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Xtandi

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Xtandi

CLINICAL PHARMACOLOGY

Mechanism Of Action

Enzalutamide is an androgen receptor inhibitor that acts on different steps in the androgen receptor signaling pathway. Enzalutamide has been shown to competitively inhibit androgen binding to androgen receptors and inhibit androgen receptor nuclear translocation and interaction with DNA. A major metabolite, N-desmethyl enzalutamide, exhibited similar in vitro activity to enzalutamide. Enzalutamide decreased proliferation and induced cell death of prostate cancer cells in vitro, and decreased tumor volume in a mouse prostate cancer xenograft model.

Pharmacokinetics

The pharmacokinetics of enzalutamide and its major active metabolite (N-desmethyl enzalutamide) were evaluated in patients with metastatic CRPC and healthy male volunteers. The plasma enzalutamide pharmacokinetics are adequately described by a linear two-compartment model with first-order absorption.

Absorption

Following oral administration (XTANDI 160 mg daily) in patients with metastatic CRPC, the median time to reach maximum plasma enzalutamide concentrations (Cmax) is 1 hour (range 0.5 to 3 hours). At steady state, the plasma mean Cmax values for enzalutamide and N-desmethyl enzalutamide are 16.6 μg/mL (23% CV) and 12.7 μg/mL (30% CV), respectively, and the plasma mean predose trough values are 11.4 μg/mL (26% CV) and 13.0 μg/mL (30% CV), respectively.

With the daily dosing regimen, enzalutamide steady state is achieved by Day 28, and enzalutamide accumulates approximately 8.3-fold relative to a single dose. Daily fluctuations in enzalutamide plasma concentrations are low (mean peak-to-trough ratio of 1.25). At steady state, enzalutamide showed approximately dose proportional pharmacokinetics over the daily dose range of 30 to 360 mg.

A single 160 mg oral dose of XTANDI was administered to healthy volunteers with a high-fat meal or in the fasted condition. A high-fat meal did not alter the AUC to enzalutamide or N-desmethyl enzalutamide. The results are summarized in Figure 1.

Distribution and Protein Binding

The mean apparent volume of distribution (V/F) of enzalutamide in patients after a single oral dose is 110 L (29% CV).

Enzalutamide is 97% to 98% bound to plasma proteins, primarily albumin. N-desmethyl enzalutamide is 95% bound to plasma proteins. In vitro, there was no protein binding displacement between enzalutamide and other highly protein bound drugs (warfarin, ibuprofen, and salicylic acid) at clinically relevant concentrations.

Metabolism

Following single oral administration of 14C-enzalutamide 160 mg, plasma samples were analyzed for enzalutamide and its metabolites up to 77 days post dose. Enzalutamide, N-desmethyl enzalutamide, and a major inactive carboxylic acid metabolite accounted for 88% of the 14C-radioactivity in plasma, representing 30%, 49%, and 10%, respectively, of the total 14C-AUC0-inf.

In vitro, human CYP2C8 and CYP3A4 are responsible for the metabolism of enzalutamide. Based on in vivo and in vitro data, CYP2C8 is primarily responsible for the formation of the active metabolite (Ndesmethyl enzalutamide).

In vitro, N-desmethyl enzalutamide is not a substrate of human CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5.

Elimination

Enzalutamide is primarily eliminated by hepatic metabolism. Following single oral administration of 14Cenzalutamide 160 mg, 85% of the radioactivity is recovered by 77 days post dose: 71% is recovered in urine (including only trace amounts of enzalutamide and N-desmethyl enzalutamide), and 14% is recovered in feces (0.4% of dose as unchanged enzalutamide and 1% as N-desmethyl enzalutamide).

The mean apparent clearance (CL/F) of enzalutamide in patients after a single oral dose is 0.56 L/h (range 0.33 to 1.02 L/h).

The mean terminal half-life (t½) for enzalutamide in patients after a single oral dose is 5.8 days (range 2.8 to 10.2 days). Following a single 160 mg oral dose of enzalutamide in healthy volunteers, the mean terminal t½ for N-desmethyl enzalutamide is approximately 7.8 to 8.6 days.

