SUMMARY

• Cerebrovascular and ischemic cardiovascular events, including events leading to death, occurred in patients receiving ERLEADA(apalutamide). Monitor for signs and symptoms of ischemic heart disease and cerebrovascular disorders. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia.¹ Please refer to local labeling for additional considerations and data.
• In a randomized study (SPARTAN)² of patients with non-metastatic castration-resistant prostate cancer (nmCRPC), ischemic cardiovascular events occurred in 4% of patients treated with ERLEADA and 3% of patients treated with placebo.¹ Cerebrovascular events occurred in 4% of patients treated with ERLEADA and 1% of patients treated with placebo.¹ At the final analysis of overall survival (OS), which occurred after a median follow-up of 52 months, grade 3-4 adverse events (AEs) in the ERLEADA group vs the placebo group included ischemic heart disease (2.6% vs 1.8%) and ischemic cerebrovascular disorders (1.6% vs 0.8%).³ One AE leading to death (myocardial infarction) was considered potentially related to ERLEADA.⁴ Safety results, including cardiovascular events, were also previously reported in the second interim analysis for OS.⁵
• In a randomized study (TITAN)⁶ of patients with metastatic castration-sensitive prostate cancer (mCSPC), ischemic cardiovascular events occurred in 4% of patients treated with ERLEADA and 2% of patients treated with placebo.¹ Cerebrovascular events occurred in 1.5% of patients treated with ERLEADA and 1.5% of patients treated with placebo.¹ At the final analysis of OS, which occurred after a median follow-up of 44.0 months, grades ≥3 AEs in the ERLEADA group vs the placebo group included ischemic heart disease (3.1% vs 0.8%) and ischemic cerebrovascular disorder (1.6% vs 0.2%).^7,8
• Across the SPARTAN and TITAN studies, 6 patients (0.5%) treated with ERLEADA and 2 patients (0.2%) treated with placebo died from an ischemic cardiovascular event. Additionally, across the SPARTAN and TITAN studies, 2 patients (0.2%) treated with ERLEADA, and no patients treated with placebo died from a cerebrovascular event.¹
• 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.¹
• Specific cardiovascular AEs leading to treatment discontinuation, dose reduction, dose interruption, and/or death in the SPARTAN and TITAN studies are included in Table: Cardiovascular-Related Events in the SPARTAN Study^2,9 and Table: Cerebrovascular and Cardiovascular-Related Events in the TITAN Study,^6,10 respectively.
• Post hoc^11,12 and pooled¹³ analyses have additionally evaluated cerebrovascular and cardiovascular events reported in the SPARTAN and TITAN studies.
• An open-label, multicenter, phase 1b study evaluated the effect of ERLEADA 240 mg once daily on ventricular repolarization (corrected QT interval [QTc]) in 45 patients with castration-resistant prostate cancer (CRPC). At steady state, the maximum mean change in Fridericia-corrected QT interval (ΔQTcF) from baseline was 12.4 milliseconds and the upper bound of its associated 90% CI was 16.0 milliseconds. A concentration-dependent increase in QTcF was observed for apalutamide and its active metabolite. Most AEs were grade 1-2 in severity, and no patients discontinued due to QTc prolongation or AEs.¹⁴

CLINICAL DATA

Phase 3 Study in Patients With nmCRPC (SPARTAN)

The SPARTAN study evaluated the efficacy and safety of ERLEADA in patients with nmCRPC who had a prostate-specific antigen doubling time (PSADT) of ≤10 months and confirmation of non-metastatic disease by blinded independent central review (N=1207).²

Study Design/Methods

• Patients were randomized 2:1 to receive either ERLEADA 240 mg orally once daily (n=806) or placebo once daily (n=401).
• All patients in the study received a concomitant gonadotropin-releasing hormone (GnRH) analog or had a prior bilateral orchiectomy.
• Study exclusion criteria related to cardiovascular disease¹⁵:
  • History of uncontrolled hypertension (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg). Patients with a history of uncontrolled hypertension could participate in the study if blood pressure was controlled by anti-hypertensive treatment.
  • Any of the following conditions within 6 months prior to randomization: severe/unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (eg, pulmonary embolism and cerebrovascular accident, including transient ischemic attacks), or clinically significant ventricular arrhythmias
• Patient baseline demographic and disease characteristics were well balanced, and there were no significant differences between groups. The median age of patients in both treatment groups was 74 years.² A total of 75% (599 out of 803) and 76% (302 out of 398) of patients in the ERLEADA and placebo safety populations, respectively, had a history of cardiac disorders, diabetes, or hypertension.¹⁶
• The median treatment duration at primary analysis was 16.9 months in the ERLEADA group and 11.2 months in the placebo group.¹⁶ After unblinding of the study, 76 (19%) patients in the placebo group received therapy with ERLEADA plus ADT (crossover group). At the final analysis for OS, after a median follow-up of 52 months, the median treatment duration was 32.9 months in the ERLEADA group, 11.5 months in the placebo group, and 26.1 months in the crossover group.⁴

