Endocrine therapy, other hormone antagonists and related agents. ATC Code:
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.
Mechanism of action:
Abiraterone acetate 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 Precautions).
Androgen-sensitive prostatic carcinoma responds to treatment that decreases androgen levels. Androgen deprivation therapies eg, 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).
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=1195). In the active treatment arm, Zytiga was administered at a dose of 1000 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 was PSA progression (confirmed 25% increase over the patient's baseline/nadir) together with protocol-defined radiographic progression and symptomatic or clinical progression. Patients with prior ketoconazole treatment for prostate cancer were excluded from this study. The primary efficacy endpoint was overall survival.
The median age of enrolled patients was 69 years (range 39-95). The number of patients treated with Zytiga by racial group was Caucasian 737 (93.2%), Black 28 (3.5%), Asian 11 (1.4%) and other 14 (1.8%). Eleven percent of patients enrolled had an ECOG performance score of 2; 70% had radiographic evidence of disease progression with or without PSA progression; 70% had received one prior cytotoxic chemotherapy and 30% received two. Liver metastasis was present in 11% of patients treated with Zytiga.
In a planned analysis conducted after 552 deaths were observed, 42% (333 of 797) of patients treated with Zytiga compared with 55% (219 of 398) of patients treated with placebo, had died. A statistically significant improvement in median overall survival was seen in patients treated with Zytiga. (See Table 1).
Click on icon to see table/diagram/image
At all evaluation time points after the initial few months of treatment, a higher proportion of patients treated with Zytiga remained alive, compared with the proportion of patients treated with placebo (see Figure 1).
Click on icon to see table/diagram/image
Subgroup survival analyses showed a consistent survival benefit for treatment with Zytiga (see Figure 2).
Click on icon to see table/diagram/image
In addition to the observed improvement in overall survival, all secondary study endpoints favoured Zytiga and were statistically significant after adjusting for multiple testing as follows:
Patients receiving Zytiga demonstrated a significantly higher total PSA response rate (defined as a ≥50% reduction from baseline), compared with patients receiving placebo, 38% versus 10%, p<0.0001.
The median time to PSA progression was 10.2 months for patients treated with Zytiga and 6.6 months for patients treated with placebo (HR=0.58; 95% CI: [0.462; 0.728], p<0.0001).
The median radiographic progression-free survival was 5.6 months for patients treated with Zytiga and 3.6 months for patients who received placebo (HR=0.673; 95% CI: [0.585; 0.776], p<0.0001).
The proportion of patients with pain palliation was statistically significantly higher in the Zytiga group than in the placebo group (44% versus 27%, p=0.0002). A responder for pain palliation was defined as a patient who experienced at least a 30% reduction from baseline in the BPI-SF worst pain intensity score over the last 24 hrs without any increase in analgesic usage score observed at 2 consecutive evaluations four weeks apart. Only patients with a baseline pain score of ≥4 and at least 1 post-baseline pain score were analysed (N=512) for pain palliation.
A lower proportion of patients treated with Zytiga had pain progression compared to patients taking placebo at 6 (22% versus 28%), 12 (30% versus 38%) and 18 months (35% versus 46%). Pain progression was defined as an increase from baseline of ≥30% in the BPI-SF worst pain intensity score over the previous 24 hrs without a decrease in analgesic usage score observed at 2 consecutive visits, or an increase of ≥30% in analgesic usage score observed at 2 consecutive visits. The time to pain progression at the 25th percentile was 7.4 months in the Zytiga group, versus 4.7 months in the placebo group.
A lower proportion of patients in the Zytiga group had skeletal-related events compared with the placebo group at 6 months (18% versus 28%), 12 months (30% versus 40%) and 18 months (35% versus 40%). The time to 1st skeletal-related event at the 25th percentile in the Zytiga group was twice that of the control group at 9.9 months versus 4.9 months. A skeletal-related event was defined as a pathological fracture, spinal cord compression, palliative radiation to bone or surgery to bone.
