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 (Table: Select CYP450 Isoenzymes and Transporters Involved in the Metabolism of Apalutamide, Apixaban, Rivaroxaban, Edoxaban, Dabigatran, and Warfarin). Dose adjustments and evaluation of efficacy of warfarin, a CYP2C9 substrate, may be necessary to maintain optimal plasma concentrations if coadministration with apalutamide is unavoidable.¹
• 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),² 16 patients (3.1%) and 5 patients (1.0%) in the ERLEADA group received a direct factor Xa inhibitor or direct thrombin inhibitor, respectively, as concomitant therapy. Additionally, 14 patients (2.7%) in the ERLEADA group received Vitamin K antagonists as a concomitant therapy.³
• 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,⁴ 29 patients (3.6%) and 8 patients (1.0%) in the ERLEADA group received a direct factor Xa inhibitor or direct thrombin inhibitor, respectively, as concomitant therapy. Additionally, 66 patients (8.2%) in the ERLEADA group received Vitamin K antagonists as a concomitant therapy.⁵
• 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) in the ERLEADA and placebo groups. 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).³
• In a phase 1, open-label, multicenter study that evaluated the pharmacokinetic effects of a drug cocktail which included warfarin 10 mg administered with ERLEADA 240 mg orally once daily in 23 patients with castration-resistant prostate cancer (CRPC), the mean S-warfarin maximum plasma concentration (C_max) and area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration (AUC_last) were 16% and 46% lower, respectively, in the presence of apalutamide.⁶
• For additional information, please refer to local product labeling and the manufacturer of the OAC.

BACKGROUND

CYP450 isoenzymes and transporters involved in the metabolism of direct OACs and warfarin are shown in Table: Select CYP450 Isoenzymes and Transporters Involved in the Metabolism of Apalutamide, Apixaban, Rivaroxaban, Edoxaban, Dabigatran, and Warfarin.

Clinical Data

Phase 3 TITAN Study

Chi et al (2019)² 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.¹³

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 CYP2C9.¹³ Specifically, for warfarin, it was recommended that international normalized ratio (INR) be monitored during ERLEADA treatment.¹⁴

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.² Shown below is Table: Frequency of Concomitant Use of OACs 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 in the ERLEADA and placebo groups. Thrombotic and embolic AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA), version 22.1 and Thrombotic Events Standardized MedDRA Query (SMQ).³
  • 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)⁴ 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.⁵

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. Specifically if a patient was taking warfarin, study investigators were advised to re-assess PT/INR levels as clinically indicated and adjust the dose of warfarin accordingly.⁵

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.^4,5 Shown below is Table: Frequency of Concomitant Use of OACs 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 in the ERLEADA and placebo groups. Thrombotic and embolic AEs were coded using the MedDRA, version 22.1 and Thrombotic Events SMQ.³
  • 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).

Phase 1 Study: Coadministration with Warfarin

Duran et al (2020)⁶ conducted a phase 1, open-label, multicenter study that evaluated the pharmacokinetic effects of apalutamide 240 mg orally once daily on a drug cocktail of various CYP probes and transporter substrates, of which included warfarin 10 mg, in patients with nmCRPC or metastatic CRPC (N=23). Patients were excluded if they had a poor metabolizer genotype for CYP2C9 or CYP2C19 as well as patients who required medications known to induce or inhibit CYP3A4, CYP2C9, CYP2C19, CYP2C8, P-gp, BCRP, OATP1B1, and OATPB3. The median treatment duration for ERLEADA was 4 months and most patients received treatment for >3 months. At data cutoff, 8 patients (35%) discontinued treatment with ERLEADA: 7 discontinued due to progressive disease and 1 due to a physician’s decision. In the presence of apalutamide, mean S-warfarin C_max and AUC_last were 16% and 46% lower, respectively, compared to concentrations without the presence of apalutamide. When the drug cocktail was administered alone, 7-OH-S-warfarin concentrations were observed in all patients up to the last sampling time; however, when administered with apalutamide, the mean C_max and AUC_last values were 86% and 96% lower, respectively. Of the 23 patients, 14 (61%) experienced ≥1 TEAE, including 10 (44%) who experienced a drug related TEAE. The most commonly reported TEAEs were asthenia (n=4; 17%), blood thyroid-stimulating hormone (TSH) increased (n=4; 17%), and nausea (n=3; 13%). Grade 3-4 TEAEs occurred in 3 patients (13%). Additionally, 3 patients experienced a grade ≥3 serious AE that were considered not related to the study drug. One patient died of a serious AE related to metabolic encephalopathy considered related to a cerebrovascular accident.

Ongoing Study: Coadministration with Anticoagulants

A cross-sectional analysis of an ongoing, prospective cohort study to evaluate cardiovascular risk in patients with prostate cancer included patients receiving anticoagulants, however, results were not delineated for patients that received ERLEADA.¹⁵

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.