ERLEADA Apalutamide 60mg Film-Coated Tablet 120's

Apalutamide (Erleada) is indicated for the treatment of patients with: metastatic castration-sensitive prostate cancer (mCSPC); non-metastatic, castration-resistant prostate cancer (nmCRPC).

Dosage: The recommended dose of Apalutamide (Erleada) is 240 mg (four 60 mg tablets) administered orally once daily. Swallow the tablets whole. Apalutamide (Erleada) can be taken with or without food.
Dose modification: If a patient experiences a ≥ Grade 3 toxicity or an intolerable side effect, hold dosing until symptoms improve to ≤ Grade 1 or original grade, then resume at the same dose or a reduced dose (180 mg or 120 mg), if warranted.
Missed dose(s): If the patient misses a dose, it should be taken as soon as possible on the same day with a return to the normal schedule on the following day. The patient should not take extra tablets to make up the missed dose.
Special populations: Pediatrics (17 years of age and younger): The safety and effectiveness of Apalutamide (Erleada) in children have not been evaluated.
There is no relevant use of Apalutamide (Erleada) in pediatric patients aged 17 years and younger.
Elderly (65 years of age and older): Of the 1327 subjects who received Apalutamide (Erleada) in clinical studies, 19% of subjects were less than 65 years, 41% of subjects were 65 years to 74 years, and 40% were 75 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.
Renal impairment: A dedicated renal impairment study for Apalutamide (Erleada) has not been conducted. Based on the population pharmacokinetic analysis using data from clinical studies in subjects with castration-resistant prostate cancer (CRPC) and healthy subjects, no significant difference in systemic exposure was observed in subjects with pre-existing mild to moderate renal impairment (estimated glomerular filtration rate [eGFR] between 30 to 89 mL/min/1.73m²) compared to subjects with baseline normal renal function (eGFR ≥ 90 mL/ min/1.73m²). No dosage adjustment is necessary for patients with mild to moderate renal impairment. No data are available in patients with severe renal impairment or end-stage renal disease (eGFR ≤ 29 mL/min /1.73m²) (see Pharmacology: Pharmacokinetics under Actions).
Hepatic impairment: A dedicated hepatic impairment study compared the systemic exposure of apalutamide and N-desmethyl apalutamide in subjects with baseline mild or moderate hepatic impairment (Child-Pugh Class A or B, respectively) versus healthy controls with normal hepatic function. The systemic exposure of apalutamide and N-desmethyl apalutamide was similar in subjects with mild or moderate baseline hepatic impairment compared to subjects with normal hepatic function. No dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. No data are available in patients with severe hepatic impairment (Child-Pugh Class C) (see Pharmacology: Pharmacokinetics under Actions).
Administration: Apalutamide (Erleada) should be administered orally once daily, with or without food. Swallow the tablets whole.

There is no known specific antidote for apalutamide overdose. No dose-limiting toxicities were observed at 480 mg daily (double the recommended daily dose).
It is advisable to contact a poison control center to obtain the latest recommendations for the management of an overdose.
Treatment: In the event of an overdose, stop Apalutamide (Erleada), undertake general supportive measures until clinical toxicity has been diminished or resolved.

May be taken with or without food.

Apalutamide (Erleada) is contraindicated in women who are or may become pregnant (see Use in Pregnancy & Lactation).

