A Study to Evaluate the Potential Increased Risk of Seizures Among Metastatic Castration-Resistant Prostate Cancer (mCRPC) Patients Treated With Enzalutamide

A Multicenter, Single-arm, Open-label, Postmarketing Safety Study to Evaluate the Risk of Seizure Among Subjects With Metastatic Castration-Resistant Prostate Cancer (mCRPC) Treated With Enzalutamide Who Are at Potential Increased Risk of Seizure

The objective of this study was to evaluate the incidence of seizures and monitor the safety of enzalutamide treatment in participants with metastatic castration-resistant prostate cancer (mCRPC) known to have risk factor(s) for seizure.

This was a multicenter, single-arm, open-label, postmarketing safety study to evaluate the risk of seizure among patients with mCRPC treated with enzalutamide who were at potential increased risk of seizure.

Participants who met all inclusion and none of the exclusion criteria were enrolled into the study and participated in a 4-month treatment period, during which once daily dosing of enzalutamide (160 mg/day) occurred. At the end of the 4-month treatment period, participants who were assessed as deriving benefit from enzalutamide treatment were allowed to continue in the extension period where participants continued to receive enzalutamide until 1 of the following criteria was met:

1. The participant experienced bone disease progression per Prostate Cancer Working Group 2 (PCWG2) guidelines or soft tissue disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
2. The participant initiated treatment with another anticancer therapy or, in the opinion of the investigator, continued dosing would have led to undue risk to the patient
3. The participant met a discontinuation criterion
4. The sponsor terminated the study

Participants who continued to receive clinical benefit from treatment with enzalutamide and did not meet any discontinuation criteria may have transitioned to an open label roll-over extension study upon approval of the study protocol at the institution where they were receiving treatment.

Participants who did not continue in the extension period or who met a discontinuation criterion were discontinued from enzalutamide therapy and completed a follow-up visit 30 days from the last dose of enzalutamide or prior to the initiation of another anticancer therapy, whichever occurred first.

For participants who continued on treatment after the 12-month extension period, data collection was limited to dosing information, concomitant medications, and all adverse events (AEs) including serious adverse events (SAEs).

Inclusion Criteria:

• Subject has histologically confirmed metastatic adenocarcinoma of the prostate.

• Subject has ongoing androgen deprivation therapy with a Gonadotropin-releasing hormone (GnRH) analogue (agonist or antagonist) or bilateral orchiectomy (i.e., surgical or medical castration).

• Subject has disease progression by at least one of the following:

  1. Prostate-Specific Antigen (PSA) progression defined by a minimum of 2 rising PSA levels with an interval of at least 1 week between each draw;
  2. Bone disease progression as defined by Prostate Cancer Working Group 2 guidelines (at least 2 new lesions) on bone scan; or
  3. Soft tissue disease progression as defined by RECIST 1.1

• For subjects who have not had an orchiectomy, there must be a plan to maintain effective GnRH-analogue therapy for the duration of the study.

• Subject must have failed at least one course of androgen deprivation therapy (ADT), i.e., treatment with GnRH analogues.

• Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

• Subject has been evaluated by a local neurologist prior to study entry who has determined the subject has at least one risk factor for seizure including:

  1. past history of seizure due to any cause except a single febrile seizure in childhood. Patients with a history of seizures should not have had a seizure within 12 months of Screening and must have had no anticonvulsants for 12 months prior to Screening,
  2. history of cerebrovascular accident (CVA) or transient ischemic attack (TIA),
  3. history of traumatic brain or head injury with loss of consciousness
  4. unexplained loss of consciousness within the last 12 months,
  5. presence of a space occupying lesion in the brain including previously treated brain metastasis(es) or primary central nervous system (CNS) tumor,
  6. history of arteriovenous malformations of the brain,
  7. history of brain infection (i.e., abscess, meningitis, or encephalitis),
  8. current use of medication that may lower seizure threshold
  9. presence of Alzheimer's disease, meningioma, leptomeningeal disease from prostate cancer.

• Subject is able to swallow the study drug and comply with study requirements.

• Subject agrees not to participate in another interventional study while on treatment.

• Male subject and his female partner who is of childbearing potential must use two acceptable methods of birth control (one of which must include a condom as a barrier method of contraception) starting at Screening and continuing throughout the study period and for 3 months after final study drug administration.

  1. Two acceptable forms of birth control include:

  1. Condom (barrier method of contraception), AND

  2. One of the following acceptable forms of contraception is required:

     1. Established use of oral, injected or implanted hormonal methods of contraception.
     2. Placement of an intrauterine device (IUD) or intrauterine system (IUS).
     3. Barrier methods of contraception: Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository).
     4. Vasectomy or surgical castration at least 6 months prior to Screening.

• Male subject must use a condom, if having sex with a pregnant woman.

• Male subject must not donate sperm starting at Screening and throughout the study period and for at least 3 months after final drug administration.

Exclusion Criteria:

• Subject with a history of exposure to enzalutamide.
• Subject has severe concurrent disease, infection, or co-morbidity that, in the judgment of the Investigator, would make the subject inappropriate for enrollment.
• Subject is currently being treated with anti-epileptics.
• Subject has a history of seizure within the past 12 months of Screening as assessed by neurology examination and history.
• Subject with rapidly progressing visceral disease who has not received and is thought to be able to tolerate cytotoxic chemotherapy. (However, subject who has previously received cytotoxic chemotherapy is permitted).
• Subject has clinical signs suggestive of high or imminent risks for pathological fracture, spinal cord compression and/or cauda equina syndrome.
• Subject's absolute neutrophil count is < 1500/microliter (µL), platelet count is < 100,000/µL) or hemoglobin is < 5.6 millimoles(mmol)/liter (L) (9 grams (g)/deciliter (dL) at Screening.
• Subject's total bilirubin is ≥ 1.5 x upper limit of normal (ULN) (except for subjects with documented Gilbert's disease) or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) is ≥ 2.5x upper limit of normal (ULN) at Screening.
• Subject's estimated creatinine clearance (Cer) is less than 30 milliliter (mL)/minute (min) by the Cockcroft and Gault formula (Creatinine Clearance (mL/min) = (140 - age)(weight (wt) kilogram (kg) / 72 x serum creatinine (milligram (mg)/100 mL) [Cockcroft, 1976] at Screening.
• Subject has uncontrolled hypertension as indicated by a resting systolic blood pressure > 160 millimeter of mercury (mmHg) or diastolic blood pressure > 100 millimeter of mercury (mmHg) at Screening.
• Subject has received an investigational agent within 4 weeks or 5 half lives whichever is longer prior to Day 1.
• Subject has shown a hypersensitivity reaction to the active pharmaceutical ingredient or any of the capsule components, including Labrasol, butylated hydroxyanisole, and butylated hydroxytoluene.