Background: LVT is a β-emitting radioligand approved for pts with prostate-specific membrane antigen (PSMA)-positive mCRPC with prior treatment with androgen receptor pathway inhibitor (ARPI) and taxane-based chemotherapy. However, in the VISION trial, 50% of pts with measurable disease didn’t respond (PMID: 34161051). Prior studies have shown a significant correlation between PSMA and VEGF expression (p<0.001) in LNCaP tumors and locally recurrent PCa after radiotherapy. Cabo is an oral, small-molecule tyrosine kinase inhibitor with potent activity against multiple receptor tyrosine kinases including VEGFR2. Therefore, the combination of cabo with LVT may be synergistic. We initiated a phase 1b dose-scalation study of cabo in combination with standard of care (SOC) LVT in pts with mCRPC. Methods: This is an IRB-approved, investigator-initiated, single-arm, single-center, dose-escalation (DEsc) and dose-expansion (DExp) study. The primary hypothesis is that Cabo+LVT will be safe and effective in mCRPC pts. Key inclusion criteria: ≥18 years of age, mCRPC with histologically/cytologically confirmed adenocarcinoma without small cell histology, ECOG performance status ≤2, prior treatment with ≥2 cycles of taxane and at least 1 ARPI, adequate organ function and eligible for SOC LVT. Key exclusion criteria: Prior treatment with cabo or PSMA-targeted radioligand therapy. DEsc part will follow traditional 3+3 design to evaluate SOC LVT in combination with 3 dose levels (DL) of daily oral cabo: 40 mg (DL 1), 60 mg (DL 2) and 20 mg (DL -1). Primary objective: to determine maximal tolerated dose (MTD), and recommended dose and schedule for DExp phase. Secondary objective: To assess safety and tolerability of cabo with LVT. Expected enrollment 9 pts (range 4-18). DExp part will enroll 24 evaluable pts. Primary objective: to evaluate preliminary efficacy by estimating the progression-free survival (PFS) at 24 weeks (PFS_24w) as assessed by PCWG3-modified RECIST v1.1. 2-sided 80% and 60% confidence intervals will be constructed for PFS_24w via exponential Greenwood’s formula for Kaplan-Meier survival estimate, providing 90% and 80% 1-sided confidence for 30 pts at DExp dose (6 DEsc+24 DExp). Secondary objective: (1) To assess safety and tolerability cabo+LVT (2) assess objective response rate, duration of response, radiographic PFS, PFS at 38 weeks, PSA PFS, PSA 50% response rate, and OS. 1 patient has been enrolled. Clinical trial information: NCT05613894.