Androgen metabolism in castration-resistant prostate cancer

Androgens and prostate androgen receptors (ARs) are at the root of prostate cancer (PCa); thus, surgical or chemical castration and AR blocking have been effective methods in inhibiting growth and achieving remission. Unfortunately, the remissions are not long lasting and proliferation, invasion, and metastasis inevitably reappear. When this happens, the tumor is usually refractory to antiandrogen treatment, which is not a synonym of androgen independency but of castration resistance. The discovery of abiraterone, an inhibitor of adrenal and intratumoral androgen production, and enzalutamide an AR blocker represented an important breakthrough in PCa therapy. These drugs significantly prolong survival. However, their benefits are short lived and they do not solve the problem. Further research along the path of AR and androgen inhibition is necessary for more effective treatments. The secrets of this problem are hidden somewhere in the androgen metabolism of the castration-resistant stage and in the peculiarities of AR function. Evidently, androgen metabolism changes during PCa evolution and understanding these changes will lead to the development of new drugs such as specific AR degraders and allow the repurposing of some old pharmaceuticals. Ketoconazole is the best example of a repurposed antiandrogen that has shown some positive results. Castration-resistant PCa treatments need to evolve from an androgen-centered view to an AR-centered approach.