PRO-XL: A phase II study of zanzalintinib (XL092) in patients with metastatic castration-resistant prostate cancer (mCRPC) after progression on lutetium-177 (177Lu)-PSMA-617.

TPS285 Background: 177Lu-PSMA-617 has been approved for patients with prostate-specific membrane antigen (PSMA)-positive mCRPC who have been treated with androgen receptor (AR) pathway inhibition and taxane-based chemotherapy after demonstrating improvement in overall survival (OS) in the phase III VISION trial (PMID: 34161051). However, the tumor eventually develops resistance to 177Lu-PSMA-617 and progresses, and therefore, therapies are needed to treat 177Lu-PSMA-617 refractory mCRPC. Prior studies have demonstrated a significant VEGF expression in LNCaP tumors and locally recurrent prostate cancer after radiotherapy. Also, tumor recurrence largely depends on new vessel formation through angiogenesis when radiation inhibits angiogenesis. Zanzalintinib is a novel, potent, orally bioavailable small molecule multi-targeted inhibitor of kinases, including the receptor tyrosine kinases (RTKs), VEGFR2, MET, and TAM kinases AXL, and MER, which have been shown to be overexpressed in radiation-resistant tumors. Therefore, zanzalintinib is expected not only to inhibit tumor angiogenesis but also to mitigate resistance to antiangiogenic therapy over time. We initiated a phase 2 trial of zanzalintinib in pts with mCRPC after progression on 177Lu-PSMA-617. Methods: This IRB-approved, investigator-initiated, single-arm, single-center, non-randomized, open-label study will enroll 30 patients. Zanzalintinib will be administered orally at 100 mg once daily. Eligibility criteria: ≥ 18 years of age, mCRPC with histologically/cytologically confirmed adenocarcinoma without small cell histology, progression on or after prior treatment with 177Lu-PSMA-617, ECOG performance status ≤ 2, and adequate organ function. Any number of prior therapies will be allowed. Primary Endpoint: Proportion of participants with non-progressive disease at 16 weeks of treatment with zanzalintinib as assessed by Prostate Cancer Working Group 3 (PCWG3)-modified RECIST v1.1. Thirty patients will ensure that the disease control rate can be estimated via a 95% confidence interval with a margin of error <0.20. Secondary Endpoints: safety, tolerability, PSA 50% response rate, and OS. Tissue and blood samples will be collected for correlative studies. Clinical trial information: NCT06568562 .