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Key Points The discovery of androgen dependence in prostate cancer in 1941 by Huggins and colleagues still remains the backbone for the treatment of advance-staged prostate cancer Over the past decade, the better understanding of the mechanisms driving resistance to castration has led to development of abiraterone acetate and enzalutamide, two next-generation androgen receptor (AR) targeting agents Several challenges remain including resistance to continued blocking of the AR axis, cross-resistance between agents, ideal sequence of administration, combination strategies, and coordination with other treatments Molecular characterization of patients, through next-generation sequencing or transcriptome analysis, will help to dissect mechanisms of resistance and to identify biomarkers allowing the selection of patients for specific treatment The improved understanding of intra-patient molecular heterogeneity and of the multiple, redundant and compensatory signalling networks in cancers supports a role for rational combinatorial, targeted therapeutic approaches Abstract The discovery of androgen dependence in prostate cancer in 1941 by Huggins and colleagues has remained the backbone for the treatment of this disease