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The novel bromodomain inhibitor, ABBV-075, is being tested in a Phase I study for the treatment of solid tumors. Here, we show that potent inhibition of the BET (bromodomain and extra-terminal) family with ABBV-075 is a highly efficacious therapy in pre-clinical models of prostate cancer. The single-digit to low nanomolar anti-proliferative IC50s and potent in vivo tumor growth inhibition of ABBV-075 is mediated in part via inhibition of androgen receptor (AR)-dependent transcription. Prostate tumor incidence and CRPC clinical progression are driven by aberrant activation of the AR transcription program. Gene expression profiling and qPCR results indicate that ABBV-075 inhibited DHT-stimulated transcription of AR target genes without significant effect on AR protein expression. Further, ABBV-075 disrupted DHT-stimulated recruitment of the BET family member BRD4 to gene regulatory regions co-occupied by AR, including the well-established PSA and TMPRSS2 enhancers. Persistent BET inhibition led to the disassembly of AR occupied enhancers as measured by a reduction in AR and H3K27Ac ChIP signal and additionally downregulated enhancer RNA (eRNA) transcription. ABBV-075 displayed potent anti-proliferative activity in multiple models of resistance to the second generation anti-androgen Enzalutamide, including the F876L, L702H AR ligand binding domain mutations and the AR-V7 splicing variant. In addition to blocking the transcription activation downstream of AR, ABBV-075 is also a potent inhibitor of MYC and the TMPRSS2-ETS fusion proteins. Thus, we propose that ABBV-075 may provide a promising therapeutic option for CRPC patients who have developed resistance to second-generation anti-androgens. Citation Format: Emily J. Faivre, Denise M. Wilcox, Paul Hessler, Tamar Uziel, Paul Tapang, Terry Magoc, Daniel H. Albert, Guowei Fang, Saul Rosenberg, Keith McDaniel, Keith McDaniel, Warren Kati, Yu Shen. ABBV-075, a novel BET family inhibitor, disrupts critical transcription programs that drive prostate cancer growth to induce potent anti-tumor activity in vitro and in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4694.