SUMMARY

• Apalutamide is a strong inducer of CYP3A4 and CYP2C19, and a weak inducer of CYP2C9 and P-glycoprotein (P-gp).¹
• Clopidogrel is an inactive prodrug converted to its active metabolite by select CYP450 hepatic isoenzymes, including CYP2C19 and CYP3A (Table: Select CYP450 Isoenzymes and Transporters Involved in the Metabolism of Apalutamide and Clopidogrel).²
• In the phase 3 TITAN study, which evaluated ERLEADA compared to placebo in patients with metastatic castration-sensitive prostate cancer (mCSPC) receiving continuous androgen deprivation therapy (ADT),³ 19 patients (3.6%) and 17 patients (3.2%) in the ERLEADA and placebo groups, respectively, received clopidogrel as a concomitant therapy.⁴
• In the phase 3 SPARTAN 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 ADT⁵, 28 patients (3.5%) and 15 patients (3.8%) in the ERLEADA and placebo groups, respectively, received clopidogrel as a concomitant therapy.⁶
• Efficacy and safety analyses were not performed separately as a sub-group for patients who received an oral antiplatelet agent as a concomitant medication in the TITAN and SPARTAN studies. In addition, no published literature was identified that evaluated the concomitant use of ERLEADA and clopidogrel.
• For additional information, please refer to local product labeling and the manufacturer of clopidogrel.

BACKGROUND

CYP450 isoenzymes and transporters involved in the metabolism of apalutamide and clopidogrel are shown in Table: Select CYP450 Isoenzymes and Transporters Involved in the Metabolism of Apalutamide and Clopidogrel.

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 (PO) once daily (QD; n=525) or placebo QD (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 (eg, pulmonary embolism), or clinically significant ventricular arrhythmias within 6 months prior to randomization.⁷

In the TITAN study, investigators monitored for potential loss of efficacy for medications that are substrates of CYP3A4, CYP2C19 and CYP2C9.⁷

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 Clopidogrel Use in the TITAN Study

Efficacy and safety analyses were not performed separately as a sub-group for patients who received an oral antiplatelet agent as a concomitant medication in the TITAN study.

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 PO QD (n=806) or placebo QD (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 (eg, 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 Clopidogrel Use in the SPARTAN Study

Efficacy and safety analyses were not performed separately for patients who received an oral antiplatelet agent as a concomitant medication 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
27 August 2024.