Emerging strategies for the improvement of chemotherapy in bladder cancer: Current knowledge and future perspectives

Bladder cancer: ESMO Practice Guidelines for diagnosis, treatment and follow-up

RE-ARMing the Immune Response to Bladder Cancer with Radiotherapy

Disease-Free Survival at 2 or 3 Years Correlates With 5-Year Overall Survival of Patients Undergoing Radical Cystectomy for Muscle Invasive Bladder Cancer

Pathological Downstaging and Survival Outcomes Associated with Neoadjuvant Chemotherapy for Variant Histology Muscle Invasive Bladder Cancer.

478 Background: Patients with metastatic bladder cancer have a poor prognosis with a median survival of only 9-15 months. Understanding the biology of metastatic bladder cancer has been historically difficult due to a paucity of specimens and models that recapitulate human disease. We established a bladder cancer rapid autopsy program to systemically acquire metastases, and build patient-derived xenograft (PDX) and organoid models for biological studies. Methods: Patients with metastatic bladder cancer were consented and a rapid autopsy was performed 2-6 hours after death to allow acquisition of normal and metastasis specimens. Frozen and formalin-fixed and paraffin embedded specimens were collected and pathological evaluation was performed on each specimen. Additionally, tumors were implanted subcutaneously into SCID mice to establish PDXs. Once PDXs were developed, PDXs were dissociated for companion organoid culture. Clinical history and treatment information was documented for each patient. Results: We have performed 10 bladder cancer rapid autopsies to date, and have acquired 105 metastatic and 45 normal specimens. The pathological subtypes of patients include urothelial cell carcinoma (5/10), squamous cell carcinoma (3/10), and plasmacytoid variant of urothelial carcinoma (2/10). The cohort has been treated BCG only (1/10), chemotherapy (3/10), and chemotherapy and immune checkpoint inhibitors (6/10). The leading site of metastasis was the liver (7/10) and lung (7/10), followed by lymph node (5/10), bone (5/10), intestine (4/10), and omentum (2/10). Half (5/10) of the patients had extensive liver metastases that allow acquisition of multiple tumor foci. For the first time, PDX and organoids from two independent metastases (omentum – CoCaB 14.1 and liver –CoCaB 14.2) from the same patient were successfully developed. Conclusions: This bladder cancer rapid autopsy program provides an important volume of metastatic tumor specimens for study. Importantly, the first bladder cancer PDX derived from metastasis has been developed. The availability of metastatic bladder cancer specimens, PDXs, and organoids will allow biological studies of advanced disease.

The fact that there are now five immune checkpoint inhibitor (ICI) monoclonal antibodies approved since 2016 that target programmed cell death protein 1 or programmed death ligand-1 for the treatment of metastatic and refractory bladder cancer is an outstanding achievement. Although patients can display pronounced responses that extend survival when treated with ICIs, the main benefit of these drugs compared to traditional chemotherapy is that they are better tolerated and result in reduced adverse events (AEs). Unfortunately, response rates to ICI treatment are relatively low and, these drugs are expensive and have a high economic burden. As a result, their clinical efficacy/cost-value relationship is debated. Long sought after targeted molecular therapeutics have now emerged and are boasting impressive response rates in heavily pre-treated, including ICI treated, patients with metastatic bladder cancer. The antibody-drug conjugates (ADCs) enfortumab vedotin (EV) and sacituzumab govitecan (SG) have demonstrated the ability to provide objective response rates (ORRs) of 44% and 31% in patients with bladder tumor cells that express Nectin-4 and Trop-2, respectively. As a result, EV was approved by the U.S. Food and Drug Administration for the treatment of patients with advanced or metastatic bladder cancer who have previously received ICI and platinum-containing chemotherapy. SG has been granted fast track designation. The small molecule Erdafitinib was recently approved for the treatment of patients with advanced or metastatic bladder cancer with genetic alterations in fibroblast growth factor receptors that have previously been treated with a platinum-containing chemotherapy. Erdafitinib achieved an ORR of 40% in patients including a proportion who had previously received ICI therapy. In addition, these targeted drugs are sufficiently tolerated or AEs can be appropriately managed. Hence, the early performance in clinical effectiveness of these targeted drugs are substantially increased relative to ICIs. In this article, the most up to date follow-ups on treatment efficacy and AEs of the ICIs and targeted therapeutics are described. In addition, drug price and cost-effectiveness are described. For best overall value taking into account clinical effectiveness, price and cost-effectiveness, results favor avelumab and atezolizumab for ICIs. Although therapeutically promising, it is too early to determine if the described targeted therapeutics provide the best overall value as cost-effectiveness analyses have yet to be performed and long-term follow-ups are needed. Nonetheless, with the arrival of targeted molecular therapeutics and their increased effectiveness relative to ICIs, creates a potential novel paradigm based on ‘targeting’ for affecting clinical practice for metastatic bladder cancer treatment.

