Castration-Resistant Prostate Cancer—Hormone Therapy Redux

South Texas Accelerated Research Therapeutics, The START Center for Cancer Care, San Antonio, TX

Androgen deprivation has been the mainstay in the treatment of advanced prostate cancer and is beyond a doubt the most effective therapeutic option; nearly all patients respond to initial androgen ablation therapy, and the duration of response is routinely measured in years, not months. Nonetheless, despite the effectiveness of hormone therapy, the majority of patients with advanced disease will develop evidence of progressive disease, heretofore termed androgen-independent or hormone-refractory prostate cancer.

In contrast to the effectiveness of hormone therapy, the benefits from docetaxel, the current chemotherapy for hormone-resistant prostate cancer, are less satisfactory. Only one half of patients will have a prostate-specific antigen (PSA) response; patients experience considerable hematologic and nonhematologic toxicities; and in randomized studies, the improvement on overall survival is a modest 4 months better than that of our past chemotherapy standard, mitoxantrone.The development of effective second-line hormonal treatment therefore has been much desired, but the current agents have left much to be desired. Nonsteroidal antiandrogens induce a PSA response in some patients, but it is usually of short duration. Ketoconazole is used as an inhibitor of corticosteroid biosynthesis to achieve a medical adrenalectomy, but in most clinician's hands it is not a particularly effective therapy and is frequently quite toxic.

It is within this context that some skepticism has greeted recent second-line hormone therapies, including the novel CYP17 inhibitor abiraterone or the novel androgen receptor inhibitor MDV3100. Abiraterone acetate, a CYP17 inhibitor prodrug, possesses potent 17-hydroxylase and C_17,20-lyase inhibitory action and interferes with androgen biosynthesis, not only in the adrenal gland, but also in peripheral tissues of castrate and noncastrate men, A misunderstanding of the mechanism of action of abiraterone acetate has led some clinicians to question whether this agent is really novel, or rather just a "super-ketoconazole."

In this issue of Journal of Clinical Oncology, Ryan e report a phase I study of orally administered abiraterone acetate. This article complements the results of four other published phase I dose escalation and activity studies that demonstrate the safety and potency of testosterone suppression, as well as the high level of antitumor activity, albeit as measured by PSA decline, of abiraterone acetate.  The activity noted in chemically or surgically castrate, ketoconazole-naïve patients reported in all these studies implies that abiraterone acetate is certainly a highly active agent, but does not address the skeptic's concern of whether it is an improvement over the currently available and often-used ketoconazole. The new information from this study, that antitumor activity is nearly equivalent in both ketoconazole-pretreated and naïve populations, may well address this skepticism. Furthermore, Ryan et al⁹ demonstrated that the previously described toxicities of hypertension and hypokalemia associated with abiraterone acetate, driven in part by the aforementioned mineralocorticoid excess, could be abrogated by the use of low-dose prednisone.

Based on the mechanism of action of abiraterone acetate, androgen biosynthesis inhibition, the clinical results from Ryan  and other reports imply that many patients with prostate cancer have considerable sensitivity to peripherally produced, low-level androgen stimulation.

The unaddressed food effect, efficacy, and dosing issues notwithstanding, the encouraging results in Ryan  and other studies of abiraterone acetate that demonstrate a high rate of durable PSA responses may change the current medical lexicon used to describe patients that do not respond to LHRH agonists or surgical castration: androgen-independent or hormone-refractory prostate cancer is neither androgen independent nor hormone refractory.