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Zytiga

"The U.S. Food and Drug Administration today expanded the approved use of Zytiga (abiraterone acetate) to treat men with late-stage (metastatic) castration-resistant prostate cancer prior to receiving chemotherapy.

The FDA initially appr"...

Zytiga

CLINICAL PHARMACOLOGY

Mechanism Of Action

Abiraterone acetate (ZYTIGA) is converted in vivo to abiraterone, an androgen biosynthesis inhibitor, that 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: 1) the conversion of pregnenolone and progesterone to their 17α-hydroxy derivatives by 17α-hydroxylase activity and 2) the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, respectively, by C17, 20 lyase activity. DHEA and androstenedione are androgens and are precursors of testosterone. Inhibition of CYP17 by abiraterone can also result in increased mineralocorticoid production by the adrenals [see WARNINGS AND PRECAUTIONS].

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.

ZYTIGA decreased serum testosterone and other androgens in patients in the placebo-controlled phase 3 clinical trial. It is not necessary to monitor the effect of ZYTIGA on serum testosterone levels.

Changes in serum prostate specific antigen (PSA) levels may be observed but have not been shown to correlate with clinical benefit in individual patients.

Pharmacokinetics

Following administration of abiraterone acetate, the pharmacokinetics of abiraterone and abiraterone acetate have been studied in healthy subjects and in patients with metastatic castration-resistant prostate cancer (CRPC). In vivo, abiraterone acetate is converted to abiraterone. In clinical studies, abiraterone acetate plasma concentrations were below detectable levels ( < 0.2 ng/mL) in > 99% of the analyzed samples.

Absorption

Following oral administration of abiraterone acetate to patients with metastatic CRPC, the median time to reach maximum plasma abiraterone concentrations is 2 hours. Abiraterone accumulation is observed at steady-state, with a 2-fold higher exposure (steady-state AUC) compared to a single 1,000 mg dose of abiraterone acetate.

At the dose of 1,000 mg daily in patients with metastatic CRPC, steady-state values (mean ± SD) of Cmax were 226 ± 178 ng/mL and of AUC were 993 ± 639 ng.hr/mL. No major deviation from dose proportionality was observed in the dose range of 250 mg to 1,000 mg. However, the exposure was not significantly increased when the dose was doubled from 1,000 to 2,000 mg (8% increase in the mean AUC).

Systemic exposure of abiraterone is increased when abiraterone acetate is administered with food. Abiraterone Cmax and AUC0-∞ were approximately 7-and 5-fold higher, respectively, when abiraterone acetate was administered with a low-fat meal (7% fat, 300 calories) and approximately 17-and 10-fold higher, respectively, when abiraterone acetate was administered with a high-fat (57% fat, 825 calories) meal. Given the normal variation in the content and composition of meals, taking ZYTIGA with meals has the potential to result in increased and highly variable exposures. Therefore, no food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. The tablets should be swallowed whole with water [see DOSAGE AND ADMINISTRATION].

Distribution and Protein Binding

Abiraterone is highly bound ( > 99%) to the human plasma proteins, albumin and alpha-1 acid glycoprotein. The apparent steady-state volume of distribution (mean ± SD) is 19,669 ± 13,358 L. In vitro studies show that at clinically relevant concentrations, abiraterone acetate and abiraterone are not substrates of P-glycoprotein (P-gp) and that abiraterone acetate is an inhibitor of P-gp. No studies have been conducted with other transporter proteins.

Metabolism

Following oral administration of 14C-abiraterone acetate as capsules, abiraterone acetate is hydrolyzed to abiraterone (active metabolite). The conversion is likely through esterase activity (the esterases have not been identified) and is not CYP mediated. The two main circulating metabolites of abiraterone in human plasma are abiraterone sulphate (inactive) and N-oxide abiraterone sulphate (inactive), which account for about 43% of exposure each. CYP3A4 and SULT2A1 are the enzymes involved in the formation of N-oxide abiraterone sulphate and SULT2A1 is involved in the formation of abiraterone sulphate.