Pharmacokinetics in Special Populations

Renal Impairment

A population pharmacokinetic analysis (based on pre-existing renal function) was carried out with data from 59 healthy male volunteers and 926 patients with metastatic CRPC enrolled in clinical trials, including 512 with normal renal function (CrCL ≥ 90 mL/min), 332 with mild renal impairment (CrCL 60 to < 90 mL/min), 88 with moderate renal impairment (CrCL 30 to < 60 mL/min), and 1 with severe renal impairment (CrCL < 30 mL/min). The apparent clearance of enzalutamide was similar in patients with pre-existing mild and moderate renal impairment (CrCL 30 to < 90 mL/min) compared to patients and volunteers with normal renal function. The potential effect of severe renal impairment or end stage renal disease on enzalutamide pharmacokinetics cannot be determined as clinical and pharmacokinetic data are available from only one patient [see Use in Specific Populations].

Hepatic Impairment

The plasma pharmacokinetics of enzalutamide and N-desmethyl enzalutamide were examined in volunteers with normal hepatic function (N = 16) and with pre-existing mild (N = 8, Child-Pugh Class A) or moderate (N = 8, Child-Pugh B) hepatic impairment. XTANDI was administered as a single 160 mg dose. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. The results are summarized in Figure 1. Clinical and pharmacokinetic data are not available for patients with severe hepatic impairment (Child-Pugh Class C) [see Use in Specific Populations].

Body Weight and Age

Population pharmacokinetic analyses showed that weight (range: 46 to 163 kg) and age (range: 41 to 92 yr) do not have a clinically meaningful influence on the exposure to enzalutamide.

Gender

The effect of gender on the pharmacokinetics of enzalutamide has not been evaluated.

Race

The majority of XTANDI-treated patients in the randomized clinical trials were Caucasian (85%). Based on pharmacokinetic data from a study in Japanese patients with prostate cancer, there were no clinically relevant differences in exposure between Japanese and Caucasians. There are insufficient data to evaluate potential differences in the pharmacokinetics of enzalutamide in other races.

Drug Interactions

Effect of Other Drugs on XTANDI

In a drug-drug interaction trial in healthy volunteers, a single 160 mg oral dose of XTANDI was administered alone or after multiple oral doses of gemfibrozil (strong CYP2C8 inhibitor). Gemfibrozil increased the AUC0-inf of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold with minimal effect on Cmax. The results are summarized in Figure 1 [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS].

In a drug-drug interaction trial in healthy volunteers, a single 160 mg oral dose of XTANDI was administered alone or after multiple oral doses of itraconazole (strong CYP3A4 inhibitor). Itraconazole increased the AUC0-inf of enzalutamide plus N-desmethyl enzalutamide by 1.3-fold with no effect on Cmax. The results are summarized in Figure 1 [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS].

The effects of CYP2C8 and CYP3A4 inducers on the exposure of XTANDI have not been evaluated in vivo.

Figure 1: Effects of Other Drugs and Intrinsic/Extrinsic Factors on XTANDI

Effects of Other Drugs and Intrinsic/Extrinsic Factors on XTANDI - Illustration

# PK parameters (Cmax and AUC0-inf) are for enzalutamide plus N-desmethyl enzalutamide, except in the food-effect trial, where they are for enzalutamide alone.
* See DOSAGE AND ADMINISTRATION.

Effect of XTANDI on Other Drugs

In an in vivo phenotypic cocktail drug-drug interaction trial in patients with metastatic CRPC, a single oral dose of the CYP probe substrate cocktail (for CYP2C8, CYP2C9, CYP2C19, and CYP3A4) was administered before and concomitantly with XTANDI (following at least 55 days of dosing at 160 mg daily). The results are summarized in Figure 2. Results showed that in vivo, at steady state, XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer [see DRUG INTERACTIONS]. XTANDI did not cause clinically meaningful changes in exposure to the CYP2C8 substrate.

Figure 2: Effect of XTANDI on Other Drugs

Effect of XTANDI on Other Drugs - Illustration

*See DRUG INTERACTIONS.

In vitro, enzalutamide, N-desmethyl enzalutamide, and the major inactive carboxylic acid metabolite caused direct inhibition of multiple CYP enzymes including CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5; however, subsequent clinical data showed that XTANDI is an inducer of CYP2C9, CYP2C19, and CYP3A4 and had no clinically meaningful effect on CYP2C8 (see Figure 2). In vitro, enzalutamide caused time-dependent inhibition of CYP1A2.

In vitro studies showed that enzalutamide induces CYP2B6 and CYP3A4 and does not induce CYP1A2 at therapeutically relevant concentrations.

