Bladder cancer treatment: where are we standing?

bladder cancer treatment

According to the World Health Organisation, 573,278 new cases of bladder cancer were diagnosed in 2020, making it the 10th most common type of cancer. Bladder cancer most commonly starts in the urothelial cells lining the inside of the bladder but can also develop in other areas like the kidneys and ureters. Although survival rates are relatively high, 71% for localized bladder cancers, this type of cancer has an important chance of resurfacing, emphasizing the importance of finding more efficient treatments. But where are we standing today? 

Table of contents

    The efficacy of combination therapy in advanced metastatic bladder cancer

    The combination of enfortumab vedotin and pembrolizumab has shown notable effectiveness in treating patients with locally advanced or metastatic urothelial carcinoma (la/mUC) who are ineligible for cisplatin-containing chemotherapy, the most common treatment for bladder cancer. 

    This efficacy was demonstrated in the EV-302/KN-A39 trial, where patients who received this combination therapy exhibited statistically significant improvements in both overall survival (OS) and progression-free survival (PFS) compared to those who received platinum-based chemotherapy. Specifically, the median OS for patients receiving the combination therapy was 31.5 months, compared to 16.1 months for those on chemotherapy. The median PFS was 12.5 months for the combination therapy group versus 6.3 months for the chemotherapy group​​​​​​. These figures indicate close to double the efficacy with combination therapy.

    The results from the EV-302 trial have been impressive, with the combination therapy effectively doubling the survival rate compared to standard chemotherapy. This has led to the recognition of enfortumab vedotin plus pembrolizumab as a new standard of care for initial treatment in patients with advanced bladder cancer​​​​.

    The combination therapy has shown high response rates, with a 67.7% overall response rate and a 29.1% complete response rate. Notably, the median duration of response has not been reached, indicating long-lasting effects. This durability, coupled with the higher response rate, has contributed to the overall survival benefit observed with this therapy​​​​.

    While combination therapy has shown a manageable safety profile, some patients experienced grade ≥3 adverse events which refers to severe and significant medical events. In this case, the most common adverse event observed were ash maculo-papular, hyperglycemia, neutropenia, peripheral sensory neuropathy, diarrhea, and anemia, underscoring the need for careful monitoring and management of side effects. 

    The full approval of pembrolizumab and enfortumab vedotin combination therapy for patients with locally advanced or metastatic urothelial cancer, including the cisplatin-ineligible population, has expanded the treatment options available. This combination therapy now stands as a potential new standard of care, offering significant improvements in patient-reported outcomes and survival rates​​.

    TAR-200: a promising breakthrough in the treatment of high-risk non-muscle-invasive bladder cancer

    A gap in high-risk non-muscle-invasive bladder cancer treatment

    High-risk non-muscle-invasive bladder cancer (HR-NMIBC) represents a particularly challenging subset of bladder cancer. It is characterized by a higher likelihood of recurrence and progression compared to lower-risk variants. This type of bladder cancer remains confined to the inner lining of the bladder (urothelium) and does not invade the muscle layer.

    However, its aggressive nature carries a significant risk of becoming more invasive if not effectively treated. HR-NMIBC accounts for 15 to 44% of NMIBC cases and is distinguished by characteristics such as high-grade tumors, large tumor size, and the presence of multiple tumors, and often includes carcinoma in situ (CIS) that is particularly likely to recur or progress​​​​​​.

    The standard first-line treatment for HR-NMIBC has long been intravesical Bacillus Calmette-Guérin (BCG) immunotherapy. This treatment involves instilling a live, attenuated strain of mycobacterium bovis, a slow-growing agent of tuberculosis, directly into the bladder, which stimulates the immune system to attack cancer cells.

    Despite its effectiveness, a significant number of patients either do not respond to BCG treatment or eventually experience recurrence after initially responding. For these BCG-unresponsive patients, treatment options are limited, often involving more invasive approaches like radical cystectomy (surgical removal of the bladder), which significantly impact the patient’s quality of life​​​​​​. This is where Johnson & Johnson’s TAR-200 could make a difference.

    How does TAR-200 work?

    TAR-200 operates as a targeted releasing system. Its primary function is to sustain the local release of gemcitabine, a chemotherapy drug, directly into the bladder. This method of delivery is aimed at maintaining consistent drug exposure within the bladder over extended periods. The strategic release mechanism of TAR-200 allows for a continuous low-dose administration of gemcitabine, an antimetabolite chemotherapy, which can be more tolerable for patients compared to traditional chemotherapy regimens.

