A candidate androgen signalling signature predictive of response to abiraterone acetate in men with metastatic castration-resistant prostate cancer

BACKGROUND: The unmet need for predictive biomarkers emerged from the unpredictable pattern of response to androgen signaling inhibition in metastatic castration-resistant prostate cancer (mCRPC). Here, we report on the testing of a previously identified candidate androgen signaling signature associated with response to androgen signaling inhibition. PATIENTS AND METHODS: We report on the outcome of the first module of a phase II trial on Abiraterone acetate (AA) followed by combination with dasatinib or sunitinib. Bone marrow biopsies (BMB) with matched bone marrow aspirate and blood samples were collected at baseline and upon progression. Endpoints included assessment of a prespecified molecular signature consisting of nuclear androgen receptor (AR) overexpression, cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17) expression, and AR C-/N-terminal expression ratio of ≥0.8 by immunohistochemistry (IHC) in patients with benefit versus primary resistance to AA (i.e. progression within 4 months). Tumor markers also included v-ets avian erythroblastosis virus E26 oncogene homolog (ERG), splice variant ARV7 by IHC and steroids by Liquid chromatography-tandem mass spectrometry. RESULTS: Out of 170 patients accrued from 03/2011 to 02/2015, 44 (26%) were primary resistant to AA. 48 patients had tumor infiltrated BMB at baseline. Pretreatment androgen signaling signature was linked to benefit from AA (p