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

Neuroendocrine differentiation is associated with treatment failure and poor outcome in metastatic castration-resistant prostate cancer. We investigated the effect of circulating neuroendocrine biomarkers on the efficacy of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT). Neuroendocrine biomarker profiles (progastrin-releasing peptide, neuron-specific enolase, and chromogranin-A) were analyzed in 50 patients commencing Lu-PSMA-617 RLT. The primary endpoint was a prostate-specific antigen response in relation to baseline neuroendocrine marker profiles. An additional endpoint was progression-free survival. Tumor uptake on posttherapeutic scans, a known predictive marker for response, was used as a control variable. Neuroendocrine biomarker profiles were abnormal in most patients. Neuroendocrine biomarker levels did not predict treatment failure or early progression ( ≥ 0.13). By contrast, intense PSMA-ligand uptake in metastases predicted both treatment response ( = 0.0030) and reduced risk of early progression ( = 0.0111). Neuroendocrine marker profiles do not predict an adverse outcome from RLT. By contrast, high ligand uptake was confirmed to be crucial for achieving a tumor response.