The therapeutic landscape of advanced or metastatic urothelial carcinoma (UC) has shifted from platinum chemotherapy to precision immuno-oncology. Immune checkpoint inhibitors (ICIs)-pembrolizumab, nivolumab, and avelumab-show efficacy across platinum-refractory, maintenance, and adjuvant settings, yet benefit is limited to subsets, underscoring the need for biomarkers. Antibody-drug conjugates (ADCs), notably enfortumab vedotin(EV), and targeted agents such as FGFR inhibitors further expand options. This review synthesizes current evidence and emerging paradigms to guide combinations and sequencing. We performed a narrative synthesis of peer-reviewed trials (emphasizing pivotal phase III studies), key translational investigations, and contemporary guidelines on ICIs, ADCs, HER2-directed therapies, FGFR inhibitors, molecular subtyping, and genomic profiling in UC, integrating efficacy signals, biomarker associations, and practical implications for sequencing. ICIs now occupy multiple settings, but heterogeneous benefit highlights the importance of molecularly informed selection. EV alone and with pembrolizumab has produced unprecedented first-line activity, prompting a strategic shift. Molecular subtyping and genomic profiling delineate phenotypes with variable immune responsiveness and targetable vulnerabilities, enabling rational combinations and refined sequencing. Ongoing trials are evaluating next-generation ADCs, HER2-directed approaches, and dual checkpoint blockade to achieve durable, personalized disease control. Management of locally advanced or metastatic UC is converging on precision immuno-oncology, wherein biomarker-driven selection, molecular subtyping, and thoughtful sequencing of ICIs, ADCs, and targeted agents are central to optimizing outcomes. Active trials and translational advances are expected to refine personalized strategies and embed molecular guidance into routine care.

Bladder cancer is a significant global health challenge. Despite advances in surgery and platinum-based chemotherapy over the decades, limited improvements in clinical outcomes have been observed. However, recent years have witnessed the development of immune checkpoint inhibitors (ICIs) and antibody-drug conjugates (ADCs) that has transformed the therapeutic landscape of bladder cancer across different disease stages. ICIs block inhibitory pathways including PD-1/PD-L1 and CTLA-4 and reawake antitumor immunity, whereas ADCs, the combination of tumor-selective antibodies with potent cytotoxic payloads, ensure targeted cancer cell death with less systemic toxicity. Both therapies have exhibited clinical benefit in bladder cancer individually and in combination. Clinical trials including NIAGARA, CheckMate-274, and EV-302, have defined new perioperative and first-line standards based on ICIs and ADCs. Ongoing advancements in HER2-, Trop-2-, and Nectin-4-directed ADCs, bispecific and small-molecule conjugates, and combination with ICIs are revolutionizing the therapeutic options for bladder cancer. Of note, the combination of an ADC, enfortumab vedotin, with ICI, pembrolizumab, has improved survival in advanced disease scenarios in bladder cancer. Resistance against ICIs and ADCs remains a significant challenge, but identifying predictive biomarkers, integrating molecular profiling with these therapies, and developing effective combination strategies hold strong potential to achieve durable, precise, and personalized treatment outcomes for bladder cancer.

Management of metastatic bladder cancer

BackgroundEnfortumab vedotin (EV) is a first-in-class Nectin-4-directed antibody-drug conjugate (ADC) with demonstrated improved overall survival in patients with previously treated advanced-stage urothelial carcinoma.1 EV is comprised of a fully human...

Impact of Maximal Transurethral Resection on Pathological Outcomes at Cystectomy in a Large, Multi-institutional Cohort.