In vitro, enzalutamide, N-desmethyl enzalutamide, and the major inactive carboxylic acid metabolite are not substrates for human P-glycoprotein. In vitro, enzalutamide and N-desmethyl enzalutamide are inhibitors of human P-glycoprotein, while the major inactive carboxylic acid metabolite is not.

In vitro, enzalutamide and N-desmethyl enzalutamide do not appear to be substrates of human breast cancer resistance protein (BCRP); however, enzalutamide and N-desmethyl enzalutamide are inhibitors of human BCRP at clinically relevant concentrations.

Cardiac Electrophysiology

The effect of enzalutamide 160 mg/day at steady state on the QTc interval was evaluated in 796 patients with metastatic CRPC. No large difference (i.e., greater than 20 ms) was observed between the mean QT interval change from baseline in patients treated with XTANDI and that in patients treated with placebo, based on the Fridericia correction method. However, small increases in the mean QTc interval (i.e., less than 10 ms) due to enzalutamide cannot be excluded due to limitations of the study design.

Clinical Studies

The efficacy and safety of XTANDI in patients with metastatic CRPC were demonstrated in two randomized, placebo-controlled, multicenter phase 3 clinical trials. All patients continued on GnRH therapy or had prior bilateral orchiectomy. Patients were allowed, but not required, to continue or initiate glucocorticoids.

Study 1: Metastatic Castration-Resistant Prostate Cancer Following Chemotherapy

A total of 1199 patients who had received prior docetaxel-based chemotherapy were randomized 2:1 to receive either XTANDI orally at a dose of 160 mg once daily (N=800) or placebo orally once daily (N=399). Study treatment continued until disease progression (evidence of radiographic progression, a skeletal-related event, or clinical progression), initiation of new systemic antineoplastic treatment, unacceptable toxicity, or withdrawal. Patients with a previous history of seizure, taking medicines known to decrease the seizure threshold, or with other risk factors for seizure were not eligible [see WARNINGS AND PRECAUTIONS].

The following patient demographics and baseline disease characteristics were balanced between the treatment arms. The median age was 69 years (range 41-92) and the racial distribution was 92.7% Caucasian, 3.9% Black, 1.1% Asian, and 2.1% Other. Ninety-two percent of patients had an ECOG performance status score of 0-1 and 28% had a mean Brief Pain Inventory score of ≥ 4. Ninety-one percent of patients had metastases in bone and 23% had visceral involvement in the lung and/or liver. Fifty-nine percent of patients had radiographic evidence of disease progression and 41% had PSA-only progression on study entry. All patients had received prior docetaxel-based therapy and 24% had received two cytotoxic chemotherapy regimens. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids.

A statistically significant improvement in overall survival was demonstrated at the pre-specified interim analysis at the time of 520 deaths in patients on the XTANDI arm compared to patients on the placebo arm (Table 3 and Figure 3).

Table 3: Overall Survival of Patients Treated with Either XTANDI or Placebo in Study 1

  XTANDI
N = 800
Placebo
N = 399
Number of Deaths (%) 308 (38.5%) 212 (53.1%)
Median Survival (months) (95% CI) 18.4 (17.3, NR) 13.6 (11.3, 15.8)
P-valuea < 0.0001
Hazard Ratio (95% CI)b 0.63 (0.53, 0.75)
a P-value is derived from a log-rank test stratified by baseline ECOG performance status score (0-1 vs. 2) and mean baseline pain score (BPI-SF score < 4 vs. ≥ 4)
b Hazard Ratio is derived from a stratified proportional hazards model. Hazard ratio < 1 favors XTANDI NR denotes “not reached”.