Falls and fractures: Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone-targeted agents.
In SPARTAN, a randomized study of patients with nmCRPC, fracture was reported for 11.7% of subjects treated with Apalutamide (Erleada) and 6.5% of subjects treated with placebo. Half of the subjects experienced a fall within 7 days before the fracture event in both treatment groups. Falls were reported for 15.6% of subjects treated with Apalutamide (Erleada) versus 9.0% of subjects treated with placebo. Evaluate patients for fracture and fall risk. In TITAN, a randomized study of patients with mCSPC, nonpathological fractures occurred in 6% of patients treated with Apalutamide (Erleada) and in 5% of patients treated with placebo.
Ischemic heart disease and ischemic cerebrovascular disorders: Ischemic heart disease and ischemic cerebrovascular disorders, including events leading to death, occurred in patients treated with Apalutamide (Erleada). Monitor for signs and symptoms of ischemic heart disease and ischemic cerebrovascular disorders. Optimize management of risk factors, such as hypertension, diabetes, or dyslipidemia.
In a randomized study SPARTAN, ischemic heart disease occurred in 4% of patients treated with Apalutamide (Erleada) and 3% of patients treated with placebo. In a randomized study TITAN, ischemic heart disease occurred in 4% of patients treated with Apalutamide (Erleada) and 2% of patients treated with placebo. Across the SPARTAN and TITAN studies, 6 patients (0.5%) treated with Apalutamide (Erleada) and 2 patients (0.2%) treated with placebo died from ischemic heart disease.
In the SPARTAN study, with a median exposure of 32.9 months for Apalutamide (Erleada) and 11.5 months for placebo, ischemic cerebrovascular disorders occurred in 4% of patients treated with Apalutamide (Erleada) and 1% of patients treated with placebo (see Adverse Reactions). In the TITAN study, ischemic cerebrovascular disorders occurred in a similar proportion of patients in the Apalutamide (Erleada) (1.5%) and placebo (1.5%) groups. Across the SPARTAN and TITAN studies, 2 patients (0.2%) treated with Apalutamide (Erleada) and no patients treated with placebo died from an ischemic cerebrovascular disorder.
Patients with history of unstable angina, myocardial infarction, congestive heart failure, stroke, or transient ischemic attack within six months of randomization were excluded from the SPARTAN and TITAN studies.
Seizure: Permanently discontinue Apalutamide (Erleada) in patients who develop a seizure during treatment.
In two randomized studies, SPARTAN and TITAN, five subjects (0.4%) treated with Apalutamide (Erleada) and two subjects (0.2%) treated with placebo experienced a seizure. In these studies, subjects with a history of seizure or predisposing factors for seizure were excluded. No seizures occurred in two other studies that enrolled 145 subjects. There is no clinical experience in re-administering Apalutamide (Erleada) to patients who experienced a seizure.
Effects on Ability to Drive and Use Machines: No studies on the effects of Apalutamide (Erleada) on the ability to drive or use machines have been performed. It is not anticipated that Apalutamide (Erleada) will affect the ability to drive and use machines.

Pregnancy: Apalutamide (Erleada) is contraindicated in women who are or may become pregnant. Based on its mechanism of action, Apalutamide (Erleada) may cause fetal harm when administered during pregnancy. There are no data available with the use of Apalutamide (Erleada) during pregnancy.
Animal reproductive and development studies have not been conducted with Apalutamide (Erleada).
Contraception: Apalutamide (Erleada) may be harmful to a developing fetus. Patients having sex with female partners of reproductive potential should use a condom along with another highly effective contraceptive method during treatment and for 3 months after the last dose of Apalutamide (Erleada) (See Pregnancy as previously mentioned).
Breast-feeding: There are no data on the presence of apalutamide or its metabolites in human milk, the effect on the breastfed infant, or the effect on milk production.
Fertility: Based on animal studies, Apalutamide (Erleada) may impair fertility in males of reproductive potential (see Pharmacology: Toxicology: Non-Clinical Information under Actions).

Throughout this section, adverse reactions are presented. Adverse reactions are adverse events that were considered to be reasonably associated with the use of apalutamide based on the comprehensive assessment of the available adverse event information. A causal relationship with apalutamide cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
In studies of patients with mCSPC (TITAN) or nmCRPC (SPARTAN) who were using a GnRH analog, or were previously treated with orchiectomy, Apalutamide (Erleada) was administered at a dose of 240 mg daily.
Table 4 shows adverse reactions on the Apalutamide (Erleada) arm in the combined data that occurred with a ≥2% absolute increase in frequency compared to placebo or were events of special interest. ARs are also listed by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), and rare (≥ 1/10000 to < 1/1000). Within each frequency grouping, ARs are presented in order of decreasing frequency. (See Table 4.)




