advanced or metastatic urothelium carcinoma (UC) who had progressed after at least one systemic chemotherapy regimen^[9]. Immune checkpoint inhibitors (ICIs) have increasingly established their role in BCa management. Agents such as pembrolizumab and atezolizumab have become standard second-line treatments for advanced BCa, while combination strategies for first-line therapy are actively under investigation. Based on the strong evidence obtained from the EV-302 trial, enfolizumab vedotin-ejfv (EV + Pembro) in combination with pembrolizumab shows good efficacy in patients with locally advanced or metastatic urothelial carcinoma, which has emerged as a key first-line option for advanced MIBC^[3,10]. Targeted therapy is also expanding, with novel agents against molecular targets such as FGFR3 and HER2 offering new treatment avenues for patients harboring specific genetic alterations, promoting a shift toward precision medicine^[11]. Surgical resection remains the primary modality for local treatment of BCa. The adoption of minimally invasive techniques and robot-assisted surgery has improved surgical precision, reduced postoperative complications, and shortened recovery times. For selected MIBC cases, combined modality approaches such as TMT, integrating TURBT with radiotherapy and chemotherapy, offer new opportunities for bladder preservation^[3]. These trends collectively reflect an increasing emphasis on patient-centered care, driven by multidisciplinary team (MDT) collaboration to design individualized treatment strategies, thereby overcoming the limitations of traditional standardized protocols and significantly improving patient outcomes.

In conclusion, the current research is dominated by immunotherapy and efforts should be made to enhance the development of drugs targeting specific targets in the future. Although the clinical trial cycle has significantly shortened in recent years, the termination rate of up to 18% reminds us that we need to optimize the trial design, especially by improving the patient recruitment strategy and strengthening the early efficacy prediction. Moreover, most of the trials focus on advanced patients, while studies on early disease intervention are relatively lacking, which may lead to an imbalance in clinical treatment options. In terms of geographical distribution, the three major regions of North America, Europe, and East Asia dominate, while the participation in other regions is insufficient, which may affect the universality of the treatment plans. These findings point out the direction for future research: it is necessary to strengthen the development of targeted therapy, optimize the efficiency of clinical trials, balance the research investment for patients at different stages, and promote global research cooperation, in order to provide more effective treatment options for patients with bladder cancer at all stages.

Ethical approval

This study did not involve human participants or animals. All data analyzed were obtained from publicly accessible clinical trial registries. Therefore, ethical approval and informed consent were not required.

Consent

Patient consent was not required as this study did not involve human subjects or identifiable patient data. All information was obtained from publicly available clinical trial registries.

Sources of funding

Grants from the Jiangxi Provincial Natural Science Foundation Project (No.20224ACB206005) supported this study.

Author contributions

Y.Z.: conceptualization, data curation, formal analysis, investigation, methodology, project administration, resources, software, supervision, validation, visualization, writing – original draft and writing – review & editing. X.W.: formal analysis and investigation. J.L.: methodology and project administration, P.Z.: supervision. H.H.: funding acquisition and writing – review & editing

Conflicts of interest disclosure

The authors declare that they have no competing interests.

Guarantor

Honglin Hu.

Research registration unique identifying number (UIN)

This study is a retrospective analysis of previously registered clinical trials and was not itself a prospective clinical trial. Therefore, separate registration in a clinical trial registry was not applicable.

Provenance and peer review

Not commissioned, externally peer-reviewed.

Data availability statement

Original data generated and analyzed during this study are available in the INFORMA Pharma Intelligence database (https://pharma.id.informa.com/), a publicly accessible repository specializing in global clinical trial intelligence.

Permission to reproduce material from other sources

No copyrighted materials from other sources were reproduced in this study. Therefore, permission to reproduce material was not required.