Apalutamide, Abiraterone Acetate, and Prednisone in Treating Participants With Metastatic Castration Resistant Prostate Cancer

This is an interventional treatment trial for Castration-Resistant Prostate Carcinoma Read More

Inclusion Criteria:

• Histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features
• Presence of metastatic disease that can be biopsied by any methodology applicable
• Ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH) analogue or orchiectomy (i.e., surgical or medical castration)
• Serum testosterone level =< 50 ng/dL at the screening visit

• Progressive disease defined as one or more of the following three criteria (NOTE: Patients who received an antiandrogen must demonstrate disease progression following discontinuation of antiandrogen):

  • PSA progression defined by a minimum of two rising PSA levels with an interval of >= 1 weeks between each determination. The PSA value at the screening visit should be >= 2 ng/mL
  • Soft tissue disease progression as defined by the Response Evaluation Criteria in Solid Tumors (RECIST)
  • Bone disease progression defined by two or more new lesions on bone scan
• Patients previously treated with chemotherapy must have no more than two prior chemotherapy regimens for the treatment of metastatic prostate cancer
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
• Serum albumin >= 3.0 g/dL
• Serum potassium >= 3.5 mmol/L
• Estimated life expectancy of >= 6 months
• Able to swallow the study drug and comply with study requirements
• Willing and able to give informed consent

• Tumor specimen obtained prior to treatment initiation by interventional radiology guided biopsy will be interrogated per immunohistochemistry (IHC) and features should be as follows for a patient to be eligible

  • Overexpression of androgen receptor (AR)-C terminal and AR-N terminal and PTEN with lack of ARV7 expression along with and ki67 =<10%
  • No combined RB loss and p53 mutation and
  • No expression of neuroendocrine markers CD56 and chromogranin (all markers assessed by standardized IHC protocols)

• 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

  • The methods must consist of a condom and the use of another barrier method (such as a diaphragm or cervical/vault caps) with a spermicidal agent. Your female partner can choose to use an intrauterine device or system (intrauterine device [IUD] or intrauterine system [IUS]) or use birth control pills, injections, or implants instead of a barrier method

Exclusion Criteria:

• Known allergy to the study drugs or any of its components
• Severe, concurrent disease, infection, or co-morbidity that, in the judgment of the investigator, would make the patient inappropriate for enrollment or other medical condition that would make prednisone/prednisolone (corticosteroid) use contraindicated
• Known metastases to the brain
• Absolute neutrophil count < 1000/uL at the screening visit
• Platelet count =< 100,000 x 10^9/uL at the screening visit
• Hemoglobin < 9 g/dL at the screening visit at the screening visit
• NOTE: patients may not have received any growth factors or blood transfusions within seven days of the hematologic laboratory values obtained at the screening visit
• Total bilirubin (Tbili) > 1.5 times the upper limit of normal at the screening visit
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 times the upper limit of normal at the screening visit
• Creatinine (Cr) > 2 mg/dL at the screening visit
• History of another malignancy within the previous 2 years with > 30 % probability of relapse other than curatively treated non-melanomatous skin cancer
• Treatment with androgen receptor antagonists (bicalutamide, flutamide, nilutamide), 5-alpha reductase inhibitors (finasteride, dutasteride), estrogens, chemotherapy, or biologic therapy within 4 weeks of enrollment (day 1 visit)
• Radiation therapy within 3 weeks (if single fraction of radiotherapy within 2 weeks) of enrollment (day 1 visit)
• Planned palliative procedures for alleviation of bone pain such as radiation therapy or surgery
• Structurally unstable bone lesions suggesting impending fracture
• History of seizure or any condition that may increase the patient's seizure risk. Also, history of loss of consciousness or transient ischemic attack within 12 months of day 1

• Clinically significant cardiovascular disease including:

  • Myocardial infarction within 6 months
  • Uncontrolled angina within 6 months
  • Congestive heart failure New York Heart Association (NYHA) class 3 or 4 in the past, or history of anthracycline or anthracenedione (mitoxantrone) treatment, unless a screening echocardiogram or multi-gated acquisition scan (MUGA) performed within three months results in a left ventricular ejection fraction that is >= 45%
  • History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes)
  • Prolonged corrected QT interval by the Fridericia correction formula (QTcF) on the screening electrocardiogram (ECG) > 470 msec
  • History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place
  • Hypotension (systolic blood pressure < 86 millimeters of mercury or bradycardia with a heart rate of < 50 beats per minute on any ECG taken at the screening visit
  • Bradycardia with a heat rate of < 50 beats per minutes in the screening ECG, unless pharmaceutically induced and reversible
  • Chronically uncontrolled hypertension as indicated by consistently elevated resting blood pressure (systolic blood pressure > 170 mmHg or diastolic blood pressure > 105 mmHg) during screening

• Have used or plan to use from 30 days prior to enrollment (day 1 visit) through the end of the study the following medications known to lower the seizure threshold:

  • Aminophylline/theophylline
  • Atypical antipsychotics (e.g., clozapine, olanzapine, risperidone, ziprasidone)
  • Bupropion
  • Insulin
  • Lithium
  • Pethidine
  • Phenothiazine antipsychotics (e.g., prochlorperazine [compazine], chlorpromazine, mesoridazine, thioridazine)
  • Tricyclic and tetracyclic antidepressants (e.g., amitriptyline, desipramine, doxepin, imipramine, maprotiline, mirtazapine)
• Prior use of ketoconazloe, enzalutamide, abiraterone or apalutamide or participation in a previous clinical trial of ketoconazloe,enzalutamide, abiraterone or apalutamide unless within the neoadjuvant setting
• Use of an investigational agent within 4 weeks of enrollment (day 1)
• Gastrointestinal disorder affecting absorption (e.g., gastrectomy)
• Major surgery within 4 weeks prior to enrollment (day 1)

• History of significant bleeding disorder unrelated to cancer, including:

  • Diagnosed congenital bleeding disorders (e.g., von Willebrand's' disease)
  • Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies)
  • History of gastrointestinal (GI) bleeding within one year
• Known active or symptomatic viral hepatitis or chronic liver disease
• Known history of pituitary or adrenal dysfunction
• Baseline moderate and severe hepatic impairment (Child Pugh class B & C)