Excretion

In patients with metastatic CRPC, the mean terminal half-life of abiraterone in plasma (mean ± SD) is 12 ± 5 hours. Following oral administration of 14C-abiraterone acetate, approximately 88% of the radioactive dose is recovered in feces and approximately 5% in urine. The major compounds present in feces are unchanged abiraterone acetate and abiraterone (approximately 55% and 22% of the administered dose, respectively).

Patients with Hepatic Impairment

The pharmacokinetics of abiraterone was examined in subjects with baseline mild (n=8) or moderate (n=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. Systemic exposure to abiraterone after a single oral 1,000 mg dose given under fasting conditions increased approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively. The mean half-life of abiraterone is prolonged to approximately 18 hours in subjects with mild hepatic impairment and to approximately 19 hours in subjects with moderate hepatic impairment.

In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe (n=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone increased by approximately 7-fold in subjects with severe baseline hepatic impairment compared to subjects with normal hepatic function. In addition, the mean protein binding was found to be lower in the severe hepatic impairment group compared to the normal hepatic function group, which resulted in a two-fold increase in the fraction of free drug in patients with severe hepatic impairment.[see DOSAGE AND ADMINISTRATION and Use In Specific Populations].

Patients with Renal Impairment

The pharmacokinetics of abiraterone were examined in patients with end-stage renal disease (ESRD) on a stable hemodialysis schedule (N=8) and in matched control subjects with normal renal function (N=8). In the ESRD cohort of the trial, a single 1,000 mg ZYTIGA dose was given under fasting conditions 1 hour after dialysis, and samples for pharmacokinetic analysis were collected up to 96 hours post dose. Systemic exposure to abiraterone after a single oral 1,000 mg dose did not increase in subjects with end-stage renal disease on dialysis, compared to subjects with normal renal function [see Use in Specific Populations].

Drug Interactions

In vitro studies with human hepatic microsomes showed that abiraterone is a strong inhibitor of CYP1A2, CYP2D6 and CYP2C8 and a moderate inhibitor of CYP2C9, CYP2C19 and CYP3A4/5.

In an in vivo drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8-and 2.9-fold, respectively when dextromethorphan 30 mg was given with abiraterone acetate 1,000 mg daily (plus prednisone 5 mg twice daily). The AUC for dextrorphan, the active metabolite of dextromethorphan, increased approximately 1.3 fold [see DRUG INTERACTIONS].

In a clinical study to determine the effects of abiraterone acetate 1,000 mg daily (plus prednisone 5 mg twice daily) on a single 100 mg dose of the CYP1A2 substrate theophylline, no increase in systemic exposure of theophylline was observed.

Abiraterone is a substrate of CYP3A4, in vitro. In a clinical pharmacokinetic interaction study of healthy subjects pretreated with a strong CYP3A4 inducer (rifampin, 600 mg daily for 6 days) followed by a single dose of abiraterone acetate 1,000 mg, the mean plasma AUC∞ of abiraterone was decreased by 55% [see DRUG INTERACTIONS].

In a separate clinical pharmacokinetic interaction study of healthy subjects, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone [see DRUG INTERACTIONS].

QT Prolongation

In a multi-center, open-label, single-arm trial, 33 patients with metastatic CRPC received ZYTIGA orally at a dose of 1,000 mg once daily at least 1 hour before or 2 hours after a meal in combination with prednisone 5 mg orally twice daily. Assessments up to Cycle 2 Day 2 showed no large changes in the QTc interval (i.e., > 20 ms) from baseline. However, small increases in the QTc interval (i.e., < 10 ms) due to abiraterone acetate cannot be excluded due to study design limitations.

Animal Toxicology And/Or Pharmacology

In 13-and 26-week studies in rats and 13-and 39-week studies in monkeys, a reduction in circulating testosterone levels occurred with abiraterone acetate at approximately one half the human clinical exposure based on AUC. As a result, decreases in organ weights and toxicities were observed in the male and female reproductive system, adrenal glands, liver, pituitary (rats only), and male mammary glands. The changes in the reproductive organs are consistent with the antiandrogenic pharmacological activity of abiraterone acetate. A dose-dependent increase in cataracts was observed in rats at 26 weeks starting at > 50 mg/kg/day (similar to the human clinical exposure based on AUC). In the 39-week monkey study, no cataracts were observed at higher doses (2 times greater than the clinical exposure based on AUC). All other toxicities associated with abiraterone acetate reversed or were partially resolved after a 4-week recovery period.

