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Pharmacodynamic effects: Effect on QT/QTc interval and cardiac electrophysiology: The effect of apalutamide 240 mg once daily on the QT interval was assessed in an open-label, uncontrolled, multi-center, single-arm dedicated QT study in 45 subjects with CRPC. The maximum mean QTcF change from baseline was 12.4 ms (2-sided 90% upper CI: 16.0 ms). An exposure-QT analysis suggested a concentration-dependent increase in QTcF for apalutamide and its active metabolite.
Clinical studies: The efficacy of Apalutamide (Erleada) was established in two randomized placebo-controlled multicenter Phase 3 clinical studies of subjects with mCSPC (TITAN) or nmCRPC (SPARTAN). All subjects in these studies received concomitant GnRH analog or had prior bilateral orchiectomy.
TITAN: Metastatic Castration-sensitive Prostate Cancer (mCSPC): TITAN was a randomized, double-blind, placebo-controlled, multinational, multicenter clinical trial in which 1052 subjects with mCSPC were randomized (1:1) to receive either Apalutamide (Erleada) orally at a dose of 240 mg once daily (N = 525) or placebo once daily (N = 527). All subjects in the TITAN trial received concomitant GnRH analog or had prior bilateral orchiectomy. Subjects were stratified by Gleason score at diagnosis, prior docetaxel use, and region of the world. Subjects with both high- and low-volume mCSPC were eligible for the study.
The following patient demographics and baseline disease characteristics were balanced between the treatment arms. The median age was 68 years (range 43-94) and 23% of subjects were 75 years of age or older. The racial distribution was 68% Caucasian, 22% Asian, and 2% Black. Sixty-three percent (63%) of subjects had high-volume disease and 37% had low-volume disease. Sixteen percent (16%) of subjects had prior surgery, radiotherapy of the prostate or both. A majority of subjects had a Gleason score of 7 or higher (92%). Sixty-eight percent (68%) of subjects received prior treatment with a first-generation anti-androgen in the non-metastatic setting. All subjects except one in the placebo group, had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1 at study entry. Among the subjects who discontinued study treatment (N = 271 for placebo and N = 170 for Apalutamide (Erleada)), the most common reason for discontinuation in both arms was disease progression. A greater proportion (73%) of subjects treated with placebo received subsequent anti-cancer therapy compared to subjects treated with Apalutamide (Erleada) (54%).
The major efficacy outcome measures of the study were overall survival (OS) and radiographic progression-free survival (rPFS). An updated OS analysis was conducted at the time of final study analysis when 405 deaths were observed with a median follow-up of 44 months. Results from this updated analysis were consistent with those from the pre-specified interim analysis. Efficacy results of TITAN are summarized in Table 1 and Figures 1 and 2. (See Table 1.)
Click on icon to see table/diagram/imageA statistically significant improvement in OS and rPFS was demonstrated in subjects randomized to receive Apalutamide (Erleada) compared with subjects randomized to receive placebo in the primary analysis. At the time of updated OS analysis, a pre-specified sensitivity analysis using the inverse probability censoring weighted (IPCW) log-rank test was conducted to adjust for subject crossover from placebo to apalutamide. The improvement in OS was demonstrated even though 39% of subjects in the placebo arm crossed over to receive Apalutamide (Erleada), with a median treatment of 15 months on Apalutamide (Erleada) crossover.
Consistent improvement in rPFS was observed across the following subject subgroups: disease volume (high vs low), previous treatment for localized disease (yes or no), prior docetaxel use (yes or no), and Gleason score at diagnosis (≤7 vs. >7).
Consistent improvement in OS was observed across the following subject subgroups: disease volume (high vs low), previous treatment for localized disease (yes or no), and Gleason score at diagnosis (≤7 vs. >7). (See Figure 1 and 2.)
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Click on icon to see table/diagram/imageTreatment with Apalutamide (Erleada) statistically significantly delayed the initiation of cytotoxic chemotherapy (HR = 0.391, 95% CI = 0.274, 0.558; p < 0.0001), resulting in a 61% reduction of risk for subjects in the treatment arm compared to the placebo arm.
