Horizon scanning for novel therapeutics for the treatment of prostate cancer.

Treatment options for patients with advanced prostate cancer (PCa) remain limited. Improved understanding of the underlying molecular drivers of PCa pathogenesis, progression and resistance development has provided the fundamental basis for rational targeted drug design. Key findings in recent years include the identification of ETS gene rearrangements, the dissection of PCa molecular heterogeneity and the discovery that castration-resistant prostate cancer (CRPC) remains androgen driven despite the androgen-depleted milieu, thus making androgen receptor (AR) signaling a continued focus of molecularly targeted treatments. AR ligand-independent activation of tyrosine kinase prosurvival signaling cascades and angiogenesis have also been implicated in disease progression. A multitude of new molecularly targeted agents that abrogate AR signaling, inhibit the mitogenic and prosurvival signal transduction pathways, perturb the tumor-bone microenvironment, impair tumor vasculature, facilitate immune modulation and induce apoptosis are in clinical development and are highly likely to change the current treatment paradigm. It is clear that the success of these molecular targeted therapies hinges in part on optimal patient selection based on the molecular disease profile and an improved understanding of the mechanistic basis of acquired resistance. This review outlines the current clinical development of molecular targeted treatments in CRPC, with particular emphasis on agents that are in the later stages of clinical development, and details the challenges and future direction of developing these antitumor agents.