Clinical Studies

The efficacy and safety of ZYTIGA in patients with metastatic castration-resistant prostate cancer (CRPC) that has progressed on androgen deprivation therapy was demonstrated in two randomized, placebo-controlled, multicenter phase 3 clinical trials. Patients with prior ketoconazole treatment for prostate cancer and a history of adrenal gland or pituitary disorders were excluded from these trials.

Study 1

Patients With Metastatic Crpc Who Had Received Prior Docetaxel Chemotherapy:

A total of 1195 patients were randomized 2:1 to receive either ZYTIGA orally at a dose of 1,000 mg once daily in combination with prednisone 5 mg orally twice daily (N=797) or placebo once daily plus prednisone 5 mg orally twice daily (N=398). Patients randomized to either arm were to continue treatment until disease progression (defined as a 25% increase in PSA over the patient's baseline/nadir together with protocol-defined radiographic progression and symptomatic or clinical progression), initiation of new treatment, unacceptable toxicity or withdrawal.

The following patient demographics and baseline disease characteristics were balanced between the treatment arms. The median age was 69 years (range 39-95) and the racial distribution was 93.3% Caucasian, 3.6% Black, 1.7% Asian, and 1.6% Other. Eighty-nine percent of patients enrolled had an ECOG performance status score of 0-1 and 45% had a Brief Pain Inventory-Short Form score of ≥ 4 (patient's reported worst pain over the previous 24 hours). Ninety percent of patients had metastases in bone and 30% had visceral involvement. Seventy percent of patients had radiographic evidence of disease progression and 30% had PSA-only progression. Seventy percent of patients had previously received one cytotoxic chemotherapy regimen and 30% received two regimens.

The protocol pre-specified interim analysis was conducted after 552 deaths and showed a statistically significant improvement in overall survival in patients treated with ZYTIGA compared to patients in the placebo arm (Table 5 and Figure 1). An updated survival analysis was conducted when 775 deaths (97% of the planned number of deaths for final analysis) were observed. Results from this analysis were consistent with those from the interim analysis (Table 5).

Table 5: Overall Survival of Patients Treated with Either ZYTIGA or Placebo in Combination with Prednisone in Study 1 (Intent-to-Treat Analysis)

  ZYTIGA
(N=797)
Placebo
(N=398)
Primary Survival Analysis
  Deaths(%) 333 (42%) 219 (55%)
  Mediansurvival (months) (95% CI) 14.8 (14.1, 15.4) 10.9 (10.2, 12.0)
  p-value1 < 0.0001
  Hazard ratio (95% CI)2 0.646 (0.543, 0.768)
Updated Survival Analysis
  Deaths(%) 501 (63%) 274 (69%)
  Median survival (months) (95% CI) 15.8 (14.8, 17.0) 11.2 (10.4, 13.1)
  Hazard ratio (95% CI)2 0.740 (0.638, 0.859)
1P-value is derived from a log-rank test stratified by ECOG performance status score (0-1 vs. 2), pain score (absent vs. present), number of prior chemotherapy regimens (1 vs. 2), and type of disease progression (PSA only vs. radiographic).
2Hazard Ratio is derived from a stratified proportional hazards model. Hazard ratio < 1 favors ZYTIGA

Figure 1: Kaplan-Meier Overall Survival Curves in Study 1 (Intent-to-Treat Analysis)

Kaplan-Meier Overall Survival Curves in Study 1 - Illustration

Study 2

Patients With Metastatic Crpc Who Had Not Received Prior Cytotoxic Chemotherapy

In Study 2, 1088 patients were randomized 1:1 to receive either ZYTIGA at a dose of 1,000 mg once daily (N=546) or Placebo once daily (N=542). Both arms were given concomitant prednisone 5 mg twice daily. Patients continued treatment until radiographic or clinical (cytotoxic chemotherapy, radiation or surgical treatment for cancer, pain requiring chronic opioids, or ECOG performance status decline to 3 or more) disease progression, unacceptable toxicity or withdrawal. Patients with moderate or severe pain, opiate use for cancer pain, or visceral organ metastases were excluded.

