The study investigates the therapeutic potential of BET bromodomain inhibitors in castration-resistant prostate cancer (CRPC). The authors demonstrate that AR signaling-competent CRPC cell lines are preferentially sensitive to BET bromodomain inhibition, as evidenced by the disruption of AR recruitment to target gene loci and reduced AR-mediated gene transcription. In contrast to direct AR antagonists, BET inhibitors function downstream of AR and more potently abrogate BRD4 localization to AR target loci. In vivo studies in CRPC xenograft models show that BET bromodomain inhibition is more effective than direct AR antagonism. The study suggests that BET inhibitors may be a novel epigenetic approach to target oncogenic drivers in advanced prostate cancer, particularly in the context of AR-mediated resistance.The study investigates the therapeutic potential of BET bromodomain inhibitors in castration-resistant prostate cancer (CRPC). The authors demonstrate that AR signaling-competent CRPC cell lines are preferentially sensitive to BET bromodomain inhibition, as evidenced by the disruption of AR recruitment to target gene loci and reduced AR-mediated gene transcription. In contrast to direct AR antagonists, BET inhibitors function downstream of AR and more potently abrogate BRD4 localization to AR target loci. In vivo studies in CRPC xenograft models show that BET bromodomain inhibition is more effective than direct AR antagonism. The study suggests that BET inhibitors may be a novel epigenetic approach to target oncogenic drivers in advanced prostate cancer, particularly in the context of AR-mediated resistance.