Dr Pobel on the Prognostic Value of Phenotypic and Genomic Characterization in De Novo mCSPC

"The take-home message is that combining AR and neuroendocrine marker expressions allows for the identification of patient subgroups in mCSPC [who may have] different outcomes."

Cedric Pobel, MD, medical oncologist, PhD student, Institut de Cancérologie, Gustave Roussy, Paris, France, discusses the potential use of phenotypic and genomic characterization of de novo

metastatic castration-sensitive prostate cancer (mCSPC) to predict outcomes with androgren deprivation therapy with or without docetaxel, with or without abiraterone acetate (Zytiga) and predisone.

In this ancillary analysis of the phase 3 PEACE-1 trial (NCT01957436), Pobel and colleagues sought to identify prognostic and predictive biomarkers tied to radiographic progression-free survival (rPFS) and overall survival (OS) outcomes in patients with de novo mCSPC. Two main analyses were conducted: an immunohistochemistry (IHC) assay with 10 markers, targeting luminal and neuroendocrine features, and a restricted-panel next-generation sequencing (NGS).

The IHC assay defined 5 subgroups based on androgen receptor (AR) and neuroendocrine status: AR-high luminal, AR luminal weak, amphicrine, double negative, and neuroendocrine prostate cancer. Among 350 patients, AR-high luminal patients had better prognoses, while neuroendocrine prostate cancer showed worse outcomes, primarily driven by neuroendocrine marker expression. Although no significant difference in rPFS or OS was noted among these subgroups, patients with neuroendocrine-positive markers exhibited worse outcomes, with an rPFS HR of 1.38 (P = 0.017) and OS HR of 1.53 (P = 0.005).

Further analysis showed that neither AR nor neuroendocrine biomarkers predicted response to abiraterone acetate plus prednisone. However, tumor suppressor gene alterations in TP53, PTEN, and RB1 were prognostically significant: patients with fewer than 2 alterations in these genes had a median OS of 5.4 years vs 2.2 years in those with 2 or more alterations (HR, 2.63).

These findings suggest that both AR- and neuroendocrine- positive markers are negative prognostic indicators, and alterations in 2 or more tumor suppressor genes further predicts poor outcomes. However, a predictive biomarker for abiraterone benefit in mCSPC remains undetermined.