Androgen receptor-targeting agents, particularly enzalutamide, show promise in enhancing prostate cancer diagnostic and therapeutic strategies by modulating prostate-specific membrane antigen (PSMA). Methods: A retrospective clinical cohort study investigated 9 men with metastatic castration-resistant prostate cancer on enzalutamide. PSMA PET/CT scans were obtained before and after enzalutamide initiation to assess PSMA expression changes. Lesions and organs at risk were evaluated visually and semiquantitatively. The flare phenomenon was characterized by a significant increase (≥20%) in the SUVmax of existing lesions or the appearance of new PSMA-positive lesions. Results: Exposure to enzalutamide led to a significant PSMA expression increase in 56% of assessed lesions (n = 42), with new lesions detected in 1 patient (11%). PSMA expression in organs at risk remained largely unaffected, indicating a tumor-specific response. Conclusion: Enzalutamide induces PSMA upregulation in metastatic castration-resistant prostate cancer, potentially enhancing diagnostic and therapeutic strategies. Further exploration of the flare phenomenon's clinical implications is warranted.

Department of Clinical Pharmacology and Pharmacy Amsterdam UMC Location Vrije Universiteit Amsterdam Amsterdam The Netherlands; and

Department of Radiology and Nuclear Medicine Amsterdam UMC Location Vrije Universiteit Amsterdam Amsterdam The Netherlands

Department of Urology Prostate Cancer Network Amsterdam Amsterdam UMC Location Vrije Universiteit Amsterdam Amsterdam The Netherlands;

Imaging and Biomarkers Cancer Center Amsterdam Amsterdam The Netherlands

Nuclear Medicine Department Faculty of Medicine and Dentistry Palacký University Olomouc Olomouc Czech Republic

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