There were no significant detrimental effects to overall health-related quality of life, as measured by the FACT-P total score change from baseline, with the addition of Apalutamide (Erleada) to ADT. The addition of Apalutamide (Erleada) to ADT did not worsen the FACT-P item level score for fatigue or patient reported bother due to side effects.
SPARTAN: Non-metastatic, Castration-resistant Prostate Cancer (nmCRPC): A total of 1207 subjects with nmCRPC were randomized 2:1 to receive either Apalutamide (Erleada) orally at a dose of 240 mg once daily in combination with ADT (medical castration or surgical castration) or placebo with ADT in a multicenter, double-blind, clinical trial (SPARTAN). Subjects enrolled had a Prostate Specific Antigen (PSA) Doubling Time (PSADT) ≤ 10 months. All subjects who were not surgically castrated received ADT continuously throughout the study. Seventy-three percent (73%) of subjects received prior treatment with a first generation anti-androgen; 69% of subjects received bicalutamide and 10% of subjects received flutamide. Systemic corticosteroids were not allowed at study entry. PSA results were blinded and were not used for treatment discontinuation. Subjects randomized to either arm were to continue treatment until disease progression defined by blinded central imaging review (BICR), initiation of new treatment, unacceptable toxicity or withdrawal. Upon development of distant metastatic disease, subjects were offered ZYTIGA as an option for the first subsequent treatment after study treatment discontinuation.
The following patient demographics and baseline disease characteristics were balanced between the treatment arms. The median age was 74 years (range 48-97) and 26% of subjects were 80 years of age or older. The racial distribution was 66% Caucasian, 5.6% Black, 12% Asian, and 0.2% Other. Seventy-seven percent (77%) of subjects in both treatment arms had prior surgery or radiotherapy of the prostate. A majority of subjects had a Gleason score of 7 or higher (81%). Fifteen percent (15%) of subjects had <2 cm pelvic lymph nodes at study entry. All subjects enrolled were confirmed to be non-metastatic by blinded central imaging review and had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) performance status score of 0 or 1 at study entry.
Metastasis-free survival (MFS) is defined as the time from randomization to the time of first evidence of BICR-confirmed bone or soft tissue distant metastasis or death due to any cause, whichever occurred first. Treatment with Apalutamide (Erleada) significantly improved MFS. Apalutamide (Erleada) decreased the risk of distant metastasis or death by 72%. The median MFS for Apalutamide (Erleada) was 41 months and was 16 months for placebo (see Figures 3 and 4).
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Click on icon to see table/diagram/imageAll subjects = Intent-to Treat population
The non-stratified analysis is presented in Figure 4.
Subjects treated with Apalutamide (Erleada) and ADT showed significant improvement over those treated with ADT alone for the following secondary endpoints of time to metastasis (TTM), progression-free survival (PFS), and time to symptomatic progression. In addition, overall survival (OS) and time to initiation of cytotoxic chemotherapy were also significantly improved (see Table 2 for Interim Analysis and Table 3 for Final Analysis).
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Click on icon to see table/diagram/imageAt the interim analysis, treatment with Apalutamide (Erleada) significantly decreased the risk of symptomatic progression by 55% compared with placebo (see Table 2 and Figure 5). The final analysis corroborated that treatment with Apalutamide (Erleada) decreased the risk of symptomatic progression by 43% compared with placebo (see Table 3 and Figure 6).
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Click on icon to see table/diagram/imageAt the interim analysis, with median follow-up time of 20.3 months, the OS was longer for Apalutamide (Erleada) than placebo with a hazard ratio (HR) of 0.700 (95% CI: 0.472, 1.038). The p-value was 0.0742 which did not meet the pre-specified value for statistical significance. At the final analysis, with median follow-up time of 52.0 months, results showed that treatment with Apalutamide (Erleada) significantly decreased the risk of death by 22% compared with placebo (HR=0.784; 95% CI: 0.643, 0.956; 2-sided p=0.0161). The median OS was 73.9 months for the Apalutamide (Erleada) arm and 59.9 months for the placebo arm. The pre-specified alpha boundary (p≤0.046) for this final analysis was crossed and statistical significance was achieved. (See Figure 7.)
