Emerging Paradigms in Genitourinary Cancers: Integrating Molecular Imaging, Hypoxia-Inducible Factor-Targeted Therapies, and Antibody-Drug Conjugates in Renal Cell and Urothelial Carcinomas.

Novel approaches in molecular imaging and targeted therapeutics are transforming the management of renal cell carcinoma (RCC) and urothelial carcinoma (UC). This review focuses on three key areas of innovation: molecular imaging, hypoxia-inducible factor-2α (HIF-2α) inhibition, and antibody-drug conjugates (ADCs). In molecular imaging, prostate-specific membrane antigen positron emission tomography/computed tomography has shown promise in RCC, while novel tracers targeting carbonic anhydrase IX and nectin-4 are emerging for RCC and UC, respectively. These approaches may enable better characterization of disease and treatment response monitoring. HIF-2α inhibition represents a breakthrough in targeting the fundamental pathobiology of clear cell RCC, with belzutifan demonstrating significant clinical benefit in both von Hippel-Lindau disease and sporadic RCC. Next-generation HIF-2α inhibitors, including casdatifan, show promising early clinical results with distinct pharmacologic properties. ADCs have become a cornerstone of UC treatment, with enfortumab vedotin plus pembrolizumab now approved as first-line therapy. Multiple human epidermal growth factor receptor 2 (HER2)-directed ADCs have shown efficacy in HER2-expressing UC, including trastuzumab deruxtecan, which recently received tumor-agnostic approval. While ADC development in RCC faces unique challenges, novel approaches including immunostimulatory payloads and bispecific antibodies are being explored. The integration of these advances in molecular imaging and therapeutics offers opportunities for more personalized treatment approaches in RCC and UC.