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Solid Tumors
Translating Basic Science into the Clinic: Approval of Abiraterone By William D. Figg, PharmD Molecular Pharmacology Section and the Clinical Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
O
n April 28, 2011, the US Food and Drug Administration (FDA) approved abiraterone acetate (Zytiga, Johnson & Johnson) for the treatment of metastatic castrationresistant prostate cancer (CRPC) for patients who have failed docetaxel therapy. Prostate cancer is a leading cause of cancer mortality and morbidity in the United States.1,2 Each year approximately 215,000 men are diagnosed and 32,000 men die of the disease. Androgen ablation is the cornerstone for the treatment of metastatic prostate cancer, as a result of Huggins and Hodges’ Nobel Prize–winning work published in 1941. Depletion of circulating androgens either through surgical or medical castration is the first therapeutic maneuver for men failing definitive therapy (radical prostatectomy or external beam radiation). For several decades it was believed that the progression following androgen-deprivation therapy (ADT) was resistant to further hormonal manipulations.3
The benefit was observed across multiple subgroups, such as performance status, sites of metastatic disease, and number of previous chemotherapy regimens received. This paradigm started to change when prostate cancer gene–expression studies found that androgen-receptor activated genes, which are normally downregulated during ADT, become reactivated on transition to CRPC.4,5 Furthermore, ADT strategies resulted in castrate concentrations of testosterone; however, it was found that low levels of circulating androgen persisted (mainly through peripheral conversion of adrenal steroids). In addition, gene upregulation is involved in androgen biosynthesis, including CYP 17.6-8 Intratumoral enzymes involved in the conversion of upstream precursors of testosterone and dihydrotestosterone became a molecular target. Clinical Trials Cytochrome p450c17 is involved in androgen biosynthesis by 17-alphahydroxylation of C21 steroids and cleavage of C17,20 bond of C21 steroids.3,9 These reactions are critical in the biosynthesis of dehydroepiandro-
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sterone and androstenedione. Abiraterone is a potent, selective, irreversible inhibitor of CYP 17A1.10 In the initial
phase 1 trial of abiraterone conducted in chemotherapy-naĂŻve CRPC patients, the drug was well tolerated. The dose
(1000 mg/day) used in the phase 2 trial was determined after a plateau in the pharmacodynamic effects was observed.
Now Approved
YERVOY
™
(ipilimumab)
INDICATION YERVOY is indicated for the treatment of unresectable or metastatic melanoma.
Important Safety Information WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS YERVOY can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immunemediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY. Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs) and thyroid function tests at baseline and before each dose. Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions. *NQPSUBOU 4BGFUZ *OGPSNBUJPO DPOUJOVFE PO BEKBDFOU QBHF
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