SUMMARY

• The recommended dose of ERLEADA is 240 mg administered orally once daily.¹ For patients who require a dose reduction, ERLEADA 60 mg tablets are available for the prescribed reduced daily dose. Johnson & Johnson cannot recommend splitting a tablet or any other practices, procedures, or dosage administration techniques that deviate from the approved product labeling. Please refer to local labeling for guidance and additional considerations.
• In SPARTAN, a phase 3 trial evaluating the efficacy and safety of ERLEADA compared to placebo in patients with high-risk non-metastatic castration-resistant prostate cancer (nmCRPC; N=1207), patients were randomized 2:1 to receive either ERLEADA 240 mg orally once daily or placebo. Patients received a gonadotropin-releasing hormone (GnRH) analog concurrently or had a bilateral orchiectomy.²
  • The results for the primary endpoint, metastasis-free survival (MFS), are described below. The most common (>1%) adverse events (AEs) that led to dose reduction or interruption were rash, diarrhea, fatigue, nausea, hypertension, hematuria, and vomiting (Table: Adverse Events Leading to Dose Reduction and Dose Interruption in SPARTAN).³
• Per the SPARTAN study protocol, dose interruptions and/or reductions of study drug were permitted if study discontinuation criteria were not met.⁴
  • If a patient experienced a grade ≥3 toxicity or an intolerable side effect, dosing could be held until symptoms improved to grade ≤1 or original grade, and then resumed at the same dose or a reduced dose (180 mg or 120 mg), if warranted.
  • Permanent discontinuation of study drug was required for patients who experienced treatment-related seizure of any grade.
• A population pharmacokinetics (PK) model for plasma concentrations of apalutamide and N-desmethyl-apalutamide sampled from patients enrolled in the SPARTAN study (N=1206) evaluated the exposure-response relationship of apalutamide PK and MFS. The results are summarized below.⁵
• In TITAN, a phase 3 trial evaluating the efficacy and safety of ERLEADA compared to placebo in patients with metastatic castrationsensitive prostate cancer (mCSPC; N=1052), patients were randomized 1:1 to receive either ERLEADA 240 mg orally once daily or placebo.⁶ Patients received androgen deprivation therapy (ADT) via a GnRH analog or surgical castration.⁷
  • The results for the dual primary endpoints, radiographic progression-free survival (rPFS) and overall survival (OS), are described below. The most common (>1%) AEs that led to dose reduction or interruption were rash, aspartate aminotransferase or alanine aminotransferase increased, pain, infections, hypertension and fatigue (Table: Adverse Events Leading to Dose Reduction and Dose Interruption in TITAN).⁸
• Per the TITAN study protocol, dose modifications were permitted for drug-related toxicities (Table: Dose Modifications of ERLEADA in TITAN).⁷
  • For a grade ≥3 toxicity, dosing could be held until grade 1 or baseline, and then ERLEADA could be resumed at full dose.
  • Patients who developed a seizure of any grade or grade 4 neurotoxicity were required to discontinue study treatment.
• A PK study of the plasma concentrations of apalutamide and N-desmethyl-apalutamide sampled from patients enrolled in the TITAN study (N=1052) evaluated the relationship between apalutamide exposure and select clinical efficacy and safety endpoints. The results are summarized below.⁹
• An exploratory analysis was conducted to assess time to dose modification in patients with evaluable apalutamide plasma concentration using pooled data from the SPARTAN and TITAN studies. Results are summarized below.¹⁰
• An integrated analysis describing dose modifications in Japanese patients that experienced skin rash from SPARTAN, TITAN, and a phase 1 study has been reported.¹¹

CLINICAL DATA

Phase 3 SPARTAN Study

Smith et al (2018)² evaluated the efficacy and safety of ERLEADA compared to placebo in patients with high-risk (defined as prostate-specific antigen [PSA] doubling time [PSADT] ≤10 months) nmCRPC (N=1207).

