Pharmacology: Pharmacodynamics: Mechanism of action:
Prostate cancer is known to be androgen sensitive and responds to inhibition of androgen receptor signalling. Despite low or even undetectable levels of serum androgen, androgen receptor signalling continues to promote disease progression. Stimulation of tumour cell growth via the androgen receptor requires nuclear localization and DNA binding. Enzalutamide is a potent androgen receptor signalling inhibitor that blocks several steps in the androgen receptor signalling pathway. Enzalutamide competitively inhibits binding of androgens to androgen receptors, inhibits nuclear translocation of activated receptor overexpression and in prostate cancer cells resistant to anti-androgens. Enzalutamide treatment decreases the growth of prostate cancer cells and can induce cancer cell death and tumour regression. In preclinical studies enzalutamide lacks androgen receptor agonist activity.
In a phase 3 clinical trial of patients who failed prior chemotherapy with docetaxel, 54% of patients treated with enzalutamide, versus 1.5% of patients who received placebo, had a least a 50% decline from baseline in PSA levels.
Clinical efficacy and safety:
The efficacy and safety of enzalutamide in patients with metastatic castration-resistant prostate cancer who had received docetaxel and were using a LHRH analogue or had undergone orchiectomy were assessed in a randomised, placebo-controlled, multicentre phase 3 clinical trial. A total of 1,199 patients were randomised 2:1 to receive either enzalutamide orally at a dose of 160 mg once daily (N=800) or placebo once daily (N=399). Patients were allowed but not required to take prednisone (maximum daily dose allowed was 10 mg prednisone or equivalent). Patients randomised to either arm were to continue treatment until disease progression (defined as confirmed radiographic progression or the occurrence of a skeletal-related event) and initiation of new systemic antineoplastic treatment, unacceptable toxicity, or withdrawal.
The following patient demographics and baseline disease characteristic were balanced between the treatment arms. The median age was 69 years (range 41-92) and the racial distribution was 93% Caucasian, 4% Black, 1% Asian, and 2% Other. The ECOG performance score was 0-1 in 91.5% of patients and 2 in 8.5% of patients; 28% had a mean Brief Pain Inventory score of ≥ 4 (mean of patient's reported worst pain over the previous 24 hours calculated for seven days prior to randomization). Most (91%) patients had metastases in bone and 23% had viseral lung and/or liver involvement. At study entry, 41% of randomized patients had PSA progression only, whereas 59% of patients had radiographic progression. Fifty-one percent (51%) of patients were on biophosphonates at baseline.
The AFFIRM study excluded patients with medical conditions that may predispose them to seizures (see Adverse Effects) and medicinal products known to decrease the seizure threshold, as well as clinically significant cardiovascular disease such as uncontrolled hypertension, recent history of myocardial infarction or unstable angina, New York Heart Association class III or IV heart failure (unless ejection fraction was ≥ 45%), clinically significant ventricular arrhythmias or AV block (without permanent pacemaker).
Of the 800 patients in the phase 3 trial who received enzalutamide, 568 patients (71%) were 65 years and over and 199 patients (25%) were 75 years and over. No overall differences in safety or effectiveness were observed between these older patients and younger patients.
The protocol pre-specified interim analysis after 520 deaths showed a statistically significant superiority in overall survival in patients treated with enzalutamide compared to placebo (See Table 1 and Figures 1 & 2).
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
ECOG: Eastern Cooperative Oncology Group; BPI-SF: Brief Pain Inventory-Short Form;
PSA: Prostate Specific Antigen
In addition to the observed improvement in overall survival, key secondary endpoints (PSA progression, radiographic progression-free survival, and time to first skeletal-related event) favoured enzalutamide and were statistically significant after adjusting for multiple testing.
Radiographic progression-free survival as assessed by the investigator using RECIST v1.1 for soft tissue and appearance of 2 or more bone lessions in bone scan was 8.3 months for patients treated with enzalutamide and 2.9 months for patients who received placebo (HR=0.404, 95% CI: [0.350, 0.466]); p<0.0001). The analysis involved 216 deaths without documented progression and 645 documented progression events, of which 303 (47%) were due to soft tissue progression, 268 (42%) were due to bone lession progression and 74 (11%) were due to both soft tissue and bone lesions.
