Advanced ChemoHormonal Therapy for Treatment Naive Metastatic Prostate Cancer

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