SUMMARY

• Apalutamide is a strong inducer of CYP3A4 and CYP2C19, and a weak inducer of CYP2C9 and P-glycoprotein (P-gp). Concomitant use of medications that are substrates of CYP3A4, CYP2C19, CYP2C9, P-gp, or other select proteins with apalutamide may result in a decrease in exposure and loss of efficacy of these medications.¹
• Direct oral anticoagulant (DOAC) agents, such as apixaban, rivaroxaban, edoxaban, and dabigatran, are substrates of P-gp and certain DOAC agents are substrates of CYP3A4 (Table: Select CYP450 Isoenzymes and Transporters Involved in the Metabolism of Apalutamide, Apixaban, Rivaroxaban, Edoxaban, and Dabigatran).²
• In TITAN, a phase 3 study, which evaluated ERLEADA compared to placebo in patients with metastatic castration-sensitive prostate cancer (mCSPC) receiving continuous androgen deprivation therapy (ADT),³ 16 patients (3.1%) and 15 patients (2.8%) in the ERLEADA and placebo groups, respectively, received a direct factor Xa inhibitor as concomitant therapy. Additionally, 5 patients each in the ERLEADA and placebo groups, 1.0% and 0.9% respectively, received a direct thrombin inhibitor as a concomitant medication.⁴
• In SPARTAN, a phase 3 study, which evaluated the efficacy and safety of ERLEADA compared to placebo in patients with high-risk, non-metastatic castration-resistant prostate cancer (nmCRPC) receiving continuous ADT,⁵ 29 patients (3.6%) and
  15 patients (3.8%) in the ERLEADA and placebo groups, respectively, received a direct factor Xa inhibitor as concomitant therapy. Additionally, 8 patients (1.0%) and
  3 patients (0.8%) in the ERLEADA and placebo groups, respectively, received a direct thrombin inhibitor as a concomitant medication.⁶
• Descriptive post hoc analyses of the TITAN and SPARTAN studies were conducted to evaluate the incidence of treatment-emergent thrombotic and embolic adverse events (AEs) in patients who did or did not receive concomitant oral anticoagulants (OACs), including DOACs, in the ERLEADA and placebo groups. Results were not delineated for patients who specifically received a DOAC as a concomitant medication in the TITAN and SPARTAN studies. The occurrence of thrombotic and embolic AEs was similar between the ERLEADA and placebo groups in the overall safety population and in the subgroups that did or did not receive anticoagulants in both the TITAN and SPARTAN studies (Table: Occurrence of Treatment-Emergent Thrombotic and Embolic AEs in the TITAN Study and Table: Occurrence of Treatment-Emergent Thrombotic and Embolic AEs in the SPARTAN Study).⁴
• For additional information, please refer to local product labeling and the manufacturer of the DOAC.

BACKGROUND

Collectively known as DOACs, the anticoagulant effects of apixaban, rivaroxaban, edoxaban, and dabigatran are dependent on plasma concentration.⁷ CYP450 isoenzymes and transporters involved in the metabolism of apalutamide and DOACs are shown in Table: Select CYP450 Isoenzymes and Transporters Involved in the Metabolism of Apalutamide, Apixaban, Rivaroxaban, Edoxaban, and Dabigatran.

Clinical Data

Phase 3 TITAN Study

Chi et al (2019)³ evaluated the efficacy and safety of ERLEADA plus ADT compared to placebo plus ADT in patients with mCSPC (N=1052). 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 TITAN study received a concomitant gonadotropin-releasing hormone (GnRH) analog or had a bilateral orchiectomy. Patients were excluded if they had evidence of severe/unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (e.g., pulmonary embolism), or clinically significant ventricular arrhythmias within 6 months prior to randomization.¹⁰

In the TITAN study, investigators were advised to refer to the drug-drug interactions information provided by the study sponsor. Guidance was provided to monitor for potential loss of efficacy for medications that are substrates of CYP3A4, CYP2C19 and CYP2C9.¹⁰

Patient baseline demographic and disease characteristics were well balanced, and there were no significant differences between groups. The median treatment duration was
20.5 months in the ERLEADA group and 18.3 months in the placebo group.³ Shown below is Table: Frequency of Concomitant Use of DOACs in the TITAN Study.

Post hoc Analysis

• A descriptive post hoc analysis of the TITAN study was conducted to evaluate the incidence of treatment-emergent thrombotic and embolic AEs in patients who did or did not receive concomitant OACs, including DOACs, in the ERLEADA and placebo groups. Results were not delineated for patients who specifically received a DOAC as a concomitant medication in the TITAN study. Thrombotic and embolic AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA), version 22.1 and Thrombotic Events Standardized MedDRA Query (SMQ).⁴
  • The occurrence of thrombotic and embolic AEs was similar between the ERLEADA and placebo groups in the overall safety population and in the subgroups that did or did not receive concomitant OACs. Of the patients that received concomitant OACs, thrombotic and embolic treatment-emergent adverse events (TEAEs) occurred in 19.4% (6/31) of patients in the ERLEADA group and 21.4% (6/28) of patients in the placebo group (Table: Occurrence of Treatment-Emergent Thrombotic and Embolic AEs in the TITAN Study).
  • Treatment-emergent thrombotic and embolic AEs among patients that received concomitant anticoagulant medications are summarized in the table below. One patient receiving concomitant OACs in the ERLEADA group experienced a grade 5 AE (myocardial infarction).

Phase 3 SPARTAN Study

Smith et al (2018)⁵ evaluated the efficacy and safety of ERLEADA in patients with nmCRPC (N=1207). 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 SPARTAN study received a concomitant GnRH analog or had a bilateral orchiectomy. Patients were excluded if they had evidence of severe/unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (e.g., pulmonary embolism, cerebrovascular accident including transient ischemic attacks), or clinically significant ventricular arrhythmias within 6 months prior to randomization.⁶

Investigators were informed of the potential for drug-drug interactions of ERLEADA with concomitant medications, particularly strong CYP3A4 inducers or drugs with a narrow therapeutic index.⁶

Patient baseline demographic and disease characteristics were well balanced, and there were no significant differences between groups. The median treatment duration was
16.9 months in the ERLEADA group and 11.2 months in the placebo group.^5,6 Shown below is Table: Frequency of Concomitant Use of DOACs in the SPARTAN Study.

Post hoc Analysis

• A descriptive post hoc analysis of the SPARTAN study was conducted to evaluate the incidence of treatment-emergent thrombotic and embolic AEs in patients who did or did not receive concomitant OACs, including DOACs, in the ERLEADA and placebo groups. Results were not delineated for patients who specifically received a DOAC as a concomitant medication in the SPARTAN study. Thrombotic and embolic AEs were coded using the MedDRA, version 22.1 and Thrombotic Events SMQ.⁴
  • The occurrence of thrombotic and embolic AEs was similar between the ERLEADA and placebo groups in the overall safety population and in the subgroups that did or did not receive concomitant OACs. Of the patients that received concomitant OACs, thrombotic and embolic TEAEs occurred in 11.6% (11/95) of patients in the ERLEADA group and 12.5% (6/48) of patients in the placebo group (Table: Occurrence of Treatment-Emergent Thrombotic and Embolic AEs in the SPARTAN Study).
  • Treatment-emergent thrombotic and embolic AEs among patients that received concomitant OACs are summarized in the table below. There were no grade 5 thrombotic and embolic AEs in patients receiving concomitant OACs in the SPARTAN study.

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).

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 08 January 2025.