Maximal Androgen Depletion with Abiraterone Acetate Followed by Molecular-Targeted Therapies in Metastatic Prostate Cancer: Finding an Androgen-Signaling Signature to Predict Response
There is an important unmet need for molecular biomarkers that can predict success or failure of a specific therapy in treating men with metastatic castrate-resistant prostate cancer (mCRPC). This would allow personalized therapy of these patients with an agent that has a high probability of a successful clinical outcome. A candidate androgen-signaling signature associated with a favorable outcome to treatment with abiraterone acetate and enzalutamide has been previously identified; this molecular signature is lacking in patients with primary resistance to either abiraterone acetate or enzalutamide. At ESMO 2014, Efstathiou and colleagues reported on a rigorous evaluation of the candidate androgen-signaling signature in a phase 2 clinical trial of 170 men with mCRPC (100% with bone metastases) who were treated with abiraterone acetate, followed by dasatinib or sunitinib on disease progression (Efstathiou E, et al. ESMO 2014: Abstract LBA21).
The primary clinical or molecular end point was assessment of a prespecified androgen-signaling signature and other tumor biomarkers in patients who benefited versus those with primary resistance to abiraterone acetate (defined as disease progression in ?4 months). The tumor markers evaluated included androgen receptor N-terminal (AR-N), androgen receptor C- terminal (AR-C), cytochrome (CY)P17, Ki67 and the percent Ki67 proliferation index, glucocorticoid receptor (GR), and ERG oncogene expression. The candidate androgen-signaling signature previously identified and consisted of tumor AR-N overexpression, a ratio of AR-C terminal overexpression/AR-N terminal overexpression ?0.8, and ?10% CYP17 tumor expression (Efstathiou E, et al. J Clin Oncol. 2012;30:637-643; Ricci DS, et al. ASCO 2014: Abstract 5058).
The patients included in this new study had a mean Gleason score of ?8 and a median pretreatment prostate-specific antigen 21 ng/dL. The Table shows the results with the 41 evaluable patients presented at ESMO 2014. The presence of the prespecified candidate androgen-signaling signature was significantly predictive of a benefit for these patients from abiraterone acetate (P <.001). The presence of the ERG oncogene was significantly predictive of primary resistance to abiraterone acetate, but none of the other molecular or clinical markers were predictive of positive or negative treatment outcome.
These very promising data, in which a series of molecular biomarkers appear to be predictive of the efficacy of abiraterone acetate in patients with mCRPC, should lead to a prospective study selecting patients for maximal androgen-deprivation therapy based on the presence of this molecular signature.