Plasma progastrin‐releasing peptide level shows different predictive profiles for treatment response by androgen receptor axis‐targeted agents in patients with metastatic castration‐resistant prostate cancer

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 < 0.001, and OS 17.5 vs. 49.0 months, p < .001, respectively). In addition, ProGRP showed an independent predictive value for all survival estimates in multivariate analyses. In the AA/P series, ProGRP levels did not correlate with the PSA change or predict PSA‐PFS and r/s PFS, but they maintained a significant difference in OS (19.0 vs. 48.0 months, p = .003). CONCLUSIONS: Plasma ProGRP provides a consistent predictive value for OS in metastatic CRPC patients who underwent therapy with ARAT agents. Meanwhile, ProGRP showed different predictive profiles for PSA‐ and r/s PFS between ENZ and AA/P. These findings clinically suggest a mechanism for CRPC progression involving the NE pathway via the GRP. The underlying mechanism of different predictive profiles by the ARAT agent should be explored in future research.