Cerebrovascular and Cardiovascular-Related Events

• AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
• Rates of hypertension and cardiovascular-related safety data are reported in Table: Hypertension in the SPARTAN Study and Table: Cardiovascular-Related Events in the SPARTAN Study shown below.
  • When adjusted for exposure, the incidence of hypertension was similar between treatment arms (36.3 events per 100 patient-years in the ERLEADA arm vs 38.7 events per 100 patient-years in the placebo arm).²
• At primary analysis, ischemic heart disease (3.7% [30 out of 803] vs 2.0% [8 out of 398]) and cardiac failure (2.2% [18 out of 803] vs 1.0% [4 out of 398]) were reported in the ERLEADA group and placebo group, respectively.¹⁶
• At the final analysis for OS, grade 3-4 AEs in the ERLEADA group vs the placebo group included ischemic heart disease (2.6% vs 1.8%) and ischemic cerebrovascular disorders (1.6% vs 0.8%).³
• Cerebrovascular events occurred in 4% of patients treated with ERLEADA and 1% of patients treated with placebo.¹
• One AE leading to death (myocardial infarction) was considered potentially related to ERLEADA.⁴
• Atrial fibrillation was the most commonly reported treatment-emergent AE within the Cardiac Disorder System Organ Class (2.6% in the ERLEADA arm [21 out of 803] vs 1.8% in the placebo arm [7 out of 398]).¹⁶
  • When adjusted for exposure, the incidence of atrial fibrillation was similar between the ERLEADA and placebo arms (2.2 events per 100 patient-years for the ERLEADA arm vs 1.7 events per 100 patient-years for the placebo arm).¹⁶

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 Study in Patients With mCSPC (TITAN)

The TITAN study evaluated the efficacy and safety of ERLEADA in patients with mCSPC (N=1052).⁶

Study Design/Methods

• Patients were randomized 1:1 to receive either ERLEADA 240 mg orally once daily (n=525) or placebo once daily (n=527).
• All patients in the study received a concomitant GnRH analog or had a prior bilateral orchiectomy.
• Study exclusion criteria related to cardiovascular disease¹⁷:
  • Any of the following conditions at the time of randomization:
    • Severe/unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (eg, pulmonary embolism), or clinically significant ventricular arrhythmias within 6 months prior to randomization
    • Uncontrolled hypertension (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg). Patients with a history of hypertension could participate in the study if blood pressure was controlled by anti-hypertensive treatment.
• Patient baseline demographic and disease characteristics were well balanced, and there were no significant differences between groups. The median age of patients in the ERLEADA group and placebo group was 69 years and 68 years, respectively.⁶ A total of 66.2% (347 out of 524) and 60.7% (320 out of 527) of patients in the ERLEADA and placebo safety populations, respectively, had a history of cardiac disorders, diabetes, or hypertension.¹⁸
• The median treatment duration was 20.5 months in the ERLEADA group and 18.3 months in the placebo group.⁶ After unblinding of the study, 208 (39.5%) patients in the placebo group received therapy with ERLEADA plus ADT (crossover group). At the final analysis for OS, after a median follow-up of 44.0 months, the median treatment duration was 39.3 months in the ERLEADA group, 20.2 months in the placebo group, and 15.4 months in the crossover group.⁷

