Prostate cancer is the most frequent malignant tumor in male. Despite its incidence increased in the last few years, the mortality is gradually decreasing, even in patients with metastatic prostate cancer (mPC). Unfortunately, prolongation of survival leads to the exhaustion of therapeutic chances. Therefore, patients with good performance status (PS) may remain out of further active treatments. We report the clinical case of a 71-year-old patient with symptomatic metastatic castration-resistant prostate cancer (mCRPC) and good PS who progressed after multiple treatments and started a hormonal therapy with megestrol acetate (MA). MA is a synthetic progestin used for treatment of mPC in 1990s since it was shown to have an antiandrogen activity. In our case, MA managed to overcome resistance to androgen receptor-targeted agents (ARTAs), getting a dramatic biochemical and radiological response and a rapid improvement of symptoms. Our clinical case shows that MA is an interesting therapeutic option especially in long-survivor patients with mCRPC and a long progression-free survival during ARTAs therapies.