Muscle-invasive and advanced urothelial carcinoma (UC) are notorious for their high propensity for recurrence and metastasis. Recent advances in novel medications, surgical procedures, and radiotherapy techniques have substantially transformed the treatment landscape of muscle-invasive and advanced UC. It is crucial to navigate the optimal management approaches for muscle-invasive and advanced UC through the increasingly complex matrix of variables. Two professional organisations convened a consensus panel of six urologists and six clinical oncologists with extensive experience in treating urological malignancies. They reviewed the literature on the management of i) non-metastatic, muscle-invasive, and locally advanced UC of the bladder; ii) locally advanced upper tract UC (UTUC); and iii) unresectable locally advanced or metastatic UC (mUC). The panel held multiple meetings to discuss and draft consensus statements using the modified Delphi method. Each drafted statement was anonymously voted on by every panellist. A consensus statement was accepted if ≥ 80% of the panellists chose 'accept completely' or 'accept with some reservation' from the five options, which also included 'accept with major reservation', 'reject with reservation', and 'reject completely'. The panel reached a consensus on 63 statements based on current evidence and expert insights. These statements addressed the considerations for different treatment modalities, including surgical approaches, radiotherapy, radiosensitisers, platinum-based chemotherapy, immune checkpoint inhibitors, and antibody-drug conjugates, in the management of different disease entities, including muscle-invasive UC of the bladder, cN1 disease, locally advanced UTUC, unresectable locally advanced/mUC, and oligometastatic bladder cancer. These consensus statements are anticipated to serve as a practical recommendation for clinicians in Hong Kong, and possibly the Asia-Pacific region, regarding the management of muscle-invasive and advanced UC.

Urothelial carcinoma presents significant treatment challenges, especially in advanced stages. Traditionally managed with platinum-based chemotherapy, the advent of immunotherapies, particularly immune checkpoint inhibitors, has revolutionized urothelial carcinoma treatment. This review explores the evolution of urothelial carcinoma management, focusing on the transition from immune checkpoint inhibitors monotherapy to innovative combination therapies. Pembrolizumab, following the KEYNOTE-045 trial, emerged as a pivotal ICI in pretreated metastatic urothelial carcinoma, outperforming traditional chemotherapy. However, limitations surfaced in untreated metastatic urothelial carcinoma patients, particularly in those with low PD-L1 expression, as evidenced by trials like IMvigor130 and KEYNOTE-361. These challenges led to the exploration of combination therapies, including immune checkpoint inhibitors with platinum-based chemotherapy, tyrosine kinase inhibitors, and antibody–drug conjugates. Notably, the CheckMate 901 trial demonstrated improved outcomes with a nivolumab–chemotherapy combination. A significant breakthrough was achieved with the combination of enfortumab vedotin, an antibody–drug conjugates, and pembrolizumab, setting a new standard in first-line treatment for locally advanced or metastatic urothelial carcinoma. Future directions involve further exploration of antibody–drug conjugates and immune checkpoint inhibitors, as seen in the TROPHY-U-01 and TROPiCS-4 trials. The review concludes that the locally advanced or metastatic urothelial carcinoma treatment landscape is rapidly evolving, with combination therapies offering promising avenues for improved patient outcomes, signaling a new era in urothelial carcinoma management.

Antibody drug conjugates (ADCs) consist of an antibody, a cytotoxic payload, and a linker between the two. ADCs are becoming increasingly used in metastatic bladder cancer. Enfortumab vedotin (EV) in combination with pembrolizumab recently demonstrated impressive improvements in survival and overall responses compared to chemotherapy in the frontline metastatic setting. Sacituzumab govitecan (SG) and single agent EV are also effective, later line options for patients who have progressed on prior chemotherapy and/or immunotherapy. New ADCs, including those targeting HER2, have also displayed promising results in bladder cancer patients. Trials are exploring the use of ADCs in combination with each other as well as with immunotherapy. Novel ADCs with dual targets, dual payloads, and other augmentations are being developed and may represent new options for patients moving forward. However, these advances raise many questions. How to best manage the differing toxicities seen with ADCs? What is best sequencing of ADCs? What are the common resistance mechanisms to ADCs? How do these resistance mechanisms affect subsequent use of ADCs? And how effective are these agents in bladder cancer variants and divergent histologies? This talk with cover the expanding role of ADCs in metastatic bladder cancer. Citation Format: Nicholas Simon. Metastatic bladder cancer: The expanding role of antibody drug conjugates [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr IA018.

Immunotherapy for advanced or metastatic urothelial carcinoma.