Skin rash: In the combined data of two randomized, placebo-controlled clinical studies, skin rash associated with Apalutamide (Erleada) was most commonly described as macular or maculo-papular. Adverse reactions of skin rash were reported for 26% of subjects treated with Apalutamide (Erleada) versus 8% of subjects treated with placebo. Grade 3 skin rashes (defined as covering > 30% body surface area [BSA]) were reported with Apalutamide (Erleada) treatment (6%) versus placebo (0.5%). There were no reported events of toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome (SJS) in clinical trials.
The onset of skin rash occurred at a median of 83 days of Apalutamide (Erleada) treatment and resolved within a median of 78 days from onset of rash for 78% of subjects. Rash was commonly managed with oral antihistamines, topical corticosteroids, and 19% of subjects received systemic corticosteroids. Among subjects with skin rash, dose interruption occurred in 28% and dose reduction occurred in 14% (see Dose modification under Dosage & Administration). Of the patients who had dose interruption, 59% experienced recurrence of rash upon reintroduction of Apalutamide (Erleada). Skin rash led to Apalutamide (Erleada) treatment discontinuation in 7% of subjects who experienced skin rash.
Hypothyroidism: In the combined data of two randomized, placebo-controlled studies, hypothyroidism was reported for 8% of subjects treated with Apalutamide (Erleada) and 2% of subjects treated with placebo based on assessments of thyroid-stimulating hormone (TSH) every 4 months. There were no grade 3 or 4 adverse reactions. Hypothyroidism occurred in 30% of subjects already receiving thyroid replacement therapy in the Apalutamide (Erleada) arm and in 3% of subjects in the placebo arm. In subjects not receiving thyroid replacement therapy, hypothyroidism occurred in 7% of subjects treated with Apalutamide (Erleada) and in 2% of subjects treated with placebo. Thyroid replacement therapy, when clinically indicated, should be initiated or dose adjusted (see Effect of Apalutamide (Erleada) on drug metabolizing enzymes under Interactions).
Postmarketing data: In addition to the adverse reactions reported during clinical studies and listed previously, the following adverse reactions have been reported during postmarketing experience (Table 5). Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In the table, the frequencies are provided according to the following convention: Very common ≥ 1/10 (≥ 10%); Common ≥ 1/100 and < 1/10 (≥ 1% and < 10%); Uncommon ≥ 1/1000 and < 1/100 (≥ 0.1% and < 1%); Rare ≥ 1/10000 and < 1/1000 (≥ 0.01 and < 0.1%); Very rare < 1/10000, including isolated reports (< 0.01%); Not known: Cannot be estimated from the available data.
In Table 5, adverse reactions are presented by frequency category based on spontaneous reporting rates and by frequency category based on incidence in clinical trials or epidemiology studies, when known. (See Table 5.)

