We provided evidence that treatment with the HDAC3‐specific inhibitor RGFP966 not only effectively decreased AKT activities and the expression of full‐length AR and splicing variants in SPOP‐mutant‐expressing prostate cancer cell lines and patient‐derived organoids, but also inhibited the growth of SPOP‐mutant prostate cancer cells in 2D and 3D cultures. The gene discussed is SPOP; the disease is prostate carcinoma.