OBJECTIVES: Prostate cancer (PCa) is anandrogen-dependent disease. In some cases, the tumorprogresses despite castration levels of serum testosterone,turning into the lethal phenotype of castration-resistantprostate cancer (CRPC), still driven by androgensand requiring the androgen receptor as a driver andresponsible for progression.Enzalutamide, an androgen receptor inhibitor, isindicated for the treatment of metastatic CRPC,asymptomatic or mildly symptomatic, after failure ofandrogen deprivation. In both clinical trials that led to itsapproval, Enzalutamide was administered with an LHRHanalog, setting the “standard of care” for its use. In thisarticle we evaluate the available evidence and theoryon the use of Enzalutamide as monotherapy.METHODS: Androgen deprivation well-known adverseevents, together with the fact that its clinical benefit ismoderate and the evidence strength is weak, andthe direct negative impact on the common chronicconditions affecting this age-group led to investigationof Enzalutamide without LHRH analogs.RESULTS: There are clinical trials on Enzalutamidemonotherapy for hormone-sensitive prostate cancer withfavourable outcomes, and there are also two ongoingstudies in different advanced PCa scenarios, thePROSPER and EMBARK trials. It would be up to now asafe alternative, with less toxicity and lower costs.CONCLUSION: It is mandatory to validate theseearly results on the use on Enzalutamide monotherapyfor advanced prostate cancer, hormone-sensitive orcastration resistant, metastatic or not, but in the meantime,we wonder, why not?