Cerebrovascular and Cardiovascular-Related Events

• AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.3.
• Rates of hypertension and cardiovascular-related safety data are reported in Table: Hypertension in the TITAN Study - Primary Analysis and Table: Cerebrovascular and Cardiovascular-Related Events in the TITAN Study - Primary Analysis shown below.
• AEs classified as cardiac disorders occurred in 8.8% (46 out of 524) vs 5.9% (31 out of 527) of patients in the ERLEADA group and placebo group, respectively. Ischemic heart disease, arrhythmia, and cardiac failure were among the AEs classified as cardiac disorders.¹⁸
• Ischemic heart disease (4.4% [23 out of 524] vs 1.5% [8 out of 527]) was reported in the ERLEADA group and placebo group, respectively and ischemic events led to death in 2 patients in each group.^6,18 Arrhythmia (4.0% [21 out of 524] vs 3.2% [17 out of 527]) and cardiac failure (1.7% [9 out of 524] vs 1.9% [10 out of 527]) was reported in the ERLEADA group and placebo group, respectively.¹⁸
• Cerebrovascular events occurred in 1.5% of patients treated with ERLEADA and 1.5% of patients treated with placebo.¹
• Incidence of cerebrovascular and cardiovascular disorder events reported at the final analysis for OS is shown in the table: Cerebrovascular and Cardiovascular Disorder Events in the TITAN Study - Final Analysis.

Phase 1b QT/QTc Study

Belderbos et al (2018)¹⁴ evaluated the effect of ERLEADA 240 mg once daily on ventricular repolarization in patients with CRPC (N=45).

Study Design/Methods

• Phase 1b, open-label, multicenter study
• Time-matched electrocardiography (ECG) was collected by a continuous 12-lead Holter recording before ERLEADA treatment (day -1) and on days 1 and 57 (cycle 3 day 1).
• Apalutamide pharmacokinetic parameters were assessed on days 1 and 57 at matched time points of ECG collection.
• QT interval was corrected for heart rate using Fridericia correction (QTcF).
• Safety evaluations included AEs, clinical laboratory safety evaluations, ECGs, multigated acquisition scan or echocardiogram, Eastern Cooperative Oncology Group performance status scores, vital signs, and physical examination.
• Key inclusion criteria: adenocarcinoma of the prostate; high-risk nmCRPC (PSADT ≤10 months) or metastatic CRPC; surgical or medical castration with testosterone levels <50 ng/mL; Eastern Cooperative Oncology Group performance status 0 or 1; adequate bone marrow and organ function; QTcF ≤470 milliseconds; left ventricular ejection fraction of >45%
• Key exclusion criteria: known brain metastases; prior treatment with enzalutamide or ERLEADA; grade ≥2 electrolyte abnormalities (hypokalemia, hypocalcemia, hypomagnesemia); uncontrolled hypertension; significant cardiac function abnormalities on screening ECG; history or evidence of certain cardiac conditions; patients requiring concurrent therapy with medications known to be associated with QTc interval prolongation and an increased risk of torsades de pointes; strong cytochrome P-450 (CYP)3A4 inducers, strong CYP2C8 inducers (eg, rifampin), and strong CYP2C8 inhibitors (eg, gemfibrozil)
• Primary endpoint: maximum ΔQTcF from baseline to cycle 3 day 1 (steady state)
• Secondary endpoints: effect of ERLEADA on other ECG parameters, pharmacokinetics of apalutamide and its active metabolite, relationship between plasma concentrations of apalutamide and QTcF, and safety

Results

Patient Characteristics

• Most patients (97.8%) had metastatic CRPC at study entry.
• A total of 43 patients completed the study and were included in the primary analysis set.
• A total of 45 patients were included in the safety analysis set.
• The median treatment duration was 5 months (range, 2-8 months), and a total of 82% of patients received treatment for ≥3 months.
• Treatment was discontinued in 13 patients (n=12 due to progressive disease, and n=1 due to withdrawal of consent).

Efficacy

• At steady state, the maximum ΔQTcF was 12.4 ms and the upper bound of its associated 90% CI was 16.0 ms.
• No clinically meaningful effects of ERLEADA were reported for heart rate or other ECG parameters.
• A concentration-dependent increase in QTcF was observed for apalutamide and its active metabolite, N-desmethyl apalutamide.

Safety

• A total of 82% of patients experienced ≥1 treatment-emergent AE; most AEs were grade 1-2 in severity.
• The most common treatment-emergent AEs (≥10%) were fatigue (40%), decreased appetite (24%), back pain (16%), diarrhea (13%), dyspnea (13%), rash/erythema (13%), constipation (11%), and nausea (11%).
• No patients discontinued due to QTc prolongation or AEs.

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 03 April 2025. Summarized in this response are relevant data limited to the phase 3 SPARTAN and TITAN studies in patients with nmCRPC and mCSPC, respectively, and phase 1b QT/QTc data in patients with CRPC.