Following administration of abiraterone acetate, the pharmacokinetics of abiraterone and abiraterone acetate have been studied in healthy subjects, patients with metastatic advanced prostate cancer and subjects without cancer with hepatic or renal impairment. Abiraterone acetate is rapidly converted in vivo
to abiraterone, an androgen biosynthesis inhibitor (see Pharmacology under Actions).
Following oral administration of abiraterone acetate in the fasting state, the time to reach maximum plasma abiraterone concentration is approximately 2 hrs.
Administration of abiraterone acetate with food, compared with administration in a fasted state, results in up to a 10-fold (AUC) and up to a 17-fold (Cmax
) increase in mean systemic exposure of abiraterone, depending on the fat content of the meal. Given the normal variation in the content and composition of meals, taking Zytiga with meals has the potential to result in highly variable exposures. Therefore, Zytiga must not be taken with food. It should be taken at least 2 hrs after eating and no food should be eaten for at least 1 hr after taking Zytiga. The tablets should be swallowed whole with water (see Dosage & Administration).
The plasma protein binding of 14
C-abiraterone in human plasma is 99.8%. The apparent volume of distribution is approximately 5630 one, suggesting that abiraterone extensively distributes to peripheral tissues.
Following oral administration of 14
C-abiraterone acetate as capsules, abiraterone acetate is hydrolysed to abiraterone, which then undergoes metabolism including sulphation, hydroxylation and oxidation primarily in the liver. The majority of circulating radioactivity (approximately 92%) is found in the form of metabolites of abiraterone. Of 15 detectable metabolites, 2 main metabolites, abiraterone sulphate and N-oxide abiraterone sulphate, each represents approximately 43% of total radioactivity.
The mean t½
of abiraterone in plasma is approximately 15 hrs based on data from healthy subjects. Following oral administration of 14
C-abiraterone acetate 1000 mg, approximately 88% of the radioactive dose is recovered in faeces and approximately 5% in urine. The major compounds present in faeces are unchanged abiraterone acetate and abiraterone (approximately 55% and 22% of the administered dose, respectively).
Patients with Hepatic Impairment:
The pharmacokinetics of abiraterone acetate was examined in subjects with preexisting mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) and in healthy control subjects. Systemic exposure to abiraterone after a single oral 1000-mg dose increased by approximately 11% and 260% in subjects with mild and moderate preexisting hepatic impairment, respectively. The mean t½
of abiraterone is prolonged to approximately 18 hrs in subjects with mild hepatic impairment and to approximately 19 hrs in subjects with moderate hepatic impairment. No dose adjustment is necessary for patients with preexisting mild hepatic impairment. Zytiga should not be used in patients with preexisting moderate or severe hepatic impairment (see Dosage & Administration).
For patients who develop hepatotoxicity during treatment, suspension of treatment and dose adjustment may be required (see Dosage & Administration).
Patients with Renal Impairment:
The pharmacokinetics of abiraterone acetate was compared in patients with end-stage renal disease on a stable haemodialysis schedule versus matched control subjects with normal renal function. Systemic exposure to abiraterone after a single oral 1000-mg dose did not increase in subjects with end-stage renal disease on dialysis. Administration in patients with renal impairment, including severe renal impairment, does not require dose reduction. However, there is no clinical experience in patients with prostate cancer and severe renal impairment. Caution is advised in these patients.
Toxicology: Preclinical Safety Data:
Developmental or reproductive toxicology studies were not conducted with abiraterone acetate; however, in all animal toxicity studies, circulating testosterone levels were significantly reduced. As a result, reduction in organ weights and morphological and/or histopathological changes in the reproductive organs, and the adrenal, pituitary and mammary glands were observed. All changes showed complete or partial reversibility. The changes in the reproductive organs and androgen-sensitive organs are consistent with the pharmacology of abiraterone. All treatment-related hormonal changes reversed or were shown to be resolving after a 4-week recovery period. Zytiga is contraindicated in pregnancy (see Contraindications).
Aside from reproductive organ changes seen in all animal toxicology studies, nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity. Carcinogenicity studies were not conducted.