Patient demographics were balanced between the treatment arms. The median age was 70 years. The racial distribution of patients treated with ZYTIGA was 95.4% Caucasian, 2.8% Black, 0.7% Asian and 1.1% Other. The ECOG performance status was 0 for 76% of patients, and 1 for 24% of patients. Co-primary efficacy endpoints were overall survival and radiographic progression-free survival (rPFS). Baseline pain assessment was 0-1 (asymptomatic) in 66% of patients and 2-3 (mildly symptomatic) in 26% of patients as defined by the Brief Pain Inventory-Short Form (worst pain over the last 24 hours).

Radiographic progression-free survival was assessed with the use of sequential imaging studies and was defined by bone scan identification of 2 or more new bone lesions with confirmation (Prostate Cancer Working Group 2 criteria) and/or modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria for progression of soft tissue lesions. Analysis of rPFS utilized centrally-reviewed radiographic assessment of progression.

At the protocol pre-specified third interim analysis for overall survival, 37% (200 of 546) of patients treated with ZYTIGA, compared with 43% (234 of 542) of patients treated with placebo, had died. Overall survival was longer for ZYTIGA than placebo with a hazard ratio of 0.792 (95% CI: 0.655 -0.956). The p-value was 0.0151 which did not meet the pre-specified value for statistical significance (Table 6 and Figure 2).

Table 6: Overall Survival of Patients Treated with Either ZYTIGA or Placebo in Combination with Prednisone in Study 2 (Intent-to-Treat Analysis)

Overall Survival ZYTIGA
(N=546)
Placebo
(N=542)
Deaths 200 (37%) 234 (43%)
Median survival (months) (95% CI) 35.3 (31.24, 35.29) 30.1 (27.30, 34.10)
p-value1 0.0151
Hazard ratio2 (95% CI) 0.792 (0.655, 0.956)
1P-value is derived from a log-rank test stratified by ECOG performance status score (0 vs. 1).
2Hazard Ratio is derived from a stratified proportional hazards model. Hazard ratio < 1 favors ZYTIGA

Figure 2 : Kaplan Meier Overall Survival Curves in Study 2 ( Intent - to- Treat analysis)

Kaplan Meier Overall Survival Curves in Study 2 - Illustration

At the pre-specified rPFS analysis, 150 (28%) patients treated with ZYTIGA and 251 (46%) patients treated with placebo had radiographic progression. A significant difference in rPFS between treatment groups was observed (Table 7 and Figure 3).

Table 7: Radiographic Progression-free Survival of Patients Treated with Either ZYTIGA or Placebo in Combination with Prednisone in Study 2 (Intent-to-Treat Analysis)

Radiographic Progression-free Survival ZYTIGA
(N=546)
Placebo
(N=542)
Progression or death 150(28%) 251(46%)
Median rPFS (months) (95% CI) NR (11.66, NR) 8.28 (8.12, 8.54)
p-value1 < 0.0001
Hazard ratio2 (95% CI) 0.425 (0.347, 0.522)
NR=Not reached
1P-value is derived from a log-rank test stratified by ECOG performance status score (0 vs. 1).
2Hazard Ratio is derived from a stratified proportional hazards model. Hazard ratio < 1 favors ZYTIGA

Figure 3 : Kaplan Meier Curves of Radiographic Progression-free Survival in Study 2 (Intent-to-Treat analysis)

Kaplan Meier Curves of Radiographic Progression-free Survival in Study 2 - Illustration

The primary efficacy analyses are supported by the following prospectively defined endpoints. The median time to initiation of cytotoxic chemotherapy was 25.2 months for patients receiving ZYTIGA and 16.8 months for patients receiving placebo (HR=0.580; 95% CI: [0.487, 0.691], p < 0.0001).

The median time to opiate use for prostate cancer pain was not reached for patients receiving ZYTIGA and was 23.7 months for patients receiving placebo (HR=0.686; 95% CI: [0.566, 0.833], p=0.0001). The time to opiate use result was supported by a delay in patient reported pain progression favoring the ZYTIGA arm.

Last reviewed on RxList: 6/2/2014
This monograph has been modified to include the generic and brand name in many instances.

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