Objectives: Disease progression in metastatic castration-resistant prostate cancer (mCRPC) is dependent on androgen signaling. This case describes the complex adaptive androgen signaling mechanisms in mCRPC and illustrates that caution should be exercised when treating these patients with drugs influencing the androgen axis. Methods: Single case report and review of the literature. Results: We report the case of an 86-year-old?man with mCRPC, treated with the secondary antihormonal agent abiraterone acetate. Following association of spironolactone to deal with symptoms related to mineralocorticoid excess, biochemical and radiographic disease progression occurred. Spironolactone was discontinued and 8?months after withdrawal, the patient continues to show a?biochemical response to abiraterone. Conclusions: Although spironolactone generally exerts anti-androgenic?effects, experimental evidence exists that it acts as an androgen receptor agonist in an androgen-depleted?environment, capable of inducing prostate cancer proliferation. This is supported by the observations described in this case report. Therefore, spironolactone should be avoided in prostate cancer patients suffering from treatment-associated?side effects of abiraterone.