Endocrine Abstracts

Prostate cancer is the most commonly diagnosed non-cutaneous malignancy in men and a leading cause of male mortality. The androgen receptor (AR) remains the major therapeutic target with therapies that inhibit the AR signaling axis improving the outcome for patients with advanced castration-sensitive and castration-resistance prostate cancer. Despite these advances, primary and secondary resistance to AR targeting therapies is common, with evidence of ongoing AR signaling in the majority of cases. This is, in part, driven by the emergence of AR aberrations that include AR amplification, AR activating mutations, and constitutively active AR splice variants, that drive resistance to therapies targeting the AR. Nearly all currently available AR signaling axis inhibitors function through the AR ligand binding domain and have limited/no activity against AR aberrant oncogenic signaling. Therefore, the discovery and delivery of new therapeutic strategies that can block AR aberrant signaling, remains an area of unmet clinical need. Attractive strategies to overcome persistent oncogenic AR signaling include targeting AR transcription, AR RNA splicing, AR co-regulator activity, the AR N-terminus, and AR degradation, to directly impact aberrant AR activity. These approaches are currently in clinical development and undergoing evaluation in early phase clinical trials.