Study Design/Methods

• Patients were randomized 2:1 to receive either ERLEADA orally at a dose of 240 mg once daily (n=806) or placebo once daily (n=401).
• All patients in the SPARTAN study received a concomitant GnRH analog or had a bilateral orchiectomy.
• Patients continued treatment until protocol-defined progression, AEs, or withdrawal of consent.
• Interventions required to manage local or regional symptoms were allowed.
• The primary endpoint, MFS, was defined as the time from randomization to the first detection of distant metastasis on imaging by blinded independent central review or death from any cause, whichever occurred first.
• AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
• Dose interruptions and/or reductions were permitted if study discontinuation criteria were not met. Dose modification criteria used during the study were as follows:⁴
  • Permanent discontinuation of study drug was required for patients who experienced treatment-related seizure of any grade.
  • For patients who experienced grades 1-2 treatment-related AEs, short treatment breaks could be instituted as per the discretion of the investigator until the severity of the toxicity decreased to grade 1 or returned to baseline.
    • If toxicity recurred, dose reductions to the next lower dose level (180 mg or 120 mg) were allowed as per the discretion of the investigator.
  • For patients who experienced grade ≥3 treatment-related AEs other than seizure, study drug was to be held until the severity of the toxicity decreased to grade 1 or returned to baseline.
    • If toxicity recurred at grade ≥3, the dose of ERLEADA was to be reduced to the next lower dose level (180 mg or 120 mg).
    • A maximum of 2 dose level reductions was allowed.
  • Any patient who experienced an AE that could not be adequately managed with dose modifications, including dose interruption for ≥28 days, may have required study drug discontinuation based on consultation with the Sponsor.
  • Re-escalating doses following dose reduction for study treatment-related toxicities was generally not recommended; however, re-escalation back to the previous dose level was permitted at the discretion of the investigator and in consultation with the Sponsor (or designee).

Results

• Significant improvement in the primary endpoint, MFS, was observed: 40.5 months vs 16.2 months in the ERLEADA group vs the placebo group, respectively (HR, 0.28; 95% CI, 0.23-0.35; P<0.001).
• The most common (>1%) AEs that led to dose reduction or interruption were rash, diarrhea, fatigue, nausea, hypertension, hematuria, and vomiting (Table: Adverse Events Leading to Dose Reduction and Dose Interruption in SPARTAN).³
• Skin rash led to dose reduction and dose interruption in 2.7% and 6.8% of patients, respectively, in the ERLEADA group, and in 0.3% and 1.3% of patients, respectively, in the placebo group.³
  • Treatment for skin rash included topical corticosteroids, oral antihistamines, systemic corticosteroids, drug interruption, and dose reduction.³
  • Among the patients who were treated with ERLEADA and experienced a skin rash (n=191), 35% received antihistamines, 34% received topical corticosteroids, and 17% received systemic corticosteroids.¹²
• Hypothyroidism led to treatment discontinuation and dose reduction in 1 patient each within the ERLEADA group; dose interruption was not reported.³
  • Hypothyroidism was diagnosed with regular thyroid-stimulating hormone monitoring and was manageable with increases or initiation of thyroid replacement therapy.³

Relationship Between Apalutamide Exposure and MFS - Analysis From SPARTAN

Perez-Ruixo et al (2020)⁵ developed a population PK model for plasma concentrations of apalutamide and N-desmethyl-apalutamide sampled from patients enrolled in the SPARTAN study (N=1206) to evaluate the exposure-response relationship of apalutamide PK and MFS.

Results

Exposure Levels and Exposure-MFS Relationship

• Median quartiles of exposure (area under the concentration-time curve during 24 hours at steady state [AUC_0-24h,ss]) for apalutamide and N-desmethyl-apalutamide were corrected based on an average daily dose of 209 mg (apalutamide group) vs 222 mg (placebo group); MFS benefit was similar across the range of exposure quartiles, suggesting that efficacy is at the plateau of exposure response.
• In multivariate Cox regression models, no significant differences in the exposure-MFS relationship were observed for apalutamide and N-desmethyl-apalutamide. Results were consistent across all stratification and prognostic factors investigated.

Exposure-Safety Relationship

• A summary of the probability of experiencing treatment-emergent adverse events (TEAEs) based on apalutamide and N-desmethyl-apalutamide exposure is shown below in Table: Exposure-Safety Analysis of Treatment-Emergent Adverse Events. The analysis demonstrated that the probability of experiencing one of the described TEAEs significantly increased as apalutamide and N-desmethyl-apalutamide AUC_0-24h,ss increased.⁵

Additional Information

• Additional information regarding the SPARTAN study, including the clinical study report, protocol, and statistical analysis plan, can be found at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/Erleada_210951_toc.cfm (scroll to the “Sponsor Clinical Study Reports ARN-509-003 SPARTAN NCT #01946204” section at the bottom of the web page).

