Abstract Background The neuroendocrine (NE) pathway cannot be ignored as a mechanism for castration‐resistant prostate cancer (CRPC) progression. The neuromediator, gastrin‐releasing peptide (GRP) may be involved in the aberrant activation of the normal androgen receptor (AR) and increased AR variants. This study focused on plasma levels of progastrin‐releasing peptide (ProGRP) and examined the treatment outcomes with androgen receptor axis‐targeted (ARAT) agents. Methods One hundred patients with metastatic CRPC were enrolled. Enzalutamide (ENZ) or abiraterone acetate/prednisone (AA/P) were administered to 50 patients each in a nonrandomized manner as a first‐line or later choice. Plasma ProGRP levels were determined using a chemiluminescent enzyme immunoassay, and data were collected prospectively. The study endpoints were prostate‐specific antigen (PSA) response and survival estimates. Results In the ENZ series, ProGRP levels correlated with the maximum PSA change from baseline (high ProGRP: −34.5% vs. low ProGRP: −85.7% p = .033). PSA progression‐free survival (PFS), radiographic/symptomatic (r/s) PFS, and overall survival (OS) in patients with high ProGRP were significantly worse than those in patients with low ProGRP (median PSA‐PFS: 3.3 vs. 10.0 months, p = .001, r/s PFS: 5.0 vs. 15.0 months, p