Enzalutamide is the first second-generation nonsteroidal androgen receptor (AR) 
antagonist with a strong binding affinity to AR. Most significantly, 
enzalutamide can prolong not only overall survival time and metastatic free 
survival time for patients with lethal castration-resistant prostate cancer 
(CRPC), but also castration-resistant free survival time for patients with 
castration-sensitive prostate cancer (CSPC). Enzalutamide has thus been approved 
by the US Food and Drug Administration (FDA) for the treatment of both 
metastatic (in 2012) and non-metastatic (in 2018) CRPC, as well as CSPC (2019). 
This is an inspiring drug discovery story created by an amazing 
interdisciplinary collaboration. Equally important, the successful clinical use 
of enzalutamide proves the notion that the second-generation AR antagonists can 
serve as hormonal therapeutics for three forms of advanced prostate cancer. This 
has been further verified by the recent FDA approval of the other two 
second-generation AR antagonists, apalutamide and darolutamide, for the 
treatment of prostate cancer. This review focuses on the rational design and 
discovery of these three second-generation AR antagonists, and then highlights 
their syntheses, clinical studies, and use. Strategies to overcome the 
resistance to the second-generation AR antagonists are also reviewed.