Phase 3 TITAN Study

Chi et al (2019)⁶ evaluated the efficacy and safety of ERLEADA plus ADT compared to placebo plus ADT in patients with mCSPC (N=1052).

Study Design/Methods

• Patients were randomized 1:1 to receive either ERLEADA 240 mg orally once daily or placebo once daily.
• All patients received continuous ADT via a GnRH analog or surgical castration.⁷
• The dual primary endpoints are:
  • rPFS, defined as time from randomization to first imaging-based documentation of progressive disease (progression of soft tissue lesions measured by computed tomography or magnetic resonance imaging or new bone lesions on bone scan) or death, whichever occurred first
  • OS
• AEs were graded per National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.3.
• Table: Dose Modifications of ERLEADA in TITAN summarizes the dose modifications for drug-related toxicities (except for rash) followed in TITAN.⁷

Results

• At the final analysis for rPFS (following 365 events), treatment with ERLEADA significantly improved rPFS with a 52% risk reduction of radiographic progression or death (median rPFS could not be estimated in the ERLEADA group and 22.1 months in the placebo group; HR, 0.48; 95% CI, 0.39-0.60; P<0.001).⁶
• At the first interim analysis for OS (following 200 deaths), treatment with ERLEADA significantly improved OS with a 33% risk reduction of death (median OS could not be estimated in either group; HR, 0.67; 95% CI, 0.51-0.89; P=0.005).⁶
• The most common (>1%) AEs that led to dose reduction or interruption were rash, aspartate aminotransferase or alanine aminotransferase increased, pain, infections, hypertension and fatigue (Table: Adverse Events Leading to Dose Reduction and Dose Interruption in TITAN).⁸

Relationship Between Apalutamide Exposure and Efficacy and Safety Endpoints - Analysis From TITAN

T’jollyn et al (2022)⁹ used a population PK model to evaluate the PK of apalutamide and N-desmethyl-apalutamide and relationship between apalutamide exposure and select clinical efficacy and safety endpoints in patients enrolled in the TITAN study (N=1052).

Results

Exposure Levels and Exposure-Efficacy Relationship

• In multivariate analyses after adjusting for all prognostic factors, treatment in the apalutamide vs placebo group was found to be efficacious in extending rPFS (HR, 0.45; 95% CI, 0.36-0.56; P<0.0001) and OS (HR, 0.64; 95% CI, 0.48-0.86; P=0.003).
• No statistical association was observed among rPFS (P=0.653), OS (P=0.172), and apalutamide exposure quartiles within a relatively narrow apalutamide exposure range (coefficient of variation, 22%).

Exposure-Safety Relationship

• A summary of the probability of experiencing TEAEs based on apalutamide exposure is shown below in Table: Exposure-Safety Analysis of Treatment-Emergent Adverse Events. The analysis demonstrated that patients with increased apalutamide exposure had an increased incidence of skin rash and pruritus.

Time to Dose Modification - Exploratory Analysis From the SPARTAN and TITAN Studies

Yu et al (2023)¹⁰ conducted an exploratory analysis to assess time to dose modification in patients with evaluable apalutamide plasma concentration using pooled data from the SPARTAN and TITAN studies (N=1299). Time to dose modification was determined based on when subjects had a dose reduction to below 240 mg. Area under the curve at steady state (AUC_ss) was used. Temporary dose interruptions or reductions on the last day of treatment were not considered dose reductions. A Kaplan-Meier survival analysis was conducted based on the quartiles of apalutamide exposure (AUC_ss) and a separate subgroup analysis was conducted in patients who experienced rash.

• Of the 1299 PK eligible patients, 114 patients (8.8%) had a dose reduction due to an AE. No notable difference was identified in the number of dose modifications attributed to any AE between quartiles of exposure for the total population.
• In the subgroup analysis, 56 patients were identified to have a dose reduction due to rash with no notable difference in dose modifications with increase in exposure.
• No significant difference was observed between dose modifications due to rash vs non-rash AEs. No clear relationship between exposure and time to dose modification was identified when evaluating all dose modifications and dose modifications due to rash only.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 22 July 2024. Summarized in this response are relevant data limited to the phase 3 SPARTAN and TITAN studies in patients with nmCRPC and mCSPC, respectively.