Abstract
PURPOSE: PSMA directed therapies provide meaningful clinical benefit in metastatic castration-resistant prostate cancer (mCRPC), yet responses remain limited, underscoring the need for additional biomarkers of PSMA expression heterogeneity. Here, we explored the relationship of PSMA imaging and PSMA expression on circulating tumor cells (CTCs) in our early phase trial using a PSMA-targeted small molecule. PATIENTS AND METHODS: This Phase 1 study investigated EC1169, a small molecule conjugated to tubulysin analog warhead, and 99mTc-EC0652, a PSMA imaging agent. Part A (dose-escalation) identified the recommended phase 2 dose. Part B (dose-expansion) assessed radiographic progression-free survival (rPFS) as its primary endpoint. We enrolled and treated 103 mCRPC patients. Most Part B patients underwent 99mTc-EC0652 PSMA imaging. A CTC assay assessed for PSMA-positive CTCs and their association with response and PSMA imaging. RESULTS: 99mTc-EC0652 SPECT imaging demonstrated increased sensitivity for detecting bone lesions compared with standard scans (CT/bone scans). Using an optimized CTC assay, we observed that patients with a decrease in PSMA+ CTCs at baseline versus C3D1 displayed a longer rPFS (8.0 vs. 2.9 months; P=0.04). Importantly, patients with predominantly PSMA-positive disease on 99mTc-EC0652 imaging also harbored PSMA-negative CTCs, with a subset displaying NEPC-like morphology. CONCLUSIONS: While EC1169 showed limited activity, CTC and imaging analyses showed significant heterogeneity in PSMA expression on CTCs in patients with predominantly PSMA-positive lesions on SPECT. Our study highlights the importance of assessing both PSMA-based CTC and imaging assays in future validation trials.