We read with interest the report from Richards and colleagues (1) on the potential interactions of abiraterone, eplerenone, and prednisolone with wild-type and mutant androgen receptor (AR). Abiraterone is a CYP17A1 inhibitor that blocks androgen biosynthesis in the testes, adrenals, and castration-resistant prostate cancer (CRPC) tumors, producing androgen ablation with significant clinical benefit in patients with metastatic CRPC. The current report (1) and other studies (2) suggesting that abiraterone downregulates AR expression and produces antiandrogen activity beyond androgen depletion merit further investigation.

The suppression of adrenal steroid biosynthesis via abiraterone inhibition of CYP17A1 reduces circulating cortisol, with compensatory release of adrenocorticotropic hormone (3). This induces increased adrenal secretion of mineralocorticoids that can contribute to hypokalemia and hypertension. These manifestations of mineralocorticoid excess are managed by coadministration of low-dose prednisone (a prodrug of prednisolone) in patients treated with abiraterone acetate.

Richards and colleagues reported that prednisolone activated the AR in cells transfected with T877A-mutant AR with an EC50 of 25.1 μmol/L. This suggested that coadministration of prednisolone with abiraterone acetate could contribute to disease progression. However, the EC50 is much higher than the plasma concentrations of prednisolone (4–305 nmol/L) measured in 15 patients with CRPC receiving abiraterone acetate plus prednisolone. Furthermore, the authors extrapolated the reported prednisolone plasma concentrations to a prior publication on the in vitro androgen agonist activity of glucocorticoids at nanomolar concentrations in a cell line bearing an AR ligand-binding domain double mutation (T877A plus L701H) to ascribe clinical significance (4). We feel that this comparison is inappropriate in relation to the current findings and the interpretation of the findings related to abiraterone acetate therapy. The prevalence of this double mutation is unknown without established clinical relevance.

The authors also reported findings using spironolactone and eplerenone, which produced androgen agonist activity in vitro in cells transfected with wild-type (spironolactone only) or mutant AR at concentrations relevant to clinical activity. The report suggested that this could contribute to disease progression if these drugs were used in patients with prostate cancer. However, neither agent is proposed for use with abiraterone acetate to ameliorate symptoms of mineralocorticoid excess.

Abiraterone acetate was studied in conjunction with low-dose prednisone/prednisolone in registration trials leading to approval (5); only prednisone/prednisolone, not spironolactone or eplerenone, are specified in approved labeling. Given the high concentrations of prednisolone investigated in the reported in vitro studies, the clinical significance of the findings is not obvious.

D. End is employed as Director of Johnson and Johnson/Janssen and has ownership interest (including patents) in Johnson and Johnson. A. Molina is the Vice President of Johnson and Johnson and has ownership interest (including patents) in the stock options of Johnson and Johnson. No potential conflicts of interest were disclosed by the other authors.

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