Apalutamide, Abiraterone Acetate, and Prednisone in Treating Patients with Chemotherapy-Naive Metastatic Castration-Resistant Prostate Cancer

Inclusion Criteria

• Karnofsky performance status >= 70
• Life expectancy of >= 12 months as determined by treating investigator
• Written Authorization for Use and Release of Health and Research Study Information (Health Insurance Portability and Accountability Act [HIPAA] authorization per institutional requirements)
• Willing/able to adhere to the prohibitions and restrictions specified in this protocol
• Willing to take abiraterone acetate on an empty stomach, and should be able to swallow tablets whole, without crushing/chewing tablets; must have the ability to swallow, retain, and absorb oral medication
• Medications known to lower the seizure threshold must be discontinued or substituted at least 4 weeks prior to study entry
• Agrees to use a condom (even men with vasectomies) and another effective method of birth control if he is having sex with a woman of childbearing potential or agrees to use a condom if he is having sex with a woman who is pregnant while on study drug and for 3 months following the last dose of study drug; must also agree not to donate sperm during the study and for 3 months after receiving the last dose of study drug; abstinence is an acceptable method of birth control
• Absolute neutrophil count (ANC) >= 1.0 x 10^9/L
• Platelets >= 100 x 10^9/L
• Hemoglobin (Hb) >= 9 g/dL (independent of transfusion and/or growth factors within 3 months prior to cycle 1 day 1)
• Serum potassium >= 3.5 mEq/L
• Serum albumin of >= 3.0 g/dl
• Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) < 2.5 x institutional upper limit of normal (ULN)
• Serum total bilirubin =< 1.5 x institutional ULN (Note: In subjects with Gilbert’s syndrome, if total bilirubin is > 1.5 x ULN, measure direct and indirect bilirubin and if direct bilirubin is =< 1.5 x ULN, subject may be eligible)
• Glomerular filtration rate (GFR) >= 45 mL/min
• Histologically confirmed diagnosis of adenocarcinoma of the prostate; histologic variants of prostate cancer comprising of > 50% of the tumor including neuroendocrine features and small cell carcinoma of the prostate are excluded
• Radiographic evidence of metastatic disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria OR by prostate cancer-specific positron emission tomography (PET) imaging; evaluable non-target lesions and/or bone only metastasis are permitted per RECIST 1.1 and Prostate Cancer Clinical Trials Working Group (PCWG3) guidelines; non-target, pathological lymph nodes >= 10 mm and less than 15 mm in the short axis are permitted
• Ongoing androgen deprivation therapy (ADT) using a luteinizing hormone-releasing hormone (LHRH) agonist (e.g. leuprolide, goserelin) or antagonist (e.g. degarelix) must continue on therapy unless prior bilateral orchiectomy has been performed
• PSA >= 2.0 ng/mL
• Evidence of castration resistant disease in the setting of ongoing ADT (medical or surgical) as evidenced by at least one of the following: * Absolute rise in PSA of 2.0 ng/mL or an increase > 25% from the nadir, minimum 2 consecutive rising PSA levels with an interval of >= 1 week between each PSA level, OR * Computed tomography (CT) or magnetic resonance imaging (MRI) based evidence of disease progression (soft tissue, nodal or visceral disease progression) according to RECIST 1.1 criteria, OR * At least 1 new bone scan lesion as compared to the most immediate prior radiologic studies
• A minimum of 2 weeks elapsed off of antiandrogen therapy prior to start of study drug (i.e. flutamide, nilutamide, bicalutamide)
• A minimum of 2 weeks elapsed off of sipuleucel-T and radiation therapy prior to start of study drug
• A minimum of 4 weeks from any major surgery prior to start of study drug
• Self-reported race of either African American or Caucasian
• Ability to understand and the willingness to sign a written informed consent document; if the subject is unable to understand the consent due to comorbidity, such as Alzheimer’s disease, consent by a legally authorized representative and assent by the subject will be obtained

Exclusion Criteria

• Prior treatment with abiraterone acetate, enzalutamide, apalutamide, galeterone (TOK-001), orteronel (TAK-700), or similar agent
• Active infection or other medical condition that would make prednisone/prednisolone (corticosteroid) use contraindicated
• Active or symptomatic infection including human immunodeficiency virus (HIV), viral hepatitis or chronic liver disease
• Any chronic medical condition requiring a higher dose of corticosteroid than 5 mg prednisone/prednisolone bid
• Have known allergies, hypersensitivity, or intolerance to abiraterone acetate, apalutamide or prednisone or their excipients
• Pathological finding consistent with small cell carcinoma of the prostate
• Symptomatic liver or visceral organ metastasis
• Have a history of gastrointestinal disorders (medical disorders or extensive surgery) that may interfere with the absorption of the study agents
• Known brain metastasis
• Prior cytotoxic chemotherapy or biologic therapy for the treatment of CRPC; Note: sipuleucel-T is permitted with a 2-week washout
• Previously treated with ketoconazole for prostate cancer for greater than 7 days
• Prior systemic treatment with an azole anti-fungal drug (e.g. fluconazole, itraconazole) within 4 weeks of cycle 1, day 1
• Uncontrolled hypertension (systolic blood pressure [BP] >= 140 mmHg or diastolic BP >= 90 mmHg); patients with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment
• Poorly controlled diabetes, fasting blood sugar (FBS) >= 200 mg/dL
• History of pituitary or adrenal dysfunction
• Symptomatic atrial fibrillation, or other symptomatic cardiac arrhythmia
• Other malignancy, except non-melanoma skin cancer, with a >= 30% probability of recurrence within 24 months
• History of any of the following: * Seizure or known condition that may pre-dispose to seizure (e.g. prior stroke within 6 months of cycle 1 day 1, brain arteriovenous malformation, Schwannoma, meningioma, or other benign central nervous system [CNS] or meningeal disease which may require treatment with surgery or radiation therapy) * Severe or 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 first dose of study drug; venous thrombotic events within 6 months are permitted IF they are not attributed to prostate cancer (in the opinion of the treating physician)
• Avoid concomitant strong CYP3A4 inducers during abiraterone acetate treatment
• Avoid co-administration of abiraterone acetate with CYP2D6 substrates that have a narrow therapeutic index; if an alternative treatment cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate
• Baseline moderate or severe hepatic impairment (Child Pugh class B & C)
• Use of herbal products that may decrease PSA levels (i.e., saw palmetto) (no washout period required)
• Administration of an investigational therapeutic within 30 days prior to cycle 1, day 1
• Any condition which, in the opinion of the investigator, would preclude participation in this trial