Neuroendocrine Differentiation and Response to PSMA-Targeted Radioligand Therapy in Advanced Metastatic Castration-Resistant Prostate Cancer: A Single-Center Retrospective Study

Treatment response to ¹⁷⁷Lu-PSMA-617 radioligand therapy and neuroendocrine markers in subgroup without factors potentially influencing marker levels (n = 29). (A) Waterfall plot of PSA change after 2 cycles of ¹⁷⁷Lu-PSMA-617 RLT presented in order of increasing PSA response ranging from +122% to −100%. (B) Interindividual heterogeneity in PSA levels and neuroendocrine marker levels before therapy. High marker levels are observed in both responders and nonresponders. (C) PSMA-ligand uptake in metastases depicted as categoric heat map. High PSMA-ligand uptake is significantly associated with PSA response (P = 0.0439). (D) Hematoxylin and eosin staining (left) and immunohistochemistry (right) of biopsy samples. At top is nonresponder to ¹⁷⁷Lu-PSMA-617 at time of prostate cancer diagnosis; biopsy sample contains prostate adenocarcinoma cancer cells with no detectable NSE expression; 2 of 3 serum markers were elevated at time of PSMA-targeted therapy (progastrin-releasing peptide, 164 ng/L; CgA, 136 μg/L), consistent with therapy-induced neuroendocrine differentiation. At bottom is responder to ¹⁷⁷Lu-PSMA-617 at time of prostate cancer diagnosis; biopsy sample from transurethral resection of prostate (TURP) contains prostate adenocarcinoma cancer cells with moderate cytoplasmatic NSE expression; all 3 serum markers were elevated at time of PSMA-targeted therapy (progastrin-releasing peptide, 81 ng/L; NSE, 25 μg/L; CgA, 196 μg/L), consistent with neuroendocrine differentiation and preexisting NSE protein expression in primary tumor. ProGRP = progastrin-releasing peptide.