UNLABELLED: Initial reports of a clinical response in patients treated with the radioligand [177Lu]-PSMA-617 for castration-resistant prostate cancer (CRPC) are promising, despite known inter- and intrapatient heterogeneity. In metastatic CRPC, we examined the association of baseline immunohistochemical (IHC) expression of prostate-specific membrane antigen (PSMA) in a single lesion and responsiveness to [177Lu]-PSMA-617 therapy, measured as the PSMA maximum standardized uptake value (SUVmax). Between 2015 and 2020, 19 patients with multiple metastases underwent single-lesion biopsy, [68Ga]-PSMA positron emission tomography (PET) imaging, and treatment with [177Lu]-PSMA-617. A monoclonal anti-PSMA antibody was used to semiquantitatively assess PSMA IHC in the biopsy specimen. Imaging evaluation of the biopsied single lesion and overall response was performed according to Positron Emission Tomography Response Criteria in Solid Tumors. The PSMA IHC histoscore correlated positively with pretreatment same-site PSMA SUVmax (r s = 0.6). Nine patients had imaging after three cycles of [177Lu]-PSMA-617 and were included in the lesion-specific analysis. Of these, five patients (55.6%) had an SUVmax response at the biopsy site, but three experienced overall progression. The histoscore was unable to predict the lesion-specific change in SUVmax (95% confidence interval [CI] -44.2 to 69.2) or PSA (95% CI-125.2 to 17.2). There was no correlation between single-lesion SUVmax and overall progression (r s = 0.1) on [68Ga]-PSMA PET imaging. Additional studies need to interrogate the clinical consequence of PSMA expression heterogeneity in metastases and the association with response to [177Lu]-PSMA-671. PATIENT SUMMARY: Treatment with a radioactive binding molecule called [177Lu]-PSMA-617 for men with prostate cancer resistant to castration (CRPC) is showing promise. We investigated the association between the presence of PSMA protein in metastatic lesions at biopsy and response to [177Lu]-PSMA-617 among men with metastatic CRPC. We found that assessment of PSMA presence at biopsy is not a reliable predictor of response to [177Lu]-PSMA-617. Additional studies are needed to better determine which CRPC metastatic sites will respond to this therapy.

Department of Biomedical Imaging and Image guided Therapy Division of Nuclear Medicine Medical University of Vienna Vienna Austria

Department of Pathology Medical University of Vienna Vienna Austria

Department of Urology 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Urology Medical University of Vienna Vienna Austria

Department of Urology Michigan Medicine Ann Arbor MI USA

Department of Urology University of Texas Southwestern Dallas TX USA

Department of Urology Weill Cornell Medical College New York NY USA

Division of Urology Department of Special Surgery Jordan University Hospital The University of Jordan Amman Jordan

European Association of Urology Research Foundation Arnhem The Netherlands

Institute for Urology and Reproductive Health Sechenov University Moscow Russia

Karl Landsteiner Institute Vienna Austria

Rogel Cancer Center University of Michigan Ann Arbor MI USA

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