Single-lesion Prostate-specific Membrane Antigen Protein Expression (PSMA) and Response to [<sup>177</sup>Lu]-PSMA-ligand Therapy in Patients with Castration-resistant Prostate Cancer.

Overview

abstract

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 (SUV_max). 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 SUV_max (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 SUV_max response at the biopsy site, but three experienced overall progression. The histoscore was unable to predict the lesion-specific change in SUV_max (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 SUV_max 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.