Abiraterone (zytiga), a novel agent for the management of castration-resistant prostate cancer.

INTRODUCTION Prostate cancer is the second most common cancer diagnosed in men living in the U.S. The disease was expected to account for more than 28,000 deaths in 2012,1 and more than 241,700 new cases were expected to be diagnosed that year.2 Prostate cancer usually affects men after the age of 40. Besides age, other risk factors include ethnicity, dietary practices, and genetic predisposition.3 The highest incidence is seen in African-American patients, followed by Caucasian and Hispanic patients, respectively (Ta-ble 1).4 Prostate cancer is highly dependent on androgen levels. The testes secrete 95% of testosterone, and the remaining 5% is produced by the adrenal glands.5 The diagnosis is made by prostate-specifi c antigen (PSA) screening, a digital rectal examination, and genitourinary symptoms. A small percentage of men may present with symptoms of metastatic disease such as bone pain. PSA is a marker that is specifi c to the prostate. PSA levels may also be elevated in benign conditions such as benign prostatic hyperplasia (BPH). Cancerous tissue produces more PSA, thus making it a good diagnostic and prognostic biomarker. After an initial elevation in PSA levels, a biopsy is recommended to confi rm the diagnosis. As a result of the implementation of PSA screening in the U.S., almost 90% of cases are diagnosed at an early stage; however, up to 40% of men will develop metastasis.6 For most patients with metastasis, progression of the disease occurs despite treatment.6 The tumor-node-metastasis (TNM) staging system guides clinicians with initial therapy. Androgen-deprivation therapy (ADT) remains the mainstay of treatment.7 In metastatic disease, ADT is used alone or in combination with radiation therapy.8 Castration-resistant prostate cancer (CRPC) may develop regardless of surgical or pharmacological castration therapies.8,9 CRPC is currently managed with cytotoxic chemotherapy, with docetaxel (Taxotere, Sanofi ) remaining as the therapy of choice.10,11 Mitoxantrone (Novantrone, Serono/OSI) is an option for men who are not candidates for docetaxelbased regimens.10 Abiraterone acetate (Zytiga, Janssen Biotech) is a new cytochrome P450 (CYP) 17 inhibitor that was approved by the FDA in 2011 in combination with prednisone for CRPC in patients who have received prior docetaxel chemotherapy. It is also being studied in patients with earlier-stage prostate cancer and in women with metastatic breast cancer.12 In December 2012, Janssen received the FDA’s approval to market abiraterone preceding chemotherapy in men with CRPC.13 CLINICAL PHARMACOLOGY Abiraterone acetate is converted to abiraterone in vivo. Abiraterone inhibits 17α-hydroxylase CYP17, which is required for androgen biosynthesis and is expressed in testicular, adrenal, and prostatic tumor tissues. CYP17 serves as a catalyst for the conversion of pregnenolone and progesterone to their 17α-hydroxy derivatives and the formation of dehydroepiandrosterone (DHEA) and androstenedione. DHEA and androstenedione are precursors of testosterone. Inhibition of CYP17 at the sites outside of the testes provides advantages over traditional ADT.14 The administration of abiraterone may potentiate mineralocorticoid production by the adrenal glands via inhibition of CYP17. Increased mineralocorticoid synthesis occurs as a result of enhanced deoxycorticosterone conversion from pregnenolone. This may potentially lead to fl uid retention, hypertension, and hypokalemia.15