Antiandrogen withdrawal syndrome is an unpredictable event diagnosed in patients with
hormone-sensitive
prostate cancer treated with combined
androgen blockade
therapy. It is defined by
prostate-specific antigen value reduction, occasionally associated with a radiological response, that occurs 4-6 weeks after first-generation
antiandrogen therapy discontinuation. New-generation hormonal
therapies, such as
enzalutamide and
abiraterone acetate, improved the overall survival in patients with metastatic
castration-resistant
prostate cancer, and recent trials have also shown the efficacy of
abiraterone in
hormone-sensitive disease. In the last few years, several case reports and retrospective studies suggested that the withdrawal syndrome may also occur with these new drugs. This review summarizes literature data and hypothesis about the biological rationale underlying the syndrome and its potential clinical relevance, focusing mainly on new-generation hormonal
therapies. Several in vitro studies suggest that
androgen receptor gain-of-function mutations are involved in this syndrome, shifting the
antiandrogen activity from antagonist to agonist. Several different drug-specific point mutations have been reported. The association of the withdrawal syndrome for
enzalutamide and
abiraterone needs confirmation by additional investigations. However, new-generation hormonal
therapies being increasingly used in all stages of disease, more patients may experience the syndrome when stopping the treatment at the time of
disease progression, although the clinical relevance of this phenomenon in the management of metastatic
castration-resistant
prostate cancer remains to be defined.