In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
On December 10, 2012, abiraterone acetate (Zytiga) received an expanded indication for use in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer.1,2 The initial indication was limited to patients who had previously received docetaxel-containing therapy.
Approval was based on a phase III trial in which 1,088 patients with metastatic castration-resistant prostate cancer who had not received prior cytotoxic chemotherapy were randomly assigned to abiraterone at 1,000 mg daily plus prednisone at 5 mg twice daily (n = 546) or placebo plus prednisone (n = 542).2,3 (See page 37 for more on this trial.) Patients had to have prostate-specific antigen or radiographic progression in soft tissue or bone and had to have ongoing androgen deprivation with a serum testosterone level of < 50 ng/dL. Patients with moderate to severe cancer pain or opiate use for cancer pain were excluded.
Overall, patients had a median age of 70 years, 95% were Caucasian, and ECOG performance status was 0 in 76% of patients and 1 in 24%. Treatment continued until radiographic or clinical disease progression, unacceptable toxicity, or withdrawal.
The coprimary endpoints were radiographic progression-free survival and overall survival. Median radiographic progression-free survival was not reached in the abiraterone group vs 8.3 months in the placebo group, representing a significant 57% reduction in risk for radiographic progression (hazard ratio [HR] = 0.43, P < .0001). At the third prespecified interim analysis, overall survival was prolonged in the abiraterone group (median, 35.3 vs 30.1 months, HR = 0.79, 95% confidence interval = 0.66–0.96), but these results did not cross the prespecified (O’Brien-Fleming) boundary for statistical significance. The finding of benefit was supported by statistically significant improvements in time to opiate use and time to cytotoxic chemotherapy in the abiraterone group.
How It Works
Abiraterone acetate is converted to abiraterone, an androgen biosynthesis inhibitor that inhibits CYP17 (17 α-hydroxylase/C17,20-lyase). This enzyme is expressed in testicular, adrenal, and prostatic tumor tissues and is required for biosynthesis of the androgen precursors of testosterone. In contrast, androgen deprivation therapies such as GnRH agonists or orchiectomy decrease androgen production in the testes but do not affect androgen production by the adrenals or in tumors.
How It Is Given
The recommended dose of abiraterone is 1,000 mg orally once daily in combination with prednisone at 5 mg twice daily. Abiraterone must be taken on an empty stomach. No food should be consumed for at least 2 hours before and for at least 1 hour after a dose. Exposure to abiraterone increases up to 10-fold when abiraterone acetate is taken with food.
The starting dose of abiraterone should be reduced to 250 mg/d in patients with moderate hepatic impairment, and ALT, AST, and bilirubin must be monitored prior to the start of treatment, every week for the first month, every 2 weeks for the following 2 months, and monthly thereafter in such patients. The drug should not be used in patients with severe hepatic impairment. If hepatotoxicity occurs during treatment, treatment should be interrupted and resumed after resolution of liver function abnormalities at a dose of 750 mg and at 500 mg for subsequent recurrence; treatment should be discontinued for recurrence of liver toxicity at a dose of 500 mg.
Abiraterone is a CYP2D6 inhibitor. Coadministration with drugs that are CYP2D6 substrates and that have a narrow therapeutic index should be avoided. If an alternative treatment cannot be used, caution should be exercised and a dose reduction of the concomitant CYP2D6 substrate should be considered.
Abiraterone should be used with caution in patients with a history of cardiovascular disease. In addition to being regularly monitored for hepatic function, patients should be regularly monitored for adrenocortical insufficiency and mineralocorticoid excess. Hypertension and hypokalemia should be controlled before starting treatment. Increased doses of corticosteroids may be required before, during, and after stressful situations.
Safety data are available from 1,333 patients with metastatic castration-resistant prostate cancer who received abiraterone plus prednisone and in 934 patients who received placebo plus prednisone in the current clinical trial and in the previous pivotal trial in patients with prior chemotherapy including docetaxel.
In this pooled analysis, adverse events that occurred in at least 10% of abiraterone recipients and more frequently (> 2% difference) than in placebo recipients were fatigue, joint swelling/discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection, and bone pain. The most common laboratory abnormalities (> 20%) that occurred more frequently (≥ 2%) in abiraterone patients were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT, and hypokalemia. Grade 3 or 4 adverse events occurred in 55% of abiraterone patients and 50% of placebo patients.
In the pooled analysis, cardiac failure occurred more frequently in abiraterone patients (2.1% vs 0.7%); grade 3 or 4 cardiac failure occurred in 1.6% of abiraterone patients, leading to five treatment discontinuations and two deaths, and in 0.2% of placebo patients, leading to no discontinuations and one death. The majority of arrhythmias detected were grade 1 or 2; there was one death associated with arrhythmia and one sudden death among abiraterone patents and no deaths in placebo patients. Adrenal insufficiency occurred in 0.5% of abiraterone patients and in 0.2% of placebo patients.
The median duration of treatment with abiraterone in the current trial was 13.8 months. In this trial, the most common adverse events of any grade in abiraterone patients (compared to those receiving placebo) were fatigue (39% vs 34%), joint swelling/discomfort (30% vs 25%), edema (25% vs 21%), constipation (23% vs 19%), hot flush (22% vs 18%), diarrhea (22% vs 18%), and hypertension (22% vs 13%). The most common grade 3 or 4 adverse events were hypertension (4%vs 3%), dyspnea (2% vs 1%), fatigue (2% vs 2%), and joint swelling/discomfort (2% vs 2%). The most common laboratory abnormalities of any grade were hyperglycemia (57% vs 51%), elevated ALT (42% vs 29%), lymphopenia (38% vs 32%), elevated AST (37% vs 29%), and hypernatremia (33% vs 25%). The most common grade 3 or 4 abnormalities were lymphopenia (9% vs 7%), hyperglycemia (6.5% vs 5%), elevated ALT (6% vs 1%), elevated AST (3% vs 1%), and hypokalemia (3% vs 2%).
The abiraterone label carries warnings/precautions for mineralocorticoid excess, adrenocortical insufficiency, hepatotoxicity, and food effect. The safety of abiraterone was not established in patients with left-ventricular ejection fraction < 50% or New York Heart Association (NYHA) class III or IV heart failure in the trial in previously treated patients or in patients with left-ventricular ejection fraction < 50% or NYHA class II to IV heart failure in the trial supporting the expanded indication. ■
1. U.S. Food and Drug Administration: Abiraterone acetate. Available at http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm331628.htm. Accessed January 3, 2013.
2. ZYTIGA® (abiraterone acetate) tablets prescribing information. Janssen Biotech, Inc, December 2012. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202379s005lbl.pdf. Accessed January 3, 2013.
3. Ryan CJ, Smith MR, de Bono JS, et al: Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 368:138-148, 2013.