Antiandrogen withdrawal syndrome (AAWS) in the treatment of patients with prostate cancer

Abstract

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 castrationresistant 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 newgeneration 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.

Drivers of AR indifferent anti-androgen resistance in prostate cancer cells

“…We observed that low anti-androgen concentrations increased the proliferation rate of ResB cells (Fig. 1a) in medium supplemented with androgen containing normal FCS, suggesting an anti-androgen withdrawal effect in ResB but not ResA cells 33,34 . Interestingly, enzalutamide on its own did not induce AR activity (Fig.…”

Metastatic prostate cancer remains incurable, why?

“…The antiandrogen withdrawal syndrome (AAWS) is defined as a further significant (>50%) reduction in PSA values after the discontinuation of antiandrogen therapy, which can be explained by AR mutations shifting the antiandrogen activity from antagonist to agonist. Several studies have reported AAWS after discontinuation of abiraterone or enzalutamide [110] , [111] , [112] . The second one is the L701H mutation that results in activation of the AR by glucocorticoids such as prednisone [113] .…”

Case Report: A castration-resistant terminal prostate cancer patient’s survival prolonged after practicing Falun Gong

“…Some may attribute the objective responses seen in this patient after discontinuing the antiandrogen (bicalutamide) to antiandrogen withdrawal syndrome (AAWS). AAWS, usually defined as >50% decline in PSA following cessation of the antiandrogen, has been increasingly recognized and reviewed [9][10][11] . A large multi-institutional clinical trial (CALGB 9583) to investigate AAWS in androgen-independent prostate cancer patients (with a median age of 72 years) has shown that 11% of patients experienced AAWS with the median time to PSA progression at 5.9 months, and objective responses of measurable disease were observed in 2% of patients 12 .…”