Baseline Imaging Derived Factors of Response Following [225Ac]Ac‐J591 Therapy in Metastatic Castration‐Resistant Prostate Cancer: A Lesion Level Analysis

ABSTRACT Purpose Actinium‐225 labeled prostate‐specific membrane antigen (PSMA) targeted radionuclide therapy has emerged as a potential treatment option in the management of men with metastatic castrate‐resistant prostate cancer (mCRPC). This study investigated molecular imaging‐derived parameters and compared imaging response of lesions categorized by tumor site. Methods Men with mCRPC treated with [225Ac]Ac‐J591 from 2017 to 2022 at our center on two prospective trials (NCT03276572 and NCT04506567) with pre‐ and post‐treatment [68Ga]Ga‐PSMA‐11 Positron Emission Tomography (PET) imaging studies available were included. SUVpeak of the 3 most‐ and 3 least‐avid lesions of the tumor sites were manually assessed. The median change of the SUVpeak from pre‐ to post‐treatment per tumor site was evaluated using the paired Wilcox test. An objective response (OR) in the follow‐up image was defined as complete or partial response using PET Response Criteria in Solid Tumors (PERCIST) 1.0. Results A total of 46 cases met the criteria for image review; most of them ( n = 25, 54.3%) had more than one tumor site category. In total, 445 PSMA PET‐positive lesions were assessed: 220 osseous, 163 nodal, 41 visceral, and 21 prostatic lesions. After treatment with [225Ac]Ac‐J591, absolute SUVpeak values per tumor site declined significantly ( p < 0.05) except for prostatic lesions ( p = 1). The PERCIST‐OR rate for osseous, nodal, visceral, and prostatic lesions was 53%, 28%, 56%, and 38%, respectively. Conclusion [225Ac]Ac‐J591 is an active treatment in men with mCRPC. Tumor distribution patterns may influence treatment response and potentially prognosis. Our findings warrant further validation in a larger cohort but may be considered in treatment planning and trial design.