New drug combo tested for Tough-to-Treat prostate cancer

Copied word for word from the study's registry entry, so the wording is the study team's rather than ours.

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)