Abstract The development of castration resistance in prostate cancer most commonly involves reactivation of androgen receptor (AR) signaling; this knowledge has informed the clinical development of potent AR-targeted agents now commonly used in the clinic. However, a subset of prostate cancers may evolve under therapeutic pressure of the AR towards non-AR driven, or “androgen indifferent,” disease. This has been associated with aggressive clinical features with repeat biopsies enriched with TP53 and RB1 genomic loss, overexpression of MYCN, epigenetic changes, and activation of alternative lineage programs such as neuronal and neuroendocrine pathways. One extreme manifestation is complete transformation to a small cell/neuroendocrine carcinoma with loss of AR expression. Although castration-resistant neuroendocrine prostate cancer evolves clonally from prostate adenocarcinoma likely through a trans-differentiation process, it acquires molecular alterations seen in other poorly differentiated neuroendocrine cancers. This talk will focus on emerging biomarker-driven therapeutic strategies for androgen-indifferent disease, including updates on targeting the N-myc/Aurora kinase A complex, the potential role for epigenetic therapies, and new data to inform ADC and immunotherapy development for this subset. Citation Format: Himisha Beltran. Emerging therapeutic strategies for androgen indifferent prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr IA05.