New cocktail aims to knock out prostate cancer spread

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

Inclusion Criteria: * Patients must have histologically or cytologically confirmed prostate cancer OR a strong suspicion of prostate cancer as evidenced by metastatic disease in a pattern consistent with prostate cancer (such as blastic lesions on a nuclear medicine bone scan or lymphadenopathy on the computed tomography \[CT\] scan) AND a PSA \> 50 ng/mL * Patients must meet either of the definitions for high risk disease as follows: * Definition 1: Must have at least 2 of the following 3 at the time diagnosed metastatic: * visceral metastatic disease * \>=3 bone lesions * Gleason 8-10 OR * Definition 2: \>=4 bone lesions, including \>=1 outside of the vertebral column or pelvis and/or visceral metastatic disease * If a patient has received androgen deprivation therapy (ADT) for neoadjuvant or adjuvant therapy at least 24 months MUST have elapsed since its use to day 1 of restarting ADT for metastatic castration sensitive disease * ADT sensitive disease- no evidence of PSA progression or new metastatic deposits since starting ADT; PSA progression is defined as an increase in PSA greater than 25% above nadir, and \>2 ng/ml increase confirmed by a second value obtained at least 2 weeks apart * Have completed up to 6 cycles of docetaxel since developing metastatic castration sensitive disease with no more than 16 weeks elapsed since day 21 of the final cycle * All races and ethnic groups will be included * Life expectancy of greater than 18 months * Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 * Hemoglobin \> 9.0 g/dL, independent of transfusion and/or growth factors * Leukocytes \> 3,000/uL * Absolute neutrophil count \> 1,500/uL * Platelets \>= 100,000 x 10\^9/uL, independent of transfusion and/or growth factors * Total bilirubin =\< 1.5 x upper limit of normal (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) * Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase \[SGPT\]) \< 2.5 x institutional upper limit of normal * Albumin \> 3 g/dL * Estimated glomerular filtration rate (eGFR) \> 30 mL/min/1.73 m\^2; per Modification of Diet in Renal Disease (MDRD) calculation or institutional standard * Potassium \>= 3.5 mmol/L * Medications known to lower the seizure threshold must be discontinued or substituted at least 4 weeks prior to day 1 of study * 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 * Ability to understand, and the willingness to sign, a written informed consent document, as well as comply with study requirements Exclusion Criteria: * Subjects who are unwilling to stop taking saw palmetto, PC-SPECs or other herbal agents known to affect the PSA * Patients may not have received any other investigational agents within 30 days prior to day 1 of study * Prior exposure to apalutamide, enzalutamide, abiraterone acetate, darolutamide, or any other second-generation antiandrogen therapy * Note: prior exposure to bicalutamide, flutamide, nilutamide, or any other first-generation androgen receptor antagonist is permitted. No washout is required. Subjects may be on one of these at the time of consent, but it must be stopped prior to day 1 of study treatment. These drugs are frequently used in the newly diagnosed metastatic setting to blunt the effect of the testosterone spike * History of allergic reactions attributed to compounds of similar chemical or biologic composition to apalutamide or other agents used in the study * Subject has another active malignancy other than non-melanomatous skin cancer (unless it is metastatic) or superficial bladder cancer * Either of the following: * Seizure or known condition that may pre-dispose to seizure (e.g. prior stroke within 1 year, 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 or left ventricular ejection fraction \< 50%, 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 day 1 of study * Current evidence of any of the following: * Uncontrolled hypertension * Gastrointestinal disorder affecting absorption * Active infection (e.g. human immunodeficiency virus \[HIV\] or viral hepatitis) * Any chronic medical condition requiring a higher dose of corticosteroid than a total of 10 mg prednisone/prednisolone daily * Any condition that in the opinion of the investigator, would preclude participation in this study. * Avoid concomitant strong CYP3A4 inducers during abiraterone acetate treatment. If a strong CYP3A4 inducer must be co-administered, increase the abiraterone acetate dosing frequency to twice a day only during the co-administration period (e.g., from 1,000 mg once daily to 1,000 mg twice a day). * 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 and severe hepatic impairment (Child Pugh Class B \& C) * Inability to stop a prohibited medication: * Atypical antipsychotics (e.g. clozapine, olanzapine, risperidone, ziprasidone) * Bupropion * Lithium * Meperidine and pethidine * Phenothiazine antipsychotics (e.g. chlorpromazine, mesoridazine, thioridazine) * Tricyclic antidepressants (e.g. amitriptyline, desipramine, doxepin, imipramine, maprotiline, mirtazapine * Tramadol