Neuroendocrine secretory profiles are not associated with treatment response to Lu-177-PSMA-617 radioligand therapy in patients with advanced metastatic castration-resistant prostate cancer

Ziel/Aim Neuroendocrine differentiation (NED) is a well-recognized phenotypic change by which prostate adenocarcinoma cells transdifferentiate into neuroendocrine-like cells, driving treatment failure and poor prognosis. NE-like cells secrete peptide hormones to support growth of tumor cells in a paracrine manner.

Methodik/Methods We performed an analysis of neuroendocrine secretory profiles in 50 patients with advanced metastatic castration-resistant prostate cancer (mCRPC) commencing Lu-177-prostate-specific membrane antigen (PSMA)-617 radioligand therapy after verification of PSMA expression using Ga-68-PSMA-11 PET/CT. Pre-treatment serum levels of progastrin-releasing peptide (ProGRP), neuron-specific enolase (NSE) and chromogranin-A (CgA) were determined, and correlated with patient characteristics and treatment response after up to 3 cycles of RLT. Therapy response was assessed using Prostate Cancer Working Group 3 criteria.

Ergebnisse/Results Pre-treatment serum levels of ProGRP (75±51, 29-305 ng/l), NSE (31±24, 9-152 µg/l) and CgA (191±212, 33-1241 µg/l) were abnormal in 80%, 88% and 74% of patients. Neuromediators were not associated with baseline prostate-specific antigen levels (P≥0.31) or Gleason score (P≥0.43 in all cases), and not driven by pre-treatment with chemotherapy (P≥0.18) or by presence of hepatic metastases (P≥0.11). Pre-treatment neuromediator levels were not significantly different between responders and non-responders. Consistently, percentage PSA response after 1, 2 and 3 cycles was not associated with serum levels of neuromediators (P≥0.30 in all cases). Even neuromediator levels >5x Upper limit of Normal (ProGRP, P = 1.0; NSE, P = 0.50; CgA, P = 0.22) did not reliably predict treatment failure.

Schlussfolgerungen/Conclusions Neuroendocrine secretory profiles are abnormal in the majority of advanced mCRPC patients, and highly heterogeneous. Neuroendocrine differentiation does not predict treatment failure in RLT, and patients should not be excluded from RLT based on serum-linked evidence of NED.