Click on icon to see table/diagram/imageAt the final analysis, treatment with Apalutamide (Erleada) significantly decreased the risk of initiating cytotoxic chemotherapy by 37% compared with placebo (HR = 0.629; 95% CI: 0.489, 0.808; p = 0.0002) demonstrating statistically significant improvement for Apalutamide (Erleada) versus placebo. The median time to the initiation of cytotoxic chemotherapy was not reached for either treatment arm. (See Figure 8.)
Click on icon to see table/diagram/imageIf eligible and without evidence of disease progression, subjects treated with placebo were given the opportunity to cross-over to treatment with Apalutamide (Erleada) at time of unblinding. After unblinding, 19% of the randomized placebo population crossed over to Apalutamide (Erleada). Of all the randomized subjects, a greater proportion of subjects in the placebo arm received subsequent therapy (285/401, 71%) compared with the Apalutamide (Erleada) arm (386/806, 48%).
At the interim analysis, post-progression survival (PFS-2, defined as the time to death or disease progression by PSA, radiographic, or symptomatic progression on or after first subsequent therapy) was longer for subjects treated with Apalutamide (Erleada) compared to those treated with placebo (HR = 0.489; 95%CI: 0.361, 0.662; p < 0.0001). Final analysis of PFS-2 confirmed a 44% reduction in risk of PFS-2 with Apalutamide (Erleada) versus placebo (HR = 0.565; 95% CI: 0.471, 0.677; p < 0.0001). (See Figure 9.)
Click on icon to see table/diagram/imageThere were no detrimental effects to overall health-related quality of life with the addition of Apalutamide (Erleada) to ADT and a small but not clinically meaningful difference in change from baseline in favor of Apalutamide (Erleada) observed in the analysis of the Functional Assessment of Cancer Therapy-Prostate (FACT-P) total score and subscales.
Pharmacokinetics: Following repeat once-daily dosing, apalutamide exposure (Cmax and area under the concentration curve [AUC]) increased in a dose-proportional manner across the dose range of 30 to 480 mg. Following administration of 240 mg once daily, apalutamide steady state was achieved after 4 weeks and the mean accumulation ratio was approximately 5-fold relative to a single dose. At steady-state, mean (CV%) Cmax and AUC values for apalutamide were 6 μg/mL (28%) and 100 μg.h/mL (32%), respectively. Daily fluctuations in apalutamide plasma concentrations were low, with mean peak-to-trough ratio of 1.63. An increase in apparent clearance (CL/F) was observed with repeat dosing, likely due to induction of apalutamide's own metabolism.
At steady-state, the mean (CV%) Cmax and AUC values for the major active metabolite, N-desmethyl apalutamide, were 5.9 μg/mL (18%) and 124 μg.h/mL (19%), respectively. N-desmethyl apalutamide is characterized by a flat concentration-time profile at steady-state with a mean peak-to-trough ratio of 1.27. Mean (CV%) AUC metabolite/parent drug ratio for N-desmethyl apalutamide following repeat-dose administration was about 1.3 (21%). Based on systemic exposure, relative potency, and pharmacokinetic properties, N-desmethyl apalutamide likely contributed to the clinical activity of apalutamide.
Absorption: After oral administration, median time to achieve peak plasma concentration (tmax) was 2 hours (range: 1 to 5 hours). Mean absolute oral bioavailability is approximately 100%, indicating that apalutamide is completely absorbed after oral administration.
Administration of apalutamide to healthy subjects under fasting conditions and with a high-fat meal resulted in no clinically relevant changes in Cmax and AUC. Median time to reach tmax was delayed about 2 hours with food (see Figure 3) (see Dosage & Administration).
Distribution: The mean apparent volume of distribution at steady-state of apalutamide is about 276 L. The volume of distribution of apalutamide is greater than the volume of total body water, indicative of extensive extravascular distribution. Apalutamide and N-desmethyl apalutamide are 96% and 95% bound to plasma proteins, respectively, and mainly bind to serum albumin with no concentration dependency.
Metabolism: Following single oral administration of 14C-labeled apalutamide 240 mg, apalutamide, the active metabolite, N-desmethyl apalutamide, and an inactive carboxylic acid metabolite accounted for the majority of the 14C-radioactivity in plasma, representing 45%, 44%, and 3%, respectively, of the total 14C-AUC.
