Summary Basis of Decision for Xtandi

Clinical Pharmacology

Enzalutamide, the active ingredient in Xtandi, is an androgen receptor inhibitor that inhibits activation of the androgen receptor signalling pathway. Prostate cancer is known to be androgen sensitive and responds to inhibition of androgen receptor signalling. Enzalutamide competitively inhibits binding of androgens to androgen receptors and as a result, inhibits translocation of androgen receptors and association of androgen receptors with deoxyribonucleic acid (DNA). In non-clinical studies, enzalutamide lacked androgen receptor agonist activity; however, agonist activity was only tested in cell growth assays using LNCaP cells expressing clinically relevant mutant androgen receptors (T877A and/or W741C). Other androgen receptor mutations have been detected in clinical cancer biopsies, and agonist activity against these mutated receptors cannot be excluded.

Enzalutamide is metabolized in the liver primarily by the cytochrome P450 (CYP) enzyme, CYP2C8, and to a lesser extent CYP3A4, and study results suggest that CYP2C8 is mainly responsible for the formation of the active metabolite, N-desmethyl enzalutamide (m²). Dose reductions are recommended for patients that require co-medication with CYP2C8 inhibitors as administration of strong CYP2C8 inhibitors can increase the plasma exposure to Xtandi. Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19. Medicinal products with a narrow therapeutic range that are substrates of these enzymes should be avoided, as co-administration of Xtandi may decrease their exposure. Although in vitro studies showed that enzalutamide causes time-dependent inhibition of CYP1A2, the effect of enzalutamide on CYP1A2 pharmacokinetics has not been evaluated in vivo. The sponsor has planned a drug interaction trial to evaluate the effects of enzalutamide at steady-state on the pharmacokinetics of CYP1A2 substrates. Further instructions as well as the potential for Xtandi to affect exposures to other medicinal products are discussed in the Xtandi Product Monograph.

The pharmacokinetics of enzalutamide were examined in patients with mild or moderate hepatic impairment (Child-Pugh Class A and B). Overall, the results indicated that no dose adjustment is necessary for patients with mild or moderate hepatic impairment. Patients with severe hepatic impairment (Child-Pugh C) were excluded from the clinical studies. Xtandi (enzalutamide) is not recommended in patients with severe hepatic impairment.

Clearance of enzalutamide is primarily via renal excretion of hepatic metabolites. Patients with severe renal impairment were not included in the pivotal study, and no formal renal impairment clinical studies were conducted. A population pharmacokinetic analysis of patients with renal impairment in the pivotal trial suggested that there were no dose adjustments necessary for patients with calculated creatinine clearance values of ≥30 mL/min Caution is required in patients with severe renal impairment as enzalutamide was not studied in this patient population.

A comparative bioavailability study was conducted to evaluate the effect of food on absorption. A high-fat meal did not significantly affect the extent of Xtandi absorption but led to a 30% reduction in the rate of absorption.

The clinical pharmacology labelling has been thoroughly discussed with the sponsor, and appropriate labelling has been agreed upon by both Health Canada and the sponsor. Overall, the clinical pharmacological data support the use of Xtandi for the specified indication.

Clinical Efficacy

The clinical efficacy and safety of Xtandi in patients with metastatic castration-resistant prostate cancer who had progressed after prior docetaxel-based therapy were assessed in a Phase III randomized, placebo-controlled, multicentre clinical study. Patients maintained treatment with a gonadotropin-releasing hormone (GnRH) analogue or had previously undergone surgical castration. A total of 1,199 patients were randomized 2:1 to receive either Xtandi orally at a dose of 160 mg once daily [number of patients (n) = 800] or placebo once daily (n = 399). Patients were allowed, but not required to continue or initiate corticosteroids (47.8% vs. 45.6% were administered corticosteroids in Xtandi and placebo arms, respectively). In addition, 51.0% vs. 49.6% of patients in the Xtandi and placebo arms, respectively, were using bisphosphonates at baseline.

The patient demographics and baseline disease characteristics were balanced between the treatment arms. Patients continued treatment until disease progression (defined as radiographic progression or the occurrence of a skeletal-related event) and initiation of a new systemic antineoplastic treatment, death, unacceptable toxicity, or withdrawal. Increases in prostate-specific antigen (PSA), especially during the first 12 weeks of therapy, were not considered disease progression.

The primary efficacy endpoint was overall survival defined as time from randomization to death from any cause. Key secondary efficacy endpoints included time to PSA progression, radiographic progression-free survival, and time to first skeletal-related event. Additional efficacy endpoints included the response rate for quality of life [measured by Functional Assessment of Cancer Therapy - Prostate (FACT-P)], PSA response rate, and pain palliation.

