Apalutamide and Gonadotropin-Releasing Hormone Analog With or Without Abiraterone Acetate in Treating Participants With Prostate Cancer

Patients who have had any prior chemotherapy or radiotherapy for prostate cancer.

Patients who have had \> 1 LHRH agonist or antagonist depot injection or received depot injection \> 30 days before study entry.

Patients may not be receiving any other investigational agents.

Patients may not be receiving the concomitant administration of any systemic therapy, biologic therapy, or other agents with anti-tumor activity against prostate cancer while the patients are on study.

Patients with known metastatic prostate cancer.

History of allergic reactions attributed to compounds of similar chemical or biologic composition to leuprolide acetate, abiraterone acetate, prednisone or apalutamide or other agents used in the study.

Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with apalutamide and abiraterone. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.

Avoid concomitant strong CYP3A4 inducers during abiraterone acetate treatment. If a strong CYP3A4 inducer must be co-administered, increase the abiraterone acetate dosing frequency.

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.

Patients receiving medications known to lower the seizure threshold are ineligible unless discontinued or substituted at least 4 weeks prior to study entry. These include: 1) aminophylline/theophylline; 2) atypical antipsychotics (e.g., clozapine, olanzapine, risperidone, ziprasidone); 3) bupropion; 4) lithium; 5) pethidine; 6) phenothiazine antipsychotics (e.g., prochlorperazine (compazine), chlorpromazine, mesoridazine, thioridazine); 7) tricyclic and tetracyclic antidepressants (e.g., amitriptyline, desipramine, doxepin, imipramine, maprotiline, mirtazapine).

Chronically uncontrolled hypertension, defined conventionally as consistent systolic pressures above 170 or diastolic pressures above 110 despite anti-hypertensive therapy. Note that this is NOT a criterion related to particular blood pressure (BP) results at the time of assessment for eligibility, nor does it apply to acute BP excursions that are related to iatrogenic causes, acute pain or other transient, reversible causes. (for example doctor's visit related stress i.e. "white coat syndrome".

Requirement for corticosteroids greater than the equivalent of 10 mg of prednisone daily for more than 2 weeks.

Poorly controlled diabetes defined by hemoglobin A1C \> 9.0 at screening.

Active or symptomatic viral hepatitis or chronic liver disease.

Known history of pituitary or adrenal dysfunction.

Other malignancy, except non-melanoma skin cancer, that is active or has a \>= 30% probability of recurrence within 12 months.

History of gastrointestinal disorders (medical disorders or extensive surgery) which may interfere with the absorption of the study drug.

Prior hormone therapy for prostate cancer including orchiectomy, antiandrogens, ketoconazole, or estrogens (5-alpha reductase inhibitors allowed), or LHRH agonists/antagonists (Note: LHRH allowed if begun within 1 month of day 1).

Prior systemic treatment with an azole drug within four weeks of cycle 1 day 1.

Current enrollment in an investigational drug or device study or participation in such a study within 30 days of cycle 1 day 1.

Allergies, hypersensitivity, or intolerance to prednisone, LHRH analog or excipients of prednisone LHRH analog, abiraterone acetate and apalutamide.

Previous use of abiraterone acetate or other investigational CYP17 inhibitor (e.g., TAK-700).

Previous investigational antiandrogens (e.g., apalutamide, enzalutamide, BMS-641988).

Condition or situation which, in the investigator's opinion, may put the patient at significant risk, may confound the study results, or may interfere significantly with patient's participation in the study.

Patients unable to tolerate transrectal ultrasound.

Anti-androgens (steroidal or non-steroidal) such as cyproterone acetate, flutamide, nilutamide, bicalutamide, etc. other than assigned study drug unless given for =\< 4 weeks.

Estrogens, progestational agents such as megestrol, medroxyprogesterone, diethylstilbestrol (DES), cyproterone, spironolactone \> 50 mg/kg, etc. unless discontinued at least two weeks prior to randomization.

Androgens such as testosterone, dehydroepiandrosterone (DHEA), etc. unless discontinued at least two weeks prior to randomization.

Herbal products that may decrease PSA levels (e.g., saw palmetto) unless discontinued two weeks prior to randomization.

Active infection or other medical condition that would make prednisone/prednisolone (corticosteroid) use contraindicated.

Severe hepatic impairment (Child-Pugh Class C).

History of significant bleeding disorder unrelated to cancer, including: 1) diagnosed congenital bleeding disorders (e.g., von Willebrand's disease); 2) diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies) of screening visit; 3) history of gastrointestinal (GI) bleeding within 3 months of screening visit requiring \>= 2 units packed red blood cells.

Clinically significant cardiovascular disease including: 1) myocardial infarction within 6 months of screening visit; 2) uncontrolled angina within 3 months of screening visit; 3) congestive heart failure New York Heart Association (NYHA) class 3 or 4, or subjects with history of congestive heart failure 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 of the Screening visit results in a left ventricular ejection fraction that is \>= 50%. 4) history of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsade de pointes). 5) prolonged corrected QT interval by the Fridericia correction formula (QTcF) on the screening electrocardiogram (ECG) \> 470 msec. 6) history of Mobitz II second degree or third degree heart block without a permanent pacemaker in place. 7) hypotension (systolic blood pressure \< 86 mmHg or bradycardia with a heart rate of \< 50 beats per minute on the screening ECG, unless pharmaceutically induced and thus reversible (i.e. beta blockers).

What this study is about