Medications that Inhibit CYP2C8: In a drug-drug interaction study, the C_max of apalutamide decreased by 21% while AUC increased by 68% following co-administration of Apalutamide (Erleada) as a 240 mg single dose with gemfibrozil (strong CYP2C8 inhibitor). Simulations suggest that gemfibrozil may increase the steady-state C_max and AUC of apalutamide by 32% and 44%, respectively. For the active moieties (sum of unbound apalutamide plus the potency-adjusted unbound active metabolite), the steady-state C_max and AUC may increase by 19% and 23%, respectively (see Figure 11). No initial dose adjustment is necessary however, consider reducing the Apalutamide (Erleada) dose based on tolerability (see Dose modification under Dosage & Administration). Mild or moderate inhibitors of CYP2C8 are not expected to affect the exposure of apalutamide.
Medications that Inhibit CYP3A4: In a drug-drug interaction study, the C_max of apalutamide decreased by 22% while AUC was similar following co-administration of Apalutamide (Erleada) as a 240 mg single dose with itraconazole (strong CYP3A4 inhibitor). Simulations suggest that ketoconazole (strong CYP3A4 inhibitor) may increase the steady-state C_max and AUC of apalutamide by 38% and 51%, respectively. For the active moieties, the steady-state C_max and AUC may increase by 23% and 28%, respectively (see Figure 11). No initial dose adjustment is necessary however, consider reducing the Apalutamide (Erleada) dose based on tolerability (see Dose modification under Dosage & Administration). Mild or moderate inhibitors of CYP3A4 are not expected to affect the exposure of apalutamide.
Medications that Induce CYP3A4 or CYP2C8: The effects of CYP3A4 or CYP2C8 inducers on the pharmacokinetics of apalutamide have not been evaluated in vivo. Simulations suggest that rifampin (strong CYP3A4 and moderate CYP2C8 inducer) may decrease the steady-state C_max and AUC of apalutamide by 25% and 34%, respectively. For the active moieties, the steady-state C_max and AUC may decrease by 15% and 19%, respectively (see Figure 11).
Acid lowering agents: Apalutamide is not ionizable under relevant physiological pH condition, therefore acid lowering agents (e.g. proton pump inhibitor, H₂-receptor antagonist, antacid) are not expected to affect the solubility and bioavailability of apalutamide.
Medications that affect transporters: In vitro, apalutamide and its N-desmethyl metabolite are substrates for P-gp but not BCRP, OATP1B1, and OATP1B3. Because apalutamide is completely absorbed after oral administration, P-gp does not limit the absorption of apalutamide and therefore, inhibition or induction of P-gp is not expected to affect the bioavailability of apalutamide.
Effect of Apalutamide (Erleada) on drug metabolizing enzymes: In vitro studies showed that apalutamide and N-desmethyl apalutamide are moderate to strong CYP3A4 and CYP2B6 inducers, are moderate inhibitors of CYP2B6 and CYP2C8, and weak inhibitors of CYP2C9, CYP2C19, and CYP3A4. Apalutamide and N-desmethyl apalutamide do not affect CYP1A2 and CYP2D6 at therapeutically relevant concentrations.
In humans, Apalutamide (Erleada) is a strong inducer of CYP3A4 and CYP2C19, and a weak inducer of CYP2C9. In a drug-drug interaction study using a cocktail approach, co-administration of Apalutamide (Erleada) with single oral doses of sensitive CYP substrates resulted in a 92% decrease in the AUC of midazolam (CYP3A4 substrate), 85% decrease in the AUC of omeprazole (CYP2C19 substrate), and 46% decrease in the AUC of S-warfarin (CYP2C9 substrate). Apalutamide (Erleada) did not cause clinically meaningful changes in exposure to the CYP2C8 substrate (see Figure 4). Concomitant use of Apalutamide (Erleada) with medications that are primarily metabolized by CYP3A4, CYP2C19, or CYP2C9 can result in lower exposure to these medications. Substitution for these medications is recommended when possible or evaluate for loss of efficacy if medication is continued. If given with warfarin, monitor International Normalized Ratio (INR) during Apalutamide (Erleada) treatment.
Induction of CYP3A4 by apalutamide suggests that UDP-glucuronosyl transferase (UGT) may also be induced via activation of the nuclear pregnane X receptor (PXR). Concomitant administration of Apalutamide (Erleada) with medications that are substrates of UGT can result in lower exposure to these medications. Use caution if substrates of UGT must be co-administered with Apalutamide (Erleada) and evaluate for loss of efficacy.
Effect of apalutamide on drug transporters: Apalutamide was shown to be a weak inducer of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide 1B1 (OATP1B1) clinically. A drug-drug interaction study using a cocktail approach showed that co-administration of Apalutamide (Erleada) with single oral doses of sensitive transporter substrates resulted in a 30% decrease in the AUC of fexofenadine (P-gp substrate) and 41% decrease in the AUC of rosuvastatin (BCRP/OATP1B1 substrate) but had no impact on C_max (see Figure 11). Concomitant use of Apalutamide (Erleada) with medications that are substrates of P-gp, BCRP, or OATP1B1 can result in lower exposure of these medications. Use caution if substrates of P-gp, BCRP or OATP1B1 must be co-administered with Apalutamide (Erleada) and evaluate for loss of efficacy if medication is continued.
Based on in vitro data, inhibition of organic cation transporter 2 (OCT2), organic anion transporter 3 (OAT3) and multidrug and toxin extrusions (MATEs) by apalutamide and its N-desmethyl metabolite cannot be excluded. No in vitro inhibition of organic anion transporter 1 (OAT1) was observed. Simulations suggest that apalutamide does not cause clinically meaningful changes in exposure to metformin (OCT2/MATEs substrate) and benzylpenicillin (OAT3 substrate) (see Figure 11).

Store at temperatures not exceeding 30°C.

Pharmacology: Pharmacodynamics: Mechanism of action: Apalutamide is an orally administered, selective Androgen Receptor (AR) inhibitor that binds directly to the ligand-binding domain of the AR. Apalutamide prevents AR nuclear translocation, inhibits DNA binding, impedes AR-mediated transcription, and lacks androgen receptor agonist activity in preclinical studies. In mouse models of prostate cancer, apalutamide administration causes decreased tumor cell proliferation and increased apoptosis leading to potent antitumor activity. A major metabolite, N-desmethyl apalutamide, exhibited one-third the in vitro activity of apalutamide.
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.)




A 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.)








Treatment 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).








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).








At 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).








At 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.)




At 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.)




If 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.)




There 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 (C_max 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%) C_max 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%) C_max 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 (t_max) 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 C_max and AUC. Median time to reach t_max 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.)




No 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. Results of a 24-month carcinogenicity study in the male rate are not yet available. 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.

Cancer Hormone Therapy