The androgen receptor remains a key player in metastatic hormone-refractory prostate cancer. Implications for new treatments.

Metastatic castration-resistant prostate cancer (mCRPC) shows a number of adaptive mechanisms that facilitate continued androgen receptor (AR) dependent tumor growth. In this article we reviewed the subsequent hormonal manipulation in mCRPC, including the recently approved new drugs, in relation to the AR dependent and independent growth mechanisms. Maintaining castrate levels of testosterone is mandatory. The AR amplification, a process that can occur within the hypersensitive AR escape route, can be fought by using high dose antiandrogen (bicalutamide 150mg), change in antiandrogen preparation or the use of enzalutamide. Switch to another antiandrogen, the use of LHRH antagonists, change to another LHRH agonist, bilateral orchidectomy, adrenals' inhibition and the blockade of intratumor testosterone synthesis are several ways to counter the increased AR sensitivity. Increased androgen levels can be reduced by the use of ketoconazole, dexamethasone, abiraterone acetate or 5α-reductase inhibitors. Antiandrogen withdrawal and enzalutamide can be used to counter the promiscuous AR escape route. The use of metformin, cetuximab or cabozantinib could represent ways to overcome the outlaw pathway, but further studies are needed to show the efficacy of these drugs in mCRPC. Bcl-2 inhibitors, emerging drugs still in experimental phase, show great potential in counteracting the bypass pathway. Docetaxel and cabazitaxel, the standard chemotherapy of mCRPC, are the treatment of choice when androgen-independent prostate cancer cells are selected (as supported by the lurker cell pathway).The correct and rational use of all these drugs may delay by months or even years the need to administer chemotherapy in patients with mCRPC but some AR targeted therapies may impair the subsequent response to chemotherapy.