The landscape of bladder cancer treatment is rapidly evolving with the emergence of novel intravesical and systemic therapies, offering new hope for patients with non-muscle invasive bladder cancer (NMIBC) and muscle-invasive urothelial carcinoma. Recent data presented at the 2024 Society of Urologic Oncology (SUO) annual meeting and other conferences highlight the potential of these innovative approaches to improve patient outcomes.
Intravesical Therapies for BCG-Unresponsive NMIBC
For patients with BCG-unresponsive NMIBC, several intravesical therapies are showing promise. Dr. Mark Tyson presented an overview of emerging options, emphasizing the importance of both achieving a complete response and maintaining it over time. Agents like cretostimogene (an oncolytic immunotherapy) and TAR-200 (a sustained-release gemcitabine delivery system) have demonstrated impressive complete response rates, with some trials reporting rates of 75% or higher.
However, the duration of response is a critical factor. While initial complete response rates may be high, the percentage of patients maintaining that response at one year ranges from 46% to 66%. Direct comparisons between these agents are challenging due to differences in patient populations, treatment schedules, and surveillance regimens. As Dr. Tyson noted, "we have no idea how these drugs compare," highlighting the need for more comparative studies.
Intravesical gemcitabine + docetaxel remains a common treatment in the BCG-unresponsive NMIBC setting, despite not being FDA approved. Studies have demonstrated efficacy outcomes, but limitations include early censoring and reliance on clinical complete response.
Perioperative Systemic Therapy for Muscle-Invasive Urothelial Carcinoma
Dr. Jacqueline Brown discussed emerging perioperative systemic therapies for muscle-invasive urothelial carcinoma. The current standard of care involves neoadjuvant chemotherapy (dose-dense MVAC or gemcitabine + cisplatin) followed by radical cystectomy, with adjuvant nivolumab for high-risk disease. However, the field is moving towards more personalized approaches that consider biomarkers and novel agents.
The NIAGARA trial, a phase 3 study, showed that adding durvalumab (an anti-PD-L1 checkpoint inhibitor) to neoadjuvant gemcitabine + cisplatin improved event-free survival (HR 0.68, 95% CI 0.56-0.82) and overall survival (HR 0.75, 95% CI 0.59-0.93), as well as pathologic complete response rate (37.3% vs. 27.5%).
Ongoing trials like ENERGIZE and KEYNOTE-866 are further investigating the role of perioperative chemo-immunotherapy. Additionally, ctDNA status is being explored as a tool to identify patients who may benefit from adjuvant immunotherapy, as shown in a post hoc analysis of the IMvigor010 trial.
Antibody-Drug Conjugates in Urothelial Cancer
Antibody-drug conjugates (ADCs) are emerging as a promising class of agents in urothelial cancer. Enfortumab vedotin (EV), which targets Nectin-4, has shown significant efficacy in both metastatic and perioperative settings. In combination with pembrolizumab, EV has demonstrated a landmark median overall survival of 31.5 months in metastatic urothelial carcinoma.
Other ADCs, such as disitamab vedotin (targeting HER2), are also showing promise. A phase 2 trial of disitamab vedotin plus toripalimab in treatment-naive patients with metastatic urothelial carcinoma reported a 75% overall response rate and a median overall survival of 33.1 months.
However, the use of ADCs is not without challenges. A systematic review of ADC combinations found that sacituzumab govitecan (SG)-based regimens were associated with a higher incidence of adverse events compared to EV-based regimens. This is consistent with the voluntary withdrawal of SG as monotherapy in aUC after follow-up data failed to meet overall survival endpoints.
Novel Targets and Combination Strategies
Beyond Nectin-4 and HER2, other targets are being explored in urothelial cancer, including Trop-2 and FGFR3. Dual-targeting antibodies and combinations of ADCs with immunotherapies are also under investigation.
Dr. Vadim S. Koshkin highlighted the potential of combining ADCs with different mechanisms of action to overcome resistance and improve outcomes. For example, a phase 1 study of EV + SG in a cohort of 23 patients showed an overall response rate of 70%.
The Future of Bladder Cancer Treatment
The field of bladder cancer treatment is rapidly evolving, with new therapies and strategies emerging at an unprecedented pace. As Dr. Brown concluded, the neoadjuvant setting is ideal for evaluating novel therapies, but the burden of safety is intensified given curative intent. By refining biomarkers, optimizing treatment combinations, and developing novel agents, researchers are paving the way for more effective and personalized approaches to bladder cancer treatment.
