Apalutamide and Abiraterone Acetate in African American and Caucasian Men With Metastatic Castrate Resistant Prostate Cancer

Inclusion criteria

• Male, age ≥ 18 years
• Karnofsky performance status ≥ 70 (Appendix 1)
• Life expectancy of ≥ 12 months as determined by treating investigator
• Written Authorization for Use and Release of Health and Research Study Information (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 (see list under prohibited meds, appendix 2) 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.
• Adequate bone marrow function as shown by: ANC ≥ 1.0 x 109/L, Platelets ≥ 100 x 109/L, 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
• AST/SGOT and ALT/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 × ULN, measure direct and indirect bilirubin and if direct bilirubin is ≤1.5 × ULN, subject may be eligible)
• 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 RECIST 1.1 Criteria OR by prostate cancer-specific PET imaging. Evaluable non-target lesions and/or bone only metastasis are permitted per RECIST 1.1 and PCWG3 guidelines. Non-target, pathological lymph nodes ≥ 10 mm and less than 15 mm in the short axis are permitted.
• Ongoing ADT using an 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 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
• CT or MRI based evidence of disease progression (soft tissue, nodal or visceral disease progression) according to PCWG3 criteria or 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 (ARN-509), galaterone (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 HIV, viral hepatitis or chronic liver disease
• Any chronic medical condition requiring a higher dose of corticosteroid than 5mg 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: sipulecel-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 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, 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 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 thrombolic 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) refer to section 8.3.2 (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