Joseph D. Schonhoft

Kaplan-meier estimate for A, DOT and B, PFS in patients with and without reversions enrolled on LoF in BRCA1/2, RAD51p, or PALB2 in HRD associated tumor types (breast, prostate, pancreatic, ovarian) C) On-treatment BRCA1 reversion detected (RECIST and ctDNA cTF in Fig. 3D)

Camonsertib concentration levels at 80 and 120 mg – cycle 1 day 1

Study schematic for TRESR, Module 4.

Institutional Review Boards of participating institutions

Drug combination pharmacokinetic parameters

TRAEs by schedule and grade in >5% of the total study population.

Mice bearing SUM149PT (A and C) or Granta-519 (B) tumors were treated with camonsertib (3/4d, weekly) or gemcitabine (QW) as single agents and in combination at the doses indicated. A) Tumor growth is represented as mean ± SEM; n = 7 mice/group; TGI = tumor growth inhibition (%). B, C) Body weights are represented as mean change relative to Day 0 ± SEM. Statistical differences between groups were determined using an unpaired t-test with Welch’s correction. *P < .05; **P < .01 (GraphPad Prism v10.4).

Purpose:Prostate-specific membrane antigen (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. In this study, we explored the relationship between PSMA imaging and PSMA expression on circulating tumor cells (CTC) in our early-phase trial using a PSMA-targeted small molecule.Experimental Design:This phase I study investigated EC1169, a small molecule conjugated to a tubulysin analog warhead, and 99mTc–EC0652, a PSMA imaging agent. Part A (dose escalation) identified the recommended phase II dose. Part B (dose expansion) assessed radiographic progression-free survival (rPFS) as its primary endpoint. We enrolled and treated 103 patients with mCRPC. Most part B patients underwent 99mTc–EC0652 PSMA imaging. A CTC assay assessed PSMA-positive CTCs and their association with response and PSMA imaging.Results:99mTc–EC0652 single-photon emission computed tomography (SPECT) imaging demonstrated increased sensitivity for detecting bone lesions compared with standard scans (computed tomography/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 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 neuroendocrine prostate cancer–like morphology.Conclusions:Although 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.