Figure 3: Kaplan-Meier Overall Survival Curves in Study 1

Kaplan-Meier Overall Survival Curves in Study 1 - Illustration

Study 2: Chemotherapy-naive Metastatic Castration-Resistant Prostate Cancer

In Study 2, 1717 chemotherapy-naive patients were randomized 1:1 to receive either XTANDI orally at a dose of 160 mg once daily (N=872) or placebo orally once daily (N=845). Patients with visceral metastases, patients with a history of mild to moderate heart failure (NYHA class I or II), and patients taking medications associated with lowering the seizure threshold were allowed. Patients with a previous history of seizure or a condition that might predispose to seizure and patients with moderate or severe pain from prostate cancer were excluded. Study treatment continued until disease progression (evidence of radiographic progression, a skeletal-related event, or clinical progression) and the initiation of a cytotoxic chemotherapy or an investigational agent, unacceptable toxicity, or withdrawal. Overall survival and radiographic progression-free survival (rPFS) were assessed. Radiographic progression was assessed with the use of sequential imaging and was defined by bone scan identification of 2 or more new bone lesions with confirmation (Prostate Cancer Clinical Trials Working Group 2 criteria) and/or Response Evaluation Criteria in Solid Tumors (RECIST v 1.1) criteria for progression of soft tissue lesions. The primary analysis of rPFS utilized centrally reviewed radiographic assessment of progression.

Patient demographics and baseline disease characteristics were balanced between the treatment arms at entry. The median age was 71 years (range 42-93) and the racial distribution was 77% Caucasian, 10% Asian, 2% Black and 11% Other. The ECOG performance status score was 0 for 68% of patients, and 1 for 32% of patients. Baseline pain assessment was 0-1 (asymptomatic) in 67% of patients, and 2-3 (mildly symptomatic) in 32% of patients as defined by the Brief Pain Inventory Short Form (worst pain over past 24 hours at study entry). Fifty-four percent of patients had radiographic evidence of disease progression and 43% had PSA-only progression. Twelve percent of patients had visceral (lung and/or liver) disease involvement. During the study, 27% of patients on the XTANDI arm and 30% of patients on the placebo arm received glucocorticoids for varying reasons.

A statistically significant improvement in overall survival was demonstrated at the pre-specified interim analysis, conducted after 540 deaths in patients treated with XTANDI compared to those treated with placebo (Table 4, Figure 4). Forty percent of XTANDI-treated and 70% of placebo-treated patients received subsequent therapies for metastatic CRPC that may prolong overall survival.

Table 4: Overall Survival of Patients Treated with Either XTANDI or Placebo in Study 2

  XTANDI
N = 872
Placebo
N = 845
Pre-specified Interim Analysis
  Number of Deaths (%) 241 (28%) 299 (35%)
  Median Survival (months) (95% CI) 32.4 (30.1, NR) 30.2 (28.0, NR)
  P-valuea < 0.0001
  Hazard Ratio (95% CI) 0.71 (0.60, 0.84)
a P-value is derived from an unstratified log-rank test
b Hazard Ratio is derived from an unstratified proportional hazards model. Hazard ratio < 1 favors XTANDI NR denotes “not reached”.

Figure 4: Kaplan-Meier Overall Survival Curves in Study 2

Kaplan-Meier Overall Survival Curves in Study 2 - Illustration

A statistically significant improvement in rPFS was demonstrated in patients treated with XTANDI compared to patients treated with placebo (Table 5, Figure 5).

Table 5: Radiographic Progression-free Survival of Patients Treated with Either XTANDI or Placebo in Study 2

  XTANDI
N = 832
Placebo
N = 801
Number of Progression or Deaths (%) 118 (14%) 320 (40%)
Median rPFS (months) (95% CI) NR (13.8, NR) 3.7 (3.6, 4.6)
P-valuea < 0.0001
Hazard Ratio (95% CI)b 0.17 (0.14, 0.21)
a P-value is derived from an unstratified log-rank test
b Hazard Ratio is derived from an unstratified proportional hazards model. Hazard ratio < 1 favors XTANDI NR denotes “not reached”.
Note: As of the cutoff date for the rPFS analysis, 1633 patients had been randomized.

Figure 5: Kaplan-Meier Curves for Duration of Radiographic Progression-free Survival in Study 2

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

Time to initiation of cytotoxic chemotherapy was prolonged after XTANDI treatment, with a median of 28.0 months for patients on the XTANDI arm versus a median of 10.8 months for patients on the placebo arm [HR=0.35 (95% CI: 0.30, 0.40), p < 0.0001)].

The median time to first skeletal-related event was 31.1 months for patients on the XTANDI arm versus 31.3 months for patients on the placebo arm [HR = 0.72 (95% CI: 0.61, 0.84), p < 0.0001]. A skeletal-related event was defined as radiation therapy or surgery to bone for prostate cancer, pathologic bone fracture, spinal cord compression, or change of antineoplastic therapy to treat bone pain.

Last reviewed on RxList: 9/17/2014
This monograph has been modified to include the generic and brand name in many instances.

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