Good clinical practice The clinical studies reviewed in this evaluation were in compliance with published guidelines. Pharmacokinetics Studies providing pharmacokinetic data Table 1 shows the studies relating to each pharmacokinetic topic and the location of each study summary. Table 1: Submitted pharmacokinetic studies. Study ID Study type Phase, design population Number of subjects PK, safety, Phase Ib, open-label Patients with metastatic CRPC Primary analysis 22 Efficacy, safety, PD, PK Phase II, open-label, single arm Patients with prostate cancer 1-year analysis 67 Efficacy, safety, PK Phase I-II open label, uncontrolled, Japanese patients with metastatic CRPC, with or without prior docetaxel Primary analysis 47 None of the pharmacokinetic studies had deficiencies that excluded their results from consideration. Summary of pharmacokinetics The information in the following summary is derived from conventional pharmacokinetic studies unless otherwise stated. Pharmacokinetics in the target population The effect of co-administration of docetaxel and enzalutamide on docetaxel PK was assessed in study MDV3100-06. Concomitant administration was observed to not significantly affect the Cmax, AUClast or AUCmin of docetaxel (Table 2). Table 2: Comparison of plasma docetaxel pharmacokinetic parameters in treatment period 1 (pre-enzalutamide) and 2 (during enzalutamide).
Clinical efficacy Studies providing efficacy data Table 6 shows efficacy studies. Table 6: Submitted efficacy studies. ID Study type Phase, design population Number of subjects PREVAIL Efficacy & safety Phase III, randomised, double-blind, placebo controlled, multicentre naïve patients with metastatic CRPC 871 844 placebo PK, safety, tolerability Phase Ib, Patients with metastatic CRPC 22 Efficacy, safety, tolerability, PD, PK Phase II, single arm Patients with prostate cancer 67 Proposed indication Pivotal efficacy studies Study MDV3100-03 (PREVAIL) Study design, objectives, locations and dates This was a phase 3, randomised, double-blind, placebo-controlled multicentre performed in North America, Europe, Australia and Asia to assess the efficacy and safety of enzalutamide in patients with metastatic prostate cancer that progressed on androgen deprivation therapy. Patients must have been asymptomatic or mildly symptomatic due to prostate cancer at study entry and must not have previously received cytotoxic chemotherapy. Inclusion and exclusion criteria Table shows inclusion and exclusion criteria. Table 7: Inclusion and exclusion criteria. Inclusion criteria Exclusion criteria 1. Age 18 or older and willing and able to provide informed consent 2. Histologically or cytologically confirmed adenocarcinoma of the prostate without 1. Severe, concurrent disease, infection, or comorbidity that, in the judgment of the investigator, make the patient inappropriate for enrolment
Safety, MTD, PK, efficacy Phase I, uncontrolled, dose-escalation and cohorts Patients with metastatic CRPC Primary analysis 140 PK, safety, Phase Ib, Patients with metastatic CRPC Primary analysis 22 Efficacy, safety, PD, PK Phase II, single arm Patients with prostate cancer 1-year analysis 67 Pivotal efficacy study – MDV3100-03 (PREVAIL) The safety population was defined as: All patients randomly assigned to treatment who received at least 1 dose or partial dose of study drug (enzalutamide or placebo). In PREVAIL, the sponsor reports the following safety data were collected: “General adverse events (AEs) were assessed by the frequency of adverse events, grade 3 or higher adverse events, serious adverse events, adverse events that were the primary reason for discontinuation of study drug, adverse events associated with discontinuation of study drug, adverse events leading to dose modification, and deaths, as well as the frequency of new clinically significant changes in physical examination findings, vital signs, laboratory values, and ECGs.” Non-pivotal efficacy studies Studies 9785-CL-0111 and 9785-CL-0321 provided data on safety. Patient exposure In PREVAIL, treatment duration for the interim analysis was calculated up to the data analysis cut-off date for patients receiving ongoing therapy. Patients were required to return any unused medicines; it was assumed that non-returned medicine was The exposure of patients in PREVAIL is shown in Table 20. Table 20: Exposure to enzalutamide & placebo, PREVAIL. Dose modifications were permitted in the study, with 11.8% and 10.0% of the enzalutamide and placebo arms having at least one dose modification, respectively.