Androgen receptor splice variants (AR-Vs) have been described for a number of years, but their clinical relevance has been unclear until now. In an article recently published inThe New England Journal of Medicine,1 Antonarakis and colleagues demonstrated that patients with metastatic castrate-resistant prostate cancer (mCRPC) expressing AR-V7 in circulating tumor cells (CTCs) have a 0% response rate to newer androgen axis-targeting agents such as enzalutamide and abiraterone. This is an important observation that indicates that AR-V7 is a predictive biomarker for an important class of drugs.
AR-V7 lacks the C-terminal androgen receptor ligand–binding domain and functions as a constitutively active ligand-independent transcription factor. Simply stated, that means that AR-V7 is fully functional in terms of DNA binding and transcriptional activity despite a complete lack of testosterone and dihydrotestosterone binding. Enzalutamide and abiraterone can only block the androgen-signaling axis when the androgens initiate the signaling cascade. They are ineffective therapies in the presence of ligand-independent androgen receptor variants.
The assays were performed on CTCs derived from blood of men with advanced cancers. If there were no circulating CTCs, there was no assay to perform. Patients examined by these assays all had advanced cancer; all had mCRPC, and most had undergone multiple therapies when the assays were performed. Men with earlier-stage prostate cancer are less likely to have CTCs.
The number of patients treated was small, but the clinical relevance is clear. Abiraterone and enzalutamide are important new agents in the clinician’s armamentarium. Men with CTCs positive for AR-V7 do not respond to these agents; further, they progress rapidly and die quickly. There is much more to learn, but the implications of AR-V7 detection in CTCs are important in the management of advanced prostate cancer patients.