Cariprazine Use in Patients with Neurodevelopmental Disorders Presenting with Obsessive, Ruminative and Stereotyped Behaviors: A Case Series.

The therapeutic landscape for GU malignancies has been reshaped over the last decade, which has largely been driven by the advent of immunotherapy, particularly immune checkpoint inhibitors (ICIs) (,). This class of agents, which boost the antitumor immune response in patients by suppressing inhibitory immune pathways, have established new standards of care and have demonstrated the potential to promote durable, long-term survival in a subset of patients with cancer (,). However, the success of immunotherapy remains inconsistent across GU cancer types, emphasizing the necessity for strategies to optimize immunotherapeutic efficacy, broaden its applicability and overcome mechanisms of therapeutic resistance (). The most notable effects of ICI-based treatments within GU oncology have been observed in renal cell carcinoma (RCC) and urothelial carcinoma (UC). In metastatic RCC, ICIs have become the foundation of first-line therapeutic strategies (,). Landmark clinical trials have demonstrated the improved efficacy of ICI-based combinations compared with previous standard treatments. The CheckMate-214 trial established that cotreatment with nivolumab, an anti-programmed cell death protein 1 (PD-1) antibody, and ipilimumab, an anti-cytotoxic T-lymphocyte protein 4 antibody, represents a more effective therapeutic option than sunitinib for patients with intermediate- and poor-risk RCC, leading to a marked improvement in overall survival (OS) (,). Subsequently, trials such as the KEYNOTE-426, CheckMate-9ER and CLEAR trials have validated the therapeutic efficacy of the combination of an ICI with a vascular endothelial growth factor (VEGF)-tyrosine kinase inhibitor (TKI) in RCC, demonstrating superior OS and progression-free survival (PFS) compared with TKI alone (–). The rationale for these combinations extends beyond the additive effects of individual therapeutic agents; VEGF inhibitors may help to normalize tumor vasculature and modulate the tumor microenvironment (TME) to be more permissive to immune cell infiltration, potentially contributing to a synergistic antitumor effect (). Similarly, immunotherapy has reshaped the treatment paradigm for UC. For patients with advanced or metastatic UC, pembrolizumab (P) and avelumab have demonstrated therapeutic efficacy in platinum-refractory and first-line maintenance settings, respectively (,). More recently, the EV-302 trial provided evidence that the combination of enfortumab vedotin (EV), an antibody-drug conjugate, with P represented a new standard of care in the first-line treatment of unresectable or metastatic UC, doubling the median PFS and OS of patients compared with chemotherapy (). This treatment regimen has also been studied in the perioperative setting, demonstrating improved patient outcomes, including an increase in the pathological complete response rate of patients with UC (,). Despite these transformative advancements, an important challenge remains: A notable proportion of patients with RCC or UC do not respond to ICI-based therapies, and numerous patients that initially respond to ICI-based treatments eventually develop acquired resistance (). Primary progressive disease occurs in up to 30% of patients with RCC who are treated with dual ICIs and 10–20% of those receiving ICI-TKI combination therapies (). This challenge is magnified in patients with prostate cancer, which is the most prevalent GU malignancy in male patients; notably, prostate cancer is largely considered to be immunologically cold and therefore unresponsive to ICIs (). Although ICIs have been approved for treating patients with microsatellite instability-high (MSI-H) malignancies, ICI-based treatments have failed to improve outcomes for the majority of patients (). These challenges in GU cancer treatment highlight the necessity of optimizing treatment strategies. One promising yet underexplored mechanism of optimizing cancer treatment involves the endogenous circadian clock, a system that controls the circadian rhythms of the body, including the activity of the immune system and its interactions with cancer cells. This review provides a roadmap for translating the concept of the circadian clock into clinical practice by examining its biological rationale, summarizing emerging clinical evidence supporting its influence on patient outcomes and outlining a path for prospective validation of the therapeutic potential of the circadian clock in GU oncology.