Confirmed PSA decline of 50% or 90% were 54.0% and 24.8%, respectively, for patients treated with enzalutamide and 1.5% and 0.9%, respectively, for patients who received placebo (p<0.0001). The median time to PSA progression was 8.3 months for patients treated with enzalutamide and 3.0 months for patients who received placebo (HR=0.248, 95% CI: [0.204, 0.303]; p<0.0001).
The median time to first skeletal-related event was 16.7 months for patients treated with enzalutamide and 13.3 months for patients who received placebo (HR=0.688, 85% CI: [0.566, 0.835]; p<0.0001). A skeletal-related event was defined as radiation therapy or surgery to bone, pathologic bone fracture, spinal cord compression, or change of antineoplastic therapy to treat bone pain. The analysis involved 448 skeletal-related events, of which 277 events (62%) were radiation to bone, 95 events (21%) were spinal cord compression, 47 events (10%) were pathologic bone fracture, 36 events (8%) were change in anti-neoplastic therapy to treat bone pain and 7 events (2%) were surgery to bone.
The efficacy of enzalutamide in patients who have previously received abiaterone acetate has not been studied.
: Enzalutamide is poorly water soluble. In this product, the solubility of enzalutamide is increased by caprylocaproyl macrogolglycerides as emulsifier/surfactant. In preclinical studies, the absorption of enzalutamide was increased when dissolved in caprylocaproyl macrogolglycerides.
The pharmacokinetics of enzalutamide have been evaluated in prostate cancer patients and in healthy male subjects. The mean terminal half-life (t½
) for enzalutamide in patients after a single oral dose is 5.8 days (range 2.8 to 102 days), and steady state is achieved in approximately one month. With daily oral administration, enzalutamide accumulates approximately 8.3-fold relative to a single dose. Daily fluctuations in plasma concentrations are low (peak-to-trough ratio of 1.25). Clearance of enzalutamide is primarily via hepatic metabolism, producing an active metabolite that is equally as active as enzalutamide and circulates at approximately the same plasma concentration as enzalutamide.
Maximum plasma concentration (Cmax
) of enzalutamide in patients are observed 1 to 2 hours after administration. Based on a mass balance study in humans, oral absorption of enzalutamide is estimated to be at least 84.2%. Enzalutamide is not a substrate of the efflux transporters P-gp or BCRP. At steady state, the mean Cmax
values for enzalutamide and its active metabolite are 16.6 μg/m: (23% coefficient of variation [CV]) and 12.7 μg/mL (30% CV), respectively.
Food has no clinically significant effect on the extent of absorption. In clinical trials, Xtandi was administered without regard to food.
The mean apparent volume of distribution (V/F) of enzalutamide in patients after a single oral doses is 110 L (29% CV). The volume of distribution of enzalutamide is greater than the volume of total body water, indicative of extensive extravascular distribution. Studies in rodents indicate that enzalutamide and its active metabolite can cross the blood brain barrier.
Enzalutamide is 97% to 98% bound to plasma proteins, primarily albumin. The active metabolite is 95% bound to plasma proteins. There was no protein binding displacement between enzalutamide and other highly bound drugs (warfarin, ibuprofen and salicylic acid) in vitro
Enzalutamide is extensively metabolized. There are two major metabolites in human plasma: N-desmethyl enzalutamide (active) and a carboxylic acid derivative (inactive). Enzalutamide is metabolized by CYP2C8 and to a lesser extent by CYP3A4/5 (see Interactions), both of which play a role in the formation of the active metabolite. In vitro
, N-desmethyl enzalutamide is matabolized to the carboxylic acid metabolite by carboxylesterase 1, which also plays a minor role in the metabolism of enzalutamide to the carboxylic acid metabolite. N-desmethyl enzalutamide was not metabolized by CYPs in vitro
Under conditions of clinical use, enzalutamide is a strong inducer of CYP3A4, a moderate inducer of CYP2C9 and CYP2C19, and has no clinically relevant effect on CYP2C8 (see Interactions).
The mean apparent clearance (CL/F) of enzalutamide in patients ranges from 0.520 and 0.564 L/h.
