Abiraterone acetate for prostate cancer: a new era of hormonal therapies.

T herapies targeting the androgen receptor (AR) axis have constituted the Holy Grail in the management of advanced prostate cancer for seven decades. These hormonal therapies have traditionally taken two main forms: those that suppress gonadal androgen synthesis (e.g., the gonadotropin releasing hormone agonists/antagonists, such as leuprolide), and those that inhibit the AR directly (e.g., the anti-androgens, such as bicalutamide). However, although the vast majority of patients with prostate cancer initially respond favorably to androgen-ablative therapies (manifested by tumor regressions and symptomatic improvements), all patients will eventually develop further disease progression after a median of 18–24 months. This transformed disease state, known as castration-resistant prostate cancer (CRPC), is invariably fatal. Until recently, life-prolonging therapies for patients with metastatic CRPC (mCRPC) were limited, and consisted only of docetaxel (Taxotere) chemotherapy (U.S. Food and Drug Administration (FDA)-approved in 2004 as first-line chemotherapy for mCRPC). However, in 2010, two additional modalities were added to our armamentarium of FDAapproved treatment options for men with mCRPC: the autologous immunotherapy product sipuleucel-T (Provenge) (indicated for men with asymptomatic or minimally symptomatic disease) and the taxane chemotherapy agent cabazitaxel (Jevtana) (indicated for men progressing after docetaxel). In that same year, the bone-targeting agent denosumab (Xgeva) was also FDA-approved for the prevention of skeletal-related events (bone fractures, spinal cord compression, malignant hypercalcemia, the need for surgery, or the need for radiotherapy) in men with mCRPC, after demonstrating superiority over the bisphosphonate drug, zoledronic acid. It is now known that androgen signaling remains active even in patients with CRPC, and that the AR is a critical mediator of the transition to the castration-resistant state. One mechanism by which CRPC maintains AR signaling is by overexpressing CYP17, a key enzyme in extra-gonadal (adrenal, prostatic and intratumoral) androgen biosynthesis. In the 26 May 2011 issue of the New England Journal of Medicine, de Bono and colleagues reported the results of a multicenter phase 3 trial evaluating the oral CYP17 inhibitor abiraterone acetate (1000 mg daily, administered together with prednisone 10 mg daily) compared against placebo and prednisone in men with mCRPC with progression after prior docetaxel chemotherapy. The trial met its primary end point, demonstrating a 35% reduction in the relative risk of death among men receiving abiraterone compared to those receiving placebo, with a median survival of 14.8 versus 10.9 months respectively (P,0.0001). In addition, when compared against placebo, abiraterone treatment resulted in more frequent reductions in prostate-specific antigen (PSA) level by o50% (29% vs. 6%; P,0.0001), more frequent objective radiographic responses (14% vs. 3%; P,0.0001), longer time to PSA progression (defined as a o25% PSA increase from nadir) (10.2 vs. 6.6 months; P,0.0001) and longer radiographic progression-free survival (5.6 vs. 3.6 months; P,0.0001). Additional data presented at the 2011 American Society of Clinical Oncology Annual Meeting showed that treatment with abiraterone prolonged the time to the first skeletal-related event (10.0 vs. 5.0 months; P50.0006) and also provided pain relief and a delay in the time to pain progression (9.4 vs. 4.6 months; P50.0019). The results of this trial led to the FDA-approval of abiraterone acetate on 28 April 2011 for the treatment of men with mCRPC who had received prior docetaxelcontaining chemotherapy, the second drug to be approved in the postdocetaxel setting. Adverse events related to abiraterone acetate were generally tolerable, and consisted mainly of a feedback syndrome of secondary mineralocorticoid excess resulting in fluid retention/peripheral edema (31%), hypokalemia (17%) and hypertension (10%). Notably, these toxicities had been more prevalent in prior studies of abiraterone monotherapy, suggesting that these effects were partially mitigated by the concurrent administration of a corticosteroid (i.e., prednisone). Thirteen percent of abiraterone-treated men developed mild cardiac toxicities (mainly tachycardia, or atrial fibrillation). It is therefore recommended that abiraterone be used with caution in patients with a history of cardiovascular disease, symptomatic heart failure, or a left ventricular ejection fraction of ,50%. In addition, elevated liver transaminases were observed in 10% of abirateronetreated patients; two-thirds of these cases were grade 1 events. Abiraterone is contraindicated in patients with severe liver failure, and should be administered at a reduced dose (250 mg daily) in men with moderate hepatic impairment. For patients who develop hepatotoxicity during treatment, abiraterone should be held until recovery of the transaminitis, and treatment may be reinitiated at a reduced dose once hepatic function has resolved. Therapy should be discontinued permanently in men who develop severe hepatotoxicity. How does abiraterone compare to high-dose ketoconazole (600–1200 mg daily), a nonselective competitive inhibitor of CYP17? Although ketoconazole has not demonstrated a survival benefit in men with mCRPC, it is still commonly prescribed (although not Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21231, USA Correspondence: Dr ES Antonarakis (eantona1@ jhmi.edu) Asian Journal of Andrology (2011) 13, 663–664 2011 AJA, SIMM & SJTU. All rights reserved 1008-682X/11 $32.00