ient's baseline (see section 4.2). Patients with elevations of ALT or AST > 20 x ULN were not re-treated. The safety of re-treatment in such patients is unknown. The mechanism for hepatotoxicity is not understood.
4.9 Overdose
There have been no reports of overdose during clinical studies.
There is no specific antidote. In the event of an overdose, administration should be withheld and general supportive measures undertaken, including monitoring for arrhythmias, hypokalaemia and for signs and symptoms of fluid retention. Liver function also should be assessed.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: endocrine therapy, other hormone antagonists and related agents, ATC code: L02BX03
Mechanism of action
Abiraterone acetate (ZYTIGA) is converted in vivo to abiraterone, an androgen biosynthesis inhibitor. Specifically, abiraterone selectively inhibits the enzyme 17α-hydroxylase/C17,20-lyase (CYP17). This enzyme is expressed in and is required for androgen biosynthesis in testicular, adrenal and prostatic tumour tissues. CYP17 catalyses the conversion of pregnenolone and progesterone into testosterone precursors, DHEA and androstenedione, respectively, by 17α-hydroxylation and cleavage of the C17,20 bond. CYP17 inhibition also results in increased mineralocorticoid production by the adrenals (see section 4.4).
Androgen-sensitive prostatic carcinoma responds to treatment that decreases androgen levels. Androgen deprivation therapies, such as treatment with LHRH agonists or orchiectomy, decrease androgen production in the testes but do not affect androgen production by the adrenals or in the tumour. Treatment with ZYTIGA decreases serum testosterone to undetectable levels (using commercial assays) when given with LHRH agonists (or orchiectomy).
Pharmacodynamic effects
ZYTIGA decreases serum testosterone and other androgens to levels lower than those achieved by the use of LHRH agonists alone or by orchiectomy. This results from the selective inhibition of the CYP17 enzyme required for androgen biosynthesis. Prostate specific antigen (PSA) serves as a biomarker in patients with prostate cancer. In a phase 3 clinical study of patients who failed prior chemotherapy with taxanes, 38% of patients treated with ZYTIGA, versus 10% of patients treated with placebo, had at least a 50% decline from baseline in PSA levels.
Clinical efficacy and safety
Efficacy was established in a randomised placebo-controlled multicentre phase 3 clinical study of patients with metastatic advanced prostate cancer (castration resistant prostate cancer) who had received prior chemotherapy containing a taxane. Enrolled patients had received prior docetaxel. Patients were not required to show disease progression on docetaxel, as toxicity from this chemotherapy may have led to discontinuation. Patients were using an LHRH agonist or were previously treated with orchiectomy (N=1,195). In the active treatment arm, ZYTIGA was administered at a dose of 1,000 mg daily in combination with low dose prednisone or prednisolone 5 mg twice daily (N=797). Control patients received placebo and low dose prednisone or prednisolone 5 mg twice daily (N=398).
Changes in either radiographic findings or PSA serum concentration independently do not always predict clinical benefit. Therefore, in this study it was recommended that patients be maintained on their study treatments until there |
