Phase 2 zanzalintinib (MET/VEGFR2/AXL/MER TKI) in aggressive-variant prostate cancer

This multicenter, single-arm Phase 2 NAPOLEON study evaluates the antitumor activity of oral zanzalintinib 60 mg once daily in men with aggressive variant prostate cancer (AVPC), using a 2‑stage group-sequential enrollment design (first 15 patients; limited prior chemo exposure in castration-resistant setting). Zanzalintinib (XL092) is a small-molecule multikinase inhibitor targeting MET, VEGFR2, AXL, and MER, aiming to blunt both tumor-intrinsic growth signaling and tumor angiogenesis. Eligible disease features span clinically “aggressive” CRPC biology, including poorly differentiated/transdifferentiated histology, visceral or soft-tissue metastases, bulky nodal/pelvic disease, predominantly lytic bone metastases, and molecularly enriched subsets such as combined loss/alteration patterns in TP53/RB1/PTEN and neuroendocrine marker-positive or PSMA-negative/FDG-avid disease. The trial is investigator-sponsored (Deepak Kilari) and leverages a drug program developed by Exelixis, positioning it as a targeted-kinase approach for an AVPC population where today’s care is typically platinum-based chemotherapy regimens (often carboplatin-based), sequential AR-pathway agents, and later-line taxanes, with limited durable options once aggressive features emerge.