Xtandi therapy resulted in a statistically significant prolongation of survival in patients with castration-resistant prostate cancer who had received docetaxel chemotherapy. A single formal interim overall survival analysis was conducted on event data through the date of the 520^th death event. A 2-stage group sequential approach with Lan-DeMets alpha-spending function based upon the O'Brien-Fleming boundaries was used to preserve an overall 2-sided type 1 error of 0.05 and allocate type 1 error to the interim analysis. Alpha-spending for the interim overall survival analysis and the primary overall survival analysis were 0.02 and 0.04 (both 2-sided), respectively. Study results showed a 37% decrease in the risk of death for patients that received Xtandi compared with those that received placebo [hazard ratio 0.63; 95% confidence interval (CI): 0.53, 0.75; p<0.0001]. The estimated median survival in the Xtandi arm was 18.4 months compared to 13.6 months in the placebo arm.

The survival benefit of Xtandi was seen in all pre-specified patient subgroups defined by age, geographic region, Eastern Cooperative Oncology Group (ECOG) performance status, baseline pain score, Gleason score, number of prior chemotherapy regimens, type of disease progression at study entry, baseline level of PSA, baseline level of hemoglobin, and baseline level of lactate dehydrogenase.

Subsequent therapies for prostate cancer were used more frequently among patients in the placebo arm as compared with patients in the Xtandi arm. Overall use of any subsequent therapy for prostate cancer equaled 42.0% for patients in the Xtandi arm and 61.4% for patients in the placebo arm, including abiraterone acetate (20.9% vs. 24.3%), cabazitaxel (9.8% vs. 13.8%), docetaxel (8.5% vs. 14.3%), mitoxantrone (2.6% vs. 8.0%), and mitoxantrone hydrochloride (0.0% vs. 3.0%).

Xtandi therapy resulted in significant improvements in the key secondary endpoints of time to PSA progression (median) 8.3 vs. 3.0 months for Xtandi and placebo arms, respectively (hazard ratio 0.25); radiographic progression-free survival (median) 8.3 vs. 2.9 months for Xtandi and placebo arms, respectively (hazard ratio 0.40); and time to first skeletal-related event (median) 16.7 months for Xtandi and 13.3 months for the placebo arms, respectively (hazard ratio 0.69). A hazard ratio <1 favours Xtandi.

Xtandi therapy resulted in significant improvements in the other secondary efficacy endpoints of quality of life response rates (FACT-P, 43.2% response rate in the Xtandi arm vs. 18.3% response rate in the placebo arm), and PSA response rates (≥50% decrease, 54.0% vs. 1.5%).

The results consistently favoured Xtandi therapy across all primary, key secondary, other secondary, and exploratory efficacy endpoints measured. As the median survival of patients with progressive metastatic castrate-resistant prostate cancer who were previously treated with docetaxel is estimated to be approximately 1-2 years, the 4.8 month increase in survival in the Xtandi arm compared to placebo is considered to be of clinical benefit in this patient population.

For more information, refer to the Xtandi Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Xtandi was evaluated in the pivotal Phase III study, described in Clinical Efficacy. In the placebo-controlled Phase III clinical study, Xtandi was administered at a dose of 160 mg daily (n = 800) versus placebo (n = 399). The median duration of treatment with Xtandi was 8.3 months while with placebo it was 3.0 months.

The adverse reactions that occurred more frequently in the Xtandi arm with at least a 2% increase over the rate observed in the placebo arm included: fatigue (33.6% vs. 29.1%), hot flushes (20.3% vs. 10.3%), headaches (11.6% vs. 5.5%), hypertension (6.1% vs. 2.8%), falls (4.0% vs. 1.3%), dry skin (3.5% vs. 1.3%), pruritus (3.6% vs. 1.3%), and anxiety (6.4% vs. 4.0%).

Important identified risks are described below:

• Seizures occurred in 0.9% of the Xtandi treated patients compared to 0% in placebo treated patients. There were 7 reports of seizure in the Xtandi arm (0.9%) and none in the placebo arm. Data from in vitro studies have shown that enzalutamide and its active metabolite cross the blood brain barrier, bind to, and inhibit the activity of the gamma-aminobutyric acid (GABA) receptor. In a dose escalation study involving 140 patients, no seizures were reported at or below daily doses of 240 mg, whereas three seizures were reported, one each at 360, 480, and 600 mg per day. The dose of Xtandi may therefore be a predictor of seizure in humans, with a greater risk of seizure at daily exposures higher than 160 mg. The sponsor plans to conduct a safety trial with enzalutamide in patients who are at an increased risk of seizure.
  
