CIRCULATING MICRO-RNA (miRNA) AND AR-V7 MUTATIONAL STATUS IN METASTATIC CASTRATION-RESISTANT PROSTATE CANCER (CRPC): PRIMERA+ STUDY (PROSTATE CANCER INNOVATING MARKERS OF EXPECTED RESPONSE TO AGONIST LHRH+ ANDROGEN RECEPTOR INHIBITION

Prostate cancer is the most frequent malignancy in male patients; since androgen receptor signalling is capital for cancer progression, androgen deprivation therapy with Luteineizing Hormone Release Hormone Agonists (a LHRH) is the cornerstone of its clinical management until occurrence of castration resistance, resulting in disease relapse following activation of alternative signalling pathways. In order to overcome castration resistance, new generations molecules targeting androgen receptor emerged in the last decade as an alternative to chemotherapy with taxanes: among them Abiraterone and Enzalutamide, a potent androgen receptor inhibitor that restore sensitivity to aLHRH therapy has recently been approved both in the pre-and postchemotherapy setting in metastatic castration-resistant prostate cancer (mCPRC).

Despite promising results, resistance to androgen inhibitors is a critical issue, resulting in treatment failure (primary resistance or adaptative resistance developed during the treatment course), particularly as a result of androgen receptor (AR) amplification or mutations.

This result in a dramatic need to identify predictors of response to treatment in order to choose the correct treatment sequence; nevertheless, this approach is somehow limitated due to scarce avalibility of tissue samples for biomolecular investigation in frail patients with painful bone metastasis.

Among the causes of treatment failure, AR-V7 splice variant of the androgen receptor has been extensively studied by Antonarakis et al, who reported that AR-V7 splice variant in circulating tumor cell (a cost-effective,non invasive assessment performed on blood samples) affects response both to Enzalutamide and to the cytochrome inhibitor Abiraterone, resulting in 0% of PSA response in patients displaying AR-V7(19-39% according to data from Antonarakis et al).

A recent study from Scher et al highlighted that CTC nuclear expression of AR-V7 protein in men with mCRPC as a treatment-specific biomarker was associated with superior survival on taxane therapy over hormone based therapy, advocating for future prospective clinical trials in this setting.