EARLY IN 2018, abiraterone acetate tablets (Zytiga) in combination with prednisone were approved for the treatment of metastatic high-risk castration-sensitive prostate cancer.1,2
Supporting Efficacy Data
APPROVAL WAS based on the findings of the phase III LATITUDE trial, in which 1,199 patients with newly diagnosed disease who had not received prior cytotoxic chemotherapy were randomized to receive oral abiraterone acetate at 1,000 mg once daily with prednisone at 5 mg once daily (n = 597) or oral placebos once daily (n = 602).2,3 Patients in both groups received gonadotropin-releasing hormone (GnRH) treatment or had bilateral orchiectomy. High-risk disease was defined as at least two of three risk factors: total Gleason score ≥ 8, presence of at least three lesions on a bone scan, and evidence of measurable visceral metastases. Patients with significant cardiac, adrenal, or hepatic dysfunction or liver metastases were excluded. The primary outcome measure was overall survival.
At a prespecified interim analysis (conducted after 406 deaths), the median overall survival was not estimable in the abiraterone group vs 34.7 months in the placebos group (hazard ratio [HR] = 0.621, P < .0001). Subsequent therapies were received by 21% of the abiraterone group vs 41% of the placebos group, including cytotoxic chemotherapy, abiraterone acetate, enzalutamide (Xtandi), and systemic radiotherapy. The median time to initiation of chemotherapy was not reached in the abiraterone group vs 38.9 months in the placebos group (HR = 0.44, P < .0001).
How It Works
ABIRATERONE ACETATE is converted in vivo to abiraterone, an androgen biosynthesis inhibitor, which inhibits 17 α-hydroxylase/C17, 20-lyase (CYP17). This enzyme is expressed in testicular, adrenal, and prostatic tumor tissues and is required for androgen biosynthesis. CYP17 catalyzes two sequential reactions: the conversion of pregnenolone and progesterone to their 17 α-hydroxy derivatives by 17 α-hydroxylase activity and the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, respectively, by C17, 20-lyase activity. DHEA and androstenedione are androgens and precursors of testosterone. Inhibition of CYP17 by abiraterone can also result in increased mineralocorticoid production by the adrenals. Androgen-sensitive prostatic carcinoma responds to treatment that decreases androgen levels. Androgen-deprivation therapies, such as treatment with GnRH agonists or orchiectomy, decrease androgen production in the testes but do not affect androgen production by the adrenals or in the tumor. Abiraterone decreases serum testosterone and other androgens.
How It Is Used
THE RECOMMENDED dose of abiraterone acetate is 1,000 mg once daily with oral prednisone at 5 mg once daily. The drug should be taken on an empty stomach, either 1 hour before or 2 hours after a meal. Patients should also receive a GnRH analog concurrently or should have had bilateral orchiectomy.
Abiraterone should not be used in patients with severe hepatic impairment. In patients with moderate hepatic impairment, the starting dose should be reduced to 250 mg once daily, and alanine transaminase (ALT), aspartate transaminase (AST), and bilirubin levels should 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. Treatment should be discontinued for elevations in ALT or AST > 5 × the upper limit of normal (ULN) or total bilirubin > 3 × ULN.
If hepatotoxicity occurs during treatment, treatment should be interrupted and can be resumed after resolution of liver function tests at a dose of 750 mg daily and at 500 mg daily for subsequent recurrence; treatment should be discontinued for recurrence at a dose of 500 mg. In patients resuming treatment, serum transaminases and bilirubin must be monitored at a minimum of every 2 weeks for 3 months and monthly thereafter. Abiraterone should be permanently discontinued in patients who develop a concurrent elevation of ALT > 3 × ULN and total bilirubin > 2 × ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation.
Concomitant use of abiraterone with strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) should be avoided. If concomitant use cannot be avoided, the abiraterone dosing frequency should be increased to twice a day during coadministration (eg, from 1,000 mg once daily to 1,000 mg twice daily). If the strong CYP3A4 inducer is discontinued, the abiraterone dose should be reduced to the previous dose and frequency.
Concomitant use of abiraterone with substrates of CYP2D6 with a narrow therapeutic index (eg, thioridazine) should also be avoided. If alternative treatments cannot be used, dose reduction of the concomitant CYP2D6 substrate drug should be considered.
IN CLINICAL TRIALS of abiraterone, the most common adverse events of any grade (≥ 10%) were fatigue, arthralgia, hypertension, nausea, edema, hypokalemia, hot flush, diarrhea, vomiting, upper respiratory infection, cough, and headache. The most common laboratory abnormalities of any grade (> 20%) were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, and hypokalemia.
Abiraterone acetate carries warnings/precautions for mineralocorticoid excess; adrenocortical insufficiency; and hepatotoxicity, which can be severe and fatal. Patients with cardiovascular disease must be closely monitored, with hypertension being controlled and hypokalemia corrected before treatment. Blood pressure, serum potassium, and symptoms of fluid retention must be monitored at least monthly. Patients should be monitored for symptoms and signs of adrenocortical insufficiency; increased dosage of corticosteroids may be indicated before, during, and after stressful situations. Liver function must be regularly monitored, as previously discussed, and abiraterone dosing should be modified, interrupted, or discontinued as recommended. Abiraterone is contraindicated during pregnancy. ■
1. U.S. Food and Drug Administration: FDA approves abiraterone acetate in combination with prednisone for high-risk metastatic castration-sensitive prostate cancer. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm596015.htm. Accessed July 6, 2018.
2. Zytiga (abiraterone acetate) tablets prescribing information, Janssen Pharmaceutical Companies, February 2018. Available at www.accessdata.fda.gov/ drugsatfda_docs/label/2018/202379s024lbl.pdf. Accessed July 6, 2018.
3. Fizazi K, Tran N, Fein L, et al: Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med 377:352-360, 2017.
REPORT ADVERSE EVENTS
Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/ medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).