Following oral administration of 14
C-enzalutamide, 84.6% of the radioactivity is recovered by 77 days post dose: 71.0% is recovered in urine (primarily as the inactive metabolite, with trace amounts of enzalutamide and the active metabolite), and 13.6% is recovered in faeces (0.39% of dose as unchanged enzalutamide).
data indicate that enzalutamide is not a substrate for OATP1B1, OATP1B3, or OCT1; and N-desmethyl enzalutamide is not a substrate for P-gp or BCRP.
data indicate that enzalutamide and its major metabolites do not inhibit the following transporters at clinically relevent concentrations: OATP1B1, OATP1B3, OCT2, or OAT1.
No major deviations from dose proportionality are observed over the dose range 40 to 160 mg. The steady-state Cmin
values of enzalutamide and the active metabolite in individual patients remained constant during more than one year of chronic therapy, demonstrating time-linear pharmacokinetics once steady-state is achieved.
No formal renal impairment study for enzalutamide has been completed. Patients with serum creatinine >177 μmol/L (2 mg/dL) were excluded from clinical trials. Based on a population pharmacokinetic analysis, no dose adjustment is necessary for patients with calculated creatinine clearance (CrCL) values ≥ 30 mL/min (estimated by the Cockcroft and Gault formula). Enzalutamide has not been evaluated in patients with severe renal impairment (CrCL < 30 mL.min) or end-stage renal disease, and caution is advised when treating these patients. It is unlikely that enzalutamide will be significantly removed by intermittent haemodialysis or continuous ambulatory peritoneal dialysis.
The pharmacokinetics of enzalutamide were examined in subjects with baseline mild (N=6) or moderate (N=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 14 matched control subjects with normal hepatic function. Following a single oral 160 mg dose of enzalutamide, the AUC and Cmax
for enzalutamide in subjects with mild impairment increased by 5% and 24%, respectively, and the AUC and Cmax
enzalutamide in subjects with moderate impairment increased by 29% and decreased by 11%, respectively, compared to healthy control subjects. For the sum of unbound enzalutamide plus the unbound active metabolite, the AUC and Cmax
in subjects with mild impairment increased by 14% and 19%, respectively, and the AUC and Cmax
in subjects with moderate impairment increased by 14% and decreased by 17%, respectively, compared to healthy control subjects. Overall, the results indicate that no dose adjustment is necessary for patients with baseline mild or moderate hepatic impairment.
Patients with baseline severe hepatic impairment (Child-Pugh C) were excluded from clinical trials.
As there are no data in patients with severe hepatic impairment and enzalutamide is primarily hepatically eliminated, caution is advised in patients with severe hepatic impairment (Child-Pugh Class C, see Dosage & Administration and Precautions).
Most patients in the clinical trials (>92%) were Caucasian, thus no conclusions on the impact of race on enzalutamide pharmacokinetics can be drawn.
No clinically relevant effect of age on enzalutamide pharmacokinetics was seen in the population pharmacokinetic analysis.
Toxicology: Preclinical safety data:
Enzalutamide treatment of pregnant mice resulted in an increased incidence of embryofetal deaths and external and skeletal changes. Reproductive toxicology studies were not conducted with enzalutamide, but in studies in rats (4 and 26 weeks) and dogs (4, 13 and 39 weeks), atrophy, aspermia/hypospermia, and hypertrophy/hyperplasia in the reproductive system were noted, consistent with the pharmacological activity of enzalutamide. In studies in mice (4 weeks), rats (4 and 26 weeks) and dogs (4, 13 and 39 weeks), changes in the reproductive organs associated with enzalutamide were decreases in organ weight with atrophy of the prostate and epidymis. Leydig cell hypertrophy and/or hyperplasia were observed in mice (4 weeks) and dogs (39 weeks). Additional changes to reproductive tissues included hypertrophy/hyperplasia of the pituitary gland and atrophy in seminal vesicle in rats and testicular hypospermia and seminiferous tubule degeneration in dogs. Gender differences were noted in rat mammary glands (male atrophy and female lobular hyperplasia). Changes in the reproductive organs in both species were consistent with the pharmacological activity of enzalutamide and reserved or partially resolved after an 8-week recovery period. There were no other important changes in clinical pathology or histopatology in any other organ system, including the liver, in either species.
Enzalutamide did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in either the in vitro
cytogenetic assay with mouse lymphoma cells or the in vivo
mouse micronucleus assay. Long-term animal studies to evaluate the carcinogenic potential of enzalutamide have not been conducted. Enzalutamide was not phototoxic in vitro