Metabolism is the main route of elimination of apalutamide. It is metabolized primarily by CYP2C8 and CYP3A4 to form N-desmethyl apalutamide. Apalutamide and N-desmethyl apalutamide are further metabolized to form the inactive carboxylic acid metabolite by carboxylesterase. The contribution of CYP2C8 and CYP3A4 in the metabolism of apalutamide is estimated to be 58% and 13% following single dose but changes to 40% and 37%, respectively at steady-state.
Elimination: Apalutamide, mainly in the form of metabolites, is eliminated primarily via urine. Following a single oral administration of radiolabeled apalutamide, 89% of the radioactivity was recovered up to 70 days post-dose: 65% was recovered in urine (1.2% of dose as unchanged apalutamide and 2.7% as N-desmethyl apalutamide) and 24% was recovered in feces (1.5% of dose as unchanged apalutamide and 2% as N-desmethyl apalutamide).
The CL/F of apalutamide is 1.3 L/h after single dosing and increases to 2.0 L/h at steady-state after once-daily dosing. The mean effective half-life for apalutamide in subjects is about 3 days at steady-state.
Special populations: The effects of renal impairment, hepatic impairment, age, race, and other extrinsic factors on the pharmacokinetics of apalutamide are summarized in Figure 10. (See Figure 10.)
Click on icon to see table/diagram/imageNo clinically significant differences in the pharmacokinetics of apalutamide and N-desmethyl apalutamide were observed in subjects with mild (eGFR 60-89 mL/min/1.73m2) or moderate renal impairment (eGFR 30-59 mL/ min/1.73m2), mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, age ranging from 18 to 94 years, or between different races. The potential effect of severe renal impairment or end stage renal disease (eGFR ≤29 mL/min/1.73m2) have not been established due to insufficient data. Clinical and pharmacokinetic data are not available for patients with severe hepatic impairment (Child-Pugh Class C).
Toxicology: Non-clinical Information: Carcinogenicity and Mutagenicity: Apalutamide was not carcinogenic in a 6-month study in the mae transgenic (Tg.rasH2) mouse.
In the 24-month oral carcinogenicity study in male Sprague-Dawley rats, apalutamide was administered by oral gavage at doses of 5, 15 and 50 mg/kg/ day (0.2, 0.7, and 2.5 times the AUC in patients (human exposure at recommended dose of 240 mg), respectively) for 100 weeks. Apalutamide-related neoplastic findings included an increased incidence of testicular Leydig cell adenoma and carcinoma at doses greater than or equal to 5 mg/kg/day, mammary adenocarcinoma and fibroadenoma at 15 mg/kg/day or 50 mg/kg/ day, and thyroid follicular cell adenoma at 50 mg/kg/day. These findings were considered rat-specific and therefore of limited relevance to humans.
Apalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either in vitro chromosome aberration test, the in vivo rat micronucleus assay or the in vivo rat Comet assay.
Reproductive Toxicology: Male fertility is likely to be impaired by treatment with apalutamide based on findings in repeat-dose toxicology studies which were consistent with the pharmacological activity of apalutamide. In repeat-dose toxicity studies in male rats (up to 26 weeks) and dogs (up to 39 weeks), atrophy, aspermia/hypospermia, degeneration and/or hyperplasia or hypertrophy in the reproductive system were observed at ≥ 25 mg/kg/day in rats (1.4 times the human exposure based on AUC) and ≥ 2.5 mg/kg/day in dogs (0.9 times the human exposure based on AUC).
In a fertility study in male rats, a decrease in sperm concentration and motility, copulation and fertility rates (upon pairing with untreated females) along with reduced weights of the secondary sex glands and epididymis were observed following 4 weeks of dosing at ≥ 25 mg/kg/day (approximately equal to the human exposure based on AUC). Effects on male rats were reversible after 8 weeks from the last apalutamide administration.
In a developmental toxicity study in the rat, apalutamide affected pregnancy including survival. Effects on the external genitalia were observed though apalutamide was not teratogenic.