  In the integrated safety population of patients treated with the proposed dose of 160 mg, the incidence of seizure was 0.8% (7/909). Patients experiencing seizure were discontinued from therapy, and all seizures resolved. Patients with a history of seizure or any condition that may pre-dispose them to seizure were excluded from the clinical studies, therefore the safety of Xtandi in this patient population is not known. Because of the serious nature of seizure as a potential adverse drug reaction associated with Xtandi, it was included within a Serious Warnings and Precautions Box in the Xtandi Product Monograph.
• Hypertension was reported in 6.1% of the Xtandi-treated patients and 2.0% of placebo-treated patients. Grade 3 events occurred in 2.0% of Xtandi patients and no Grade 4 events of hypertension were reported. Hypertension rarely leads to discontinuation or dose modification; however, approximately 75% of patients with this adverse event required initiation of new antihypertensive treatment or an increase in dose of prior therapy. Blood pressure should be measured at baseline and periodically during treatment. The Xtandi Product Monograph includes labelling regarding this associated adverse event in the Warnings and Precautions section.
• Adverse events of fall were reported in 32 (4.0%) Xtandi-treated patients and 5 (1.3%) placebo-treated patients. Only one patient had a serious adverse event (SAE) of fall (Xtandi arm), and no patients discontinued study treatment due to fall. The falls were not associated with a loss of consciousness or other adverse events such as balance disorder, gait disturbance, presyncope, or syncope. Some falls resulted in fracture, which also occurred with an increased incidence in Xtandi-treated patients compared to placebo patients. Treatment with Xtandi was associated with an increase in the incidence of non-pathological fracture in the pivotal study (3.5% vs. 0.8%).
• Low levels of neutrophils were measured for 121 patients (15.1%) in the Xtandi arm and 25 (6.3%) in the placebo arm. Of the 121 patients, 9 had Grade 3 or 4 neutropenic events, of which none had an infection reported as an AE. No patients in the placebo arm had Grade 3-4 low neutrophil events. Neutropenia was not reported in the 5 cases of sepsis reported in the Xtandi arm. A significant imbalance in the number of deaths due to infection was noted in the Xtandi arm (7, 0.9%) compared to the placebo arm (1, 0.3%). Although neutropenia was observed at higher frequency with enzalutamide compared to placebo, it was not associated with infection. Furthermore, those subjects who had infection adverse events (AEs) were not neutropenic.
• Thirteen patients (1.6%) in the Xtandi arm reported hallucinations compared to 1 patient (0.3%) in the placebo arm. All hallucinations in the Xtandi arm were non-serious and were Grade 1 or 2, except 1 patient with an opioid-induced hallucination. None of the patients discontinued treatment due to an adverse event of hallucination. The combined adverse events of amnesia, cognitive disorder, disturbance in attention, memory impairment, and the related term dementia were reported more frequently in Xtandi-treated patients than placebo-treated patients (4.1% vs. 1.8%). Enzalutamide and its primary metabolite are brain-penetrant and bind to the gamma-aminobutyric acid (GABA) receptor.

Overall, there were fewer patients that reported SAEs in the Xtandi arm (33.5%) compared to the placebo arm (38.6%). Serious adverse events other than seizure that occurred more frequently in the Xtandi arm than the placebo arm included: spinal cord compression (6.4% vs. 4.5%), metastatic pain (3.0% vs. 1.5%), pathological fracture (1.5% vs. 0.5%), urinary tract obstruction (1.4% vs. 0.5%), and cauda equina syndrome (1.1% vs. 0.3%). These SAEs are consistent with prostate cancer disease progression, and the increased frequency of these events observed in the Xtandi arm is likely due to the longer duration of exposure compared to the placebo arm.

Adverse events ≥Grade 3 were reported in 47% of Xtandi-treated patients and 53% of placebo-treated patients. Grade 3 and above AEs that occurred more frequently in the Xtandi arm than the placebo arm included: spinal cord compression (5.8% vs. 3.8%), anorexia (2.1% vs. 1.0%), metastatic pain (1.9% vs. 0.8%), and pathological fracture (1.5% vs. 0.5%). These ≥Grade 3 AEs are also consistent with prostate cancer disease progression, and the increased frequency of these events observed in the Xtandi arm is likely due to the longer duration of exposure compared to the placebo arm. Adverse events that led to discontinuation were reported for 7.6% of Xtandi-treated patients and 9.8% of placebo-treated patients.

Enzalutamide produced a suppression of human Ether-à-go-go-Related Gene (hERG) potassium currents, raising concerns about QTc prolongation liability. A thorough QT study was not conducted. The effects of Xtandi treatment on electrocardiographic changes were evaluated as a substudy within the Phase III study, where electrocardiogram (ECG) data was collected from patients at the trough plasma concentration. Xtandi, at the therapeutic dose of 160 mg once daily, was associated with QTc prolongation of 3.0 to 6.5 ms that was significantly different than placebo, with 2-sided 90% CI upper bounds up to 7.5 ms. Monitoring of ECG and serum electrolyte levels at baseline and during treatment should therefore be considered for patients at risk for electrolyte abnormality and QTc prolongation.

Patients with a history of significant cardiovascular disease were excluded from clinical trials, therefore the safety of Xtandi in this patient population is not known.

Overall, despite the important safety concerns associated with Xtandi, the safety profile of Xtandi is acceptable and manageable for patients with metastatic castration-resistant prostate cancer who have progressed after treatment with docetaxel. The labelling ensures proper monitoring of AEs, and appropriate warnings and precautions, including the Serious Warnings and Precautions Box, are in place in the approved Xtandi Product Monograph to address the identified and important safety concerns.

For more information, refer to the Xtandi Product Monograph, approved by Health Canada and available through the Drug Product Database.