SUMMARY

• Seizure occurred in patients receiving ERLEADA. Permanently discontinue ERLEADAin patients who develop a seizure during treatment.¹ Please refer to local labeling for additional considerations and data.
• There is no clinical experience in re-administering ERLEADA to patients who experienced a seizure.¹
• In SPARTAN, the phase 3 study in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC; N=1207), at the final analysis of overall survival (OS), which occurred after a median follow-up of 52 months, adverse events (AEs) of seizure were reported in 0.6% of patients in the ERLEADA group, 0 patients in the placebo group, and 0 patients in the crossover group. The incidence of seizure with event rate per 100 patient-years of exposure were 0.2, 0, and 0 in the ERLEADA, placebo, and crossover groups, respectively.^2,3 Safety results, including seizure, were also previously reported in the second interim analysis for OS.⁴
• In TITAN, the phase 3 study in patients with metastatic castration-sensitive prostate cancer (mCSPC; N=1052), at the primary analysis, AEs of seizure were reported in 0.6% of patients in the ERLEADA group vs 0.4% of patients in the placebo group. One seizure in the ERLEADA group was reported as grade ≥3.⁵ At the final analysis of OS, which occurred after a median follow-up of 44.0 months, no additional seizures were observed.^6,7
• Patients with a history of seizure, predisposing factors for seizure, or receiving drugs known to decrease the seizure threshold or to induce seizure were excluded.^5,8-10

BACKGROUND

In in vitro studies, androgen receptor (AR) inhibitors have been shown to inhibit the GABA_A receptor, a mechanism that is associated with inducing seizures.¹¹ Preclinical studies have shown that apalutamide binds weakly to GABA_A receptors.¹²

CLINICAL DATA

Phase 3 Study in Patients with nmCRPC (SPARTAN)

The SPARTAN study evaluated the efficacy and safety of ERLEADA in patients with nmCRPC (N=1207).⁸

• Patients were required to have a prostate-specific antigen doubling time of ≤10 months and confirmation of nonmetastatic disease by blinded independent central review.
• 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 received a concomitant gonadotropin-releasing hormone (GnRH) analog or had a bilateral orchiectomy.⁹
• Study exclusion criteria related to seizures⁹:
  • History of seizure or a condition that may predispose to seizure (eg, stroke within
    1 year prior to randomization, brain arteriovenous malformation, Schwannoma, meningioma, or other benign central nervous system or meningeal disease which may require treatment with surgery or radiation therapy)
  • Concurrent therapy with medications known to lower the seizure threshold, including aminophylline, theophylline, atypical antipsychotics (eg, clozapine, olanzapine, risperidone, and ziprasidone), bupropion, lithium, meperidine, pethidine, phenothiazine antipsychotics (eg, chlorpromazine, mesoridazine, thioridazine), and tricyclic/tetracyclic antidepressants (eg, amitriptyline, desipramine, doxepin, imipramine, maprotiline, and mirtazapine)
• Patients were closely monitored for seizures during the study.⁹
• Patients who developed a seizure of any grade were required to permanently discontinue study treatment.⁹
• Patient baseline demographic and disease characteristics were well balanced, and there were no significant differences between groups.⁸
• The median treatment duration at primary analysis was 16.9 months in the apalutamide group and 11.2 months in the placebo group.¹³ After unblinding of the study, 76 (19%) patients in the placebo group received therapy with ERLEADA plus androgen deprivation therapy (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.²

The incidence of seizures reported at the SPARTAN primary analysis and the final analysis for OS are shown in Table: Seizure in Phase 3 SPARTAN Study. AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0).⁸

Additional Information

Additional information regarding the SPARTAN study, including the clinical study report, protocol, and statistical analysis plan, can be found: 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).⁵

• Patients were randomized 1:1 to receive either ERLEADA orally at a dose of 240 mg once daily (n=525) or placebo once daily (n=527).
• All patients received a concomitant GnRH analog or had prior bilateral orchiectomy.¹⁰
• Study exclusion criteria related to seizures¹⁰:
  • History of seizure or condition that may predispose to seizure (eg, prior cerebrovascular accident, transient ischemic attack, or loss of consciousness within
    1 year prior to randomization), brain arteriovenous malformation, or intracranial masses such as a schwannoma or meningioma that is causing edema or mass effect.
  • Current or prior treatment with anti-epileptic medications for the treatment of seizures.
  • Medications known to lower the seizure threshold were required to be discontinued or substituted ≥28 days prior to randomization.
    • Prohibited concomitant therapies known to lower the seizure threshold or cause seizures included: atypical antipsychotics (eg, clozapine, olanzapine, risperidone, and ziprasidone), aminophylline/theophylline, bupropion, lithium, meperidine (pethidine), phenothiazine antipsychotics (eg, chlorpromazine, mesoridazine, thioridazine), and tricyclic antidepressants (eg, amitriptyline, desipramine, doxepin, imipramine, maprotiline, and mirtazapine)
• Patients who developed a seizure of any grade or grade 4 neurotoxicity were required to discontinue study treatment.¹⁰
• Patient baseline demographic and disease characteristics were well balanced, and there were no substantial differences between groups.⁵
• The median treatment duration at primary analysis was 20.5 months in the ERLEADA group and 18.3 months in the placebo group.⁵ After unblinding of the study, 208 (39.5%) patients in the placebo group received therapy with ERLEADA plus androgen deprivation therapy (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.⁶
• The incidence of seizure is shown in Table: Seizure in Phase 3 TITAN Study. AEs were graded according to the NCI-CTCAE v4.0.3.⁵

• In the TITAN primary analysis, among patients with seizures, dose interruption occurred in 1 (0.2%) and 0 patients in the ERLEADA and placebo groups, respectively, and resulted in treatment discontinuation in 2 (0.4%) and 1 (0.2%) patients in the ERLEADA and placebo groups, respectively.¹⁴
• At the final analysis of OS, which occurred after a median follow-up of 44.0 months, no additional seizures were observed across all three treatment groups.^6,7

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 April 2024. Summarized in this response are relevant data limited to the phase 3 SPARTAN study in patients with nmCRPC and phase 3 TITAN study in patients with mCSPC.