Zanzalintinib After Pluvicto in Chemo‑Naïve mCRPC

Zanzalintinib is being tested after Pluvicto (177Lu-PSMA-617) in metastatic castration‑resistant prostate cancer (mCRPC) because it targets several escape routes tumors use once they have survived PSMA‑directed radioligand therapy and prolonged AR pathway blockade. Pluvicto delivers beta radiation to PSMA‑expressing cells, inducing DNA damage and tumor cell death, but progression still occurs and is often driven by more heterogeneous, hypoxic, and angiogenesis‑dependent disease with an immunosuppressive microenvironment. Zanzalintinib (XL092) is a next‑generation multi‑target tyrosine kinase inhibitor that blocks VEGFR2, MET, and TAM kinases (AXL, MERTK, TYRO3), combining anti‑angiogenic effects with microenvironment and immune modulation, as shown in preclinical and early clinical work.

After radioligand therapy, prostate tumors and their stroma tend to upregulate VEGF and MET signaling, promoting endothelial survival, neovascularization, invasion, and resistance to prior therapy. By inhibiting VEGFR2, zanzalintinib is intended to blunt this “angiogenic rebound,” while MET blockade targets more invasive, mesenchymal‑like subclones that thrive in irradiated, hypoxic niches. TAM kinase inhibition hits another resistance layer: TAMs on myeloid cells favor M2‑like, immunosuppressive phenotypes and poor antigen presentation, so blocking these kinases can reduce myeloid suppression and make the tumor milieu more permissive for immune attack, whether from endogenous T‑cells or from future immunotherapies. In other solid tumors, this remodeling has been leveraged to enhance checkpoint inhibitor activity, and the same biology is relevant in CRPC.

Clinically, the sequencing logic is that Pluvicto is moving earlier into chemo‑naïve PSMA‑positive mCRPC, and many men still have good performance status and organ function at the time of post‑Pluvicto progression. Using zanzalintinib at that point exploits their remaining reserve to target pathways that are particularly active after radioligand exposure, without immediately committing them to the myelosuppressive and neuropathic toxicity of taxanes. The combination of ARPI → Pluvicto → zanzalintinib is conceptually attractive because it attacks, in turn, AR dependence, PSMA‑expressing clones, and then the VEGFR/MET/TAM‑driven, microenvironment‑adapted resistance that emerges afterward. In this view, the current phase II trial is less about zanzalintinib as an isolated drug and more about testing whether cutting off these angiogenic and immunosuppressive escape pathways right after PSMA RLT can bend the resistance trajectory of chemo‑naïve mCRPC.

Clinical trial.