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July 11, 2017. ...it’s not androgen receptor (AR) resistance. We know tumors are smart, but turning ARs into constituent activators in castrate-resistant prostate cancer (CRPC) takes tumor smarts to another level. This month’s JCO article explores the clinical significance of AR splice variants in which the ligand-binding domain is truncated, leaving the rest of the AR immune to commonly-used blockers of the ligand-binders and ligand itself. Assessing circulating tumor cells with an mRNA assay for AR splice variants was found to be prognostic in a prospective eval of over 200 men with CRPC. Although this has little impact on treatment decisions today, this is a big step towards understanding how to outsmart CRPC. Game on.