PRIMARY OBJECTIVE:
I. To assess the benefit of docetaxel as measured by improvement in freedom from progression (phase II) and subsequently metastasis free survival (phase III) when given in combination with radiation and androgen deprivation in treatment of high risk prostate cancer post-radical prostatectomy.
SECONDARY OBJECTIVES:
I. To assess overall survival. II. To assess local time to progression. III. To assess undetectable prostate-specific antigen (PSA) with a non-castrate testosterone at 2.5 years post treatment.
IV. To assess the utility of genomic profiling in making adjuvant therapy decisions post-prostatectomy.
V. To assess toxicity of docetaxel in the post-operative setting when combined with radiation and androgen deprivation therapy.
VI. To assess treatment response by genomically defined sub-groups of prostate cancer patients.
EXPLORATORY OBJECTIVE:
I. To optimize quality assurance methodologies and processes for radiotherapy and imaging, with machine learning strategies.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive androgen deprivation therapy comprising leuprolide acetate, goserelin acetate, degarelix, bicalutamide, flutamide, or nilutamide for 6 months. Beginning 8 weeks after the start of androgen deprivation therapy, patients receive external beam radiation therapy (EBRT) for 7.5 weeks.
ARM II: Patients receive androgen deprivation therapy and EBRT as in Arm I. Within 4-6 weeks after completion of radiation therapy, patients receive docetaxel intravenously (IV) over 1 hour on day 1 of every 21 days for 6 cycles in the absence of disease progression or unexpected toxicity.
After completion of study treatment, patients are followed up every 3 months for 2 years, then every 6 months for 3 years, and then yearly.
Inclusion Criteria:
* Patients post-prostatectomy with baseline Gleason \>= 7 (per prostatectomy pathology)
* Baseline PSA prior to start of androgen deprivation therapy nadir \>= 0.2 ng/ml (post-operative value is never undetectable) obtained prior to step 1 registration
* Baseline testosterone level obtained post-prostatectomy prior to start of androgen deprivation therapy and prior to step 1 registration
* Pathologically (histologically) proven diagnosis of adenocarcinoma of the prostate as confirmed at time of prostatectomy; prostatectomy must have been performed within 365 days (1 year) prior to step 1 registrationand any type of radical prostatectomy is permitted, including retropubic, perineal, laparoscopic or robotically assisted; (please note: Prior ablative treatment for benign prostatic hypertrophy or focal high-intensity focused ultrasound therapy \[HIFU\] prior to prostatectomy is allowed)
* Surgical formalin-fixed paraffin-embedded (FFPE) specimen must be available for submission to GenomeDx for genomic analysis on DECIPHER GRID platform
* Please note: If a patient already has a Decipher risk score and meets all of the other eligibility criteria, the patient is eligible to be registered; however, the Decipher risk report will need to be submitted to GenomeDx for validation
* Prior androgen deprivation (luteinizing hormone-releasing hormone \[LHRH\] agonist and/or non-steroidal anti-androgen) is allowed if:
* Androgen deprivation therapy was initiated within 30 days prior to study enrollment
* Androgen deprivation therapy was given for ≤ 90 days duration prior to radical prostatectomy
* Please note: Finasteride or dutasteride must be stopped before treatment but should not determine eligibility
* Pathologically lymph node negative by pelvic lymphadenectomy (pN0) or lymph node status pathologically unknown (undissected pelvic lymph nodes \[pNx\])
* Any pT-stage based on American Joint Committee on Cancer 7th edition eligible; study entry will be based on the following diagnostic workup:
* History/physical examination within 60 days prior to step 1 registration
* Negative distant metastatic workup:
* A computed tomography (CT) scan of the abdomen and pelvis (with contrast \[CT without contrast is permitted if the patient is not a candidate for contrast, i.e., renal function or allergy\]) or magnetic resonance imaging (MRI) of the pelvis within 120 days prior to step 1 registration; (Please note: Lymph nodes will be considered negative (NO)if they are =\< 1.5 cm short axis);
* Bone scan within 120 days prior to step 1 registration; (please note: a sodium fluoride \[NaF\] positron emission tomography \[PET\]/CT is an acceptable substitute and if the bone scan is suspicious, a plain x-ray, CT scan, NaF PET/CT and/or MRI must be obtained to rule out metastasis; Axumin scans are not allowed for determination of eligibility \[e.g. a positive Axumin can in the setting of negative bonescan and CT does not exclude a patient from being eligible for enrollment\]).
* Eastern Cooperative Oncology Group (ECOG) performance status of =\< 1 within 60 days prior to step 1 registration
* Platelets \>= 100,000 cell/mm\^3 (within 60 days prior to step 1 registration based upon a complete blood count \[CBC\])
* Hemoglobin \>= 10.0 g/dl (Note: The use of transfusion or other intervention to achieve hemoglobin \[Hgb\] \>= 10.0 g/dl is NOT allowed) (within 60 days prior to step 1 registration based upon a CBC)
* Absolute neutrophil count \>= 1500 cells/mm\^3 (within 60 days prior to step 1 registration based upon a CBC)
* Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \< 1.5 x the upper limit of normal (within 60 days prior to step 1 registration)
* Total bilirubin (=\< 1.5 mg/dl) normal unless history of Gilbert's syndrome (within 60 days prior to step 1 registration)
* The patient or a legally authorized representative must provide study-specific informed consent prior to step 1 registration
Exclusion Criteria:
* Definitive clinical or radiologic evidence of metastatic disease
* Prior invasive malignancy (except non-melanomatous skin cancer or other in-situ malignancies, or stage Ta bladder cancer) unless disease free for a minimum of 2 years
* Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields
* Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable if completed more than two years prior to step 1 registration; prior androgen deprivation is allowed
* Prior whole gland ablative therapy (i.e. cryoablation or high intensity focused ultrasound \[HIFU\]) for prostate cancer is not allowed
* Prostatectomy performed greater than 365 days (1 year) prior to step 1 registration
* Severe and/or active co-morbidity defined as follows:
* History of inflammatory bowel disease
* History of active hepatitis B or C; blood tests are not required to determine if the patient has had hepatitis B or C, unless the patient reports a history of hepatitis
* Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
* Transmural myocardial infarction within the last 6 months
* Acute bacterial or fungal infection requiring intravenous antibiotics at the time of step 1 registration
* Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization within 15 days of step 1 registration or precluding study therapy at the time of step 1 registration
* Uncontrolled severe illness or medical condition (including uncontrolled diabetes), which in the judgment of the treating physician would make the administration of chemotherapy inadvisable
* Human immunodeficiency virus (HIV) positive with cluster of differentiation 4 (CD4) count \< 200 cells/microliter; note that patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count \>= 200 cells/microliter within 30 days prior to step 1 registration; note also that HIV testing is not required for eligibility for this protocol
