Phase 2 zanzalintinib c-MET/VEGFR tyrosine kinase inhibitor in visceral/soft-tissue mCRPC.

This single-arm Phase 2 study tests zanzalintinib, an oral small-molecule multi-kinase inhibitor targeting c-MET (HGFR) and VEGFR pathways that drive tumor growth, invasion, and angiogenesis. The trial enrolls men with metastatic castration-resistant prostate cancer (mCRPC) specifically featuring soft-tissue and/or visceral metastases, a subgroup often associated with aggressive biology and poorer outcomes. It uses an early futility-style expansion approach (initial cohort then add-on enrollment if enough patients remain alive and radiographically progression-free at 6 months), with 28-day cycles and treatment continuing up to 24 months while patients derive clinical benefit. The sponsor/investigator is Pedro Barata at University Hospitals/Case Comprehensive Cancer Center; the commercial angle is repurposing a cabozantinib-like biology (MET/VEGFR blockade) into a focused, high-risk mCRPC population and exploring signal-seeking subcohorts such as MSI-H after prior immune checkpoint inhibitor and BRCA-mutated after prior PARP inhibitor. Today’s care for post–AR-pathway inhibitor mCRPC is continued androgen suppression plus sequential systemic options like docetaxel or cabazitaxel chemotherapy, PARP inhibitors for HRR/BRCA-selected disease, radiopharmaceuticals (e.g., Lu-PSMA in PSMA-positive disease and radium-223 for symptomatic bone-predominant disease), and pembrolizumab for MSI-H/TMB-high tumors—yet outcomes remain poor once visceral disease emerges.