    The approach of TAR-200 is notably different from existing bladder cancer treatments. Traditional methods often involve either systemic chemotherapy, which affects the entire body, or invasive surgeries like radical cystectomy. TAR-200’s intravesical delivery system provides a localized treatment, reducing systemic exposure and potentially lowering the risk of widespread side effects.

    The updated results of the SunRISe-1 study on the cohort receiving TAR-200 monotherapy were presented at the European Society for Medical Oncology (ESMO) 2023 and are showing great promise. The complete response rate for this group of patients was close to 80% which is significantly higher than the numbers usually witnessed in similar studies. This is encouraging for the future as the delivery system offers a wide range of possibilities in terms of the composition of the drugs delivered.

    The trials are still ongoing, notably regarding combination therapy, and the recent Breakthrough Therapy Designation (BTD) designation granted to TAR-200 by the FDA is designed to speed up the development and review processes. This puts the spotlight on TAR-200 and raises expectations about the treatment’s evolution in the near future.

    Advancement in neoadjuvant therapies

    Neoadjuvant therapies refer to any treatment given to a patient before the main cancer therapy to make it more likely to succeed. These therapies for bladder cancer, particularly muscle-invasive bladder cancer (MIBC), are showing significant potential in bladder preservation and moving away from more invasive treatments like radical cystectomy. These advancements involve combination therapies used before surgical interventions, aiming to improve patient outcomes.

    Recent studies have focused on the efficacy of combining drugs like gemcitabine and cisplatin with immune checkpoint inhibitors such as nivolumab and pembrolizumab in the neoadjuvant setting. These combinations have shown promise in achieving better outcomes for patients with MIBC. In particular, the combination of gemcitabine, cisplatin, and nivolumab has been associated with favorable survival outcomes and the possibility of prolonged bladder-intact survival in a substantial subset of patients with MIBC who achieve a complete clinical response to this treatment regimen.

    The emerging evidence from these combination therapies is leading to a reconsideration of the standard treatment approaches for MIBC. The goal is to balance the effectiveness of the treatment with the quality of life for patients, by reducing the reliance on radical cystectomy, which can have significant life-altering implications.

    Novel approach in bladder cancer treatment: Urea-powered nanorobots

    This innovative approach demonstrated in a recent study, has shown remarkable results in reducing bladder tumor size in a mouse model.

    The core of this research revolves around the use of nanorobots that are powered by urea, a substance naturally present in urine. These nanorobots have been engineered to target and effectively reduce tumor size. In the study, a single dose of these urea-powered nanorobots achieved a 90% reduction in bladder tumor size in mice, marking a significant improvement over current treatment methods that typically require multiple hospital visits.

    One of the key technological innovations in this research is the use of advanced bioimaging techniques. Traditional methods like PET scans faced challenges in locating these minuscule particles within the body. However, the research team employed a novel microscopy technique using polarized light, which allowed them to overcome this challenge and accurately visualize and locate the nanorobots in tumor tissues.

    This study has led to the creation of Nanobots Therapeutics, a spin-off company focused on advancing this technology for clinical application. The success of this study, combined with the establishment of Nanobots Therapeutics, suggests a promising future for less invasive and more targeted bladder cancer treatments.

    The use of nanotechnology in cancer therapy, as demonstrated by this study, represents an exciting and promising area of research that could redefine cancer treatment strategies, offering a new era of targeted and efficient therapies.

    A promising future for bladder cancer treatment

    The future of bladder cancer treatment is marked by a wave of innovation and progress. The integration of combination therapies is reshaping the standard of care for patients with advanced stages of the disease. The development of targeted therapies like TAR-200 for high-risk non-muscle-invasive bladder cancer is indicative of a broader shift towards personalized and less invasive treatments. Furthermore, the advancements in neoadjuvant therapies underscore a growing commitment to not only treat bladder cancer more effectively but also to prioritize the quality of life of patients through bladder preservation.

    The emerging use of nanotechnology, exemplified by urea-powered nanorobots, offers a glimpse into a future where cancer treatment is highly targeted, minimally invasive, and perhaps more efficient than ever before. As these innovative approaches progress from clinical trials to standard practice, they offer new perspectives on bladder cancer treatment.

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