Androgen receptor splice variant 7 in castration resistant prostate cancer treated with hormonal therapy: what is in the pipeline?

Prostate cancer (PC) represents the second most commonly diagnosed cancer in men (1). Localized PC is more frequently diagnosed than metastatic PC (2). However, the survival of PC is strictly dependent on the staging, with a 5-year survival rate for the localized disease >99%, and a 5-year survival rate for metastatic PC around 30% (2). Management of metastatic disease remains challenging, both in the hormone-dependent setting and in castration-resistant PC (CRPC), due to the development of resistance and disease progression to the available therapeutic options. FDA has recently approved several drugs for metastatic CRPC (mCRPC): docetaxel, cabazitaxel, androgen receptor (AR) signaling inhibitors (abiraterone acetate and enzalutamide), sipuleucel-T and radium-223. However, the optimal treatment sequence is still unknown, and the complete identification of patients who could benefit the most by each therapy remains an unmet need. In this view, the validation of objective and measurable biomarkers that correlate with the response to a specific therapy is of utmost importance (3). Numerous mechanisms of resistance have been described along with AR signaling inhibitors, including AR splice variants (AR-Vs), amplification or mutations of the AR gene, enhancement of AR transcriptional activity or stability, loss of AR, increased steroidogenesis, EGR gene rearrangement and upregulation of alternative signaling pathways (4). In particular, AR-Vs represent abnormal AR proteins, lacking the AR C-terminal ligand-binding domain, but retaining the transactivating N-terminal domain. Due to these characteristics, AR-Vs are constitutively active, promoting AR activity in the absence of the ligand (5). Several AR-Vs have been identified, and the AR splice variant 7 (AR-V7) represents the most promising and biologically significant marker in PC. Originally, the pretreatment status of AR-V7 was explored in circulating tumor cells (CTCs) of 62 patients affected by mCRPC undergoing abiraterone acetate or Enzalutamide (6). Quantitative reverse-transcriptasepolymerase-chain-reaction (RT-PCR) assays were used for AR-V7 mRNA detection in CTCs. AR-V7 was associated with primary resistance to AR signaling inhibitors. Indeed, AR-V7 positive patients who received abiraterone acetate or Enzalutamide had lower prostate-specific antigen (PSA) response rates, shorter PSA progression-free survival (PFS), clinical/radiographic PFS and overall survival (OS) than AR-V7 negative patients. Interestingly, the negative predictive role of AR-V7 was not confirmed in patients affected by mCRPC undergoing taxane chemotherapy (7). Indeed, AR-V7 status did not influence the response to chemotherapy in this setting, with no significant difference in terms of PSA response rate, PSA PFS and clinical/ radiographic PFS in AR-V7 positive versus negative patients. However, although AR-V7 was not associated with Editorial Commentary