The purpose of this prostate cancer research study is to investigate:

1. For early-stage patients, the use of a single session of high dose stereotactic body radiotherapy (SBRT) delivered to the tumor within the prostate, not to the entire prostate, as curative treatment of prostate cancer;
2. The addition of ultra short-term androgen supression (uSTAS) to a single session of high dose SBRT as a means of intensifying treatment while preserving quality of life and minimizing side effects;
3. The ability of a single session of high dose SBRT to activate your immune system to enhance eradication of prostate cancer;
4. For higher risk patients, the use of a single session of high dose SBRT to the tumor only followed by 25 sessions of radiotherapy targeting the whole prostate as a means to improve control of disease while preserving quality of life and minimizing side effects;
5. The relationship between diagnostic imaging studies and prostate biopsy results in assessing clinical outcomes; and
6. The relationship of pre- and post-treatment prostate biopsy results and imaging studies, such as MRI and PET/CT.

Inclusion Criteria:

1. Biopsy confirmed adenocarcinoma of the prostate (including intraductal adenocarcinoma, excluding small cell carcinoma).

2. T1-T3 disease based on digital rectal exam (DRE), informed by mpMRI. Prostate MRI may aid in the staging evaluation by verifying organ-confined status6,7. The ability to distinguish between organ-confined tumors (≤T2c) and those that extend beyond the prostate (≥T3a) is an important component of treatment decision making.

3. Patients with T3 disease based on DRE, mpMRI, Gleason 8-10, or a PSA of >15 ng/mL, should undergo a negative metastatic workup prior to signing of consent. A questionable bone scan is acceptable if additional imaging studies; eg, plain x-rays, CT, MRI, prostate specific membrane antigen (PSMA) positron emission tomography (PET)/CT do not confirm for metastasis.

4. No evidence of metastasis by clinical criteria or available radiographic tests (N0M0 by clinical or imaging criteria).

5. Gleason score 6-10.

6. Prostate specific antigen (PSA) ≤100 ng/mL within (≤) 3 months of signing of consent. If PSA was above 100 ng/mL and drops to ≤100 ng/mL with antibiotics, this is acceptable for enrollment.

7. Suspicious peripheral zone or central gland lesion(s) on mpMRI.

   1. Peripheral zone: Distinct lesion on dynamic contrast enhanced (DCE)-MRI with early enhancement and later washout (Note: contrast not required for enrollment), and/or distinct lesion on the apparent diffusion coefficient (ADC) map (Value <1000).
   2. Central gland: A suspicious central gland lesion on mpMRI must have a distinct lesion on the ADC map (Value <1000).

8. No previous pelvic radiotherapy.

9. No previous history of radical/total prostatectomy (suprapubic prostatectomy is acceptable).

10. No concurrent, active malignancy, other than nonmetastatic skin cancer or early-stage chronic lymphocytic leukemia (well-differentiated small cell lymphocytic lymphoma). If a prior malignancy is in remission for ≥5 years, then the patient is eligible.

11. Ability to understand and the willingness to sign a written informed consent document.

12. Zubrod performance status ≤2. Karnofsky or Eastern Cooperative Oncology Group (ECOG) performance status may be used to estimate Zubrod.

13. Age ≥35 and ≤85 years at signing of consent.

14. Serum testosterone is within 40% of normal assay limits (eg, x=0.4*lower assay limit and x=0.4*upper assay limit + upper assay limit), taken within (≤) 3 months of signing of consent.

15. For patients in HypoLEAD cohort, post-LEAD RT androgen deprivation therapy, including use of secondary agents (eg, abiraterone), is at the discretion of the treating physician but must be declared as none, short-term or long-term prior to enrollment. Note that this ADT regimen differs from the uSTADT regimen. If antiandrogen therapy (eg, bicalutamide) or ADT (LHRH agonist or antagonist injection) is planned, the following restrictions apply:

    1. Anti-androgen therapy and ADT must be started after 3-week post-LEAD RT gradient biopsy.
    2. Anti-androgen therapy and ADT are recommended to be started prior to or concurrent with start of moderately hypofractionated RT course and must be started before the end of the hypofractionated RT course.
    3. The total length planned must be ≤ 30 months.

16. Patient unable to receive iodine or gadolinium contrast due to allergy or poor renal function are still eligible for enrollment.

Exclusion Criteria:

1. Prior pelvic radiotherapy.
2. Prior androgen ablation therapy.
3. Prior or planned radical prostate surgery.
4. Clinical, radiographic, or pathologic evidence of nodal or distant metastatic disease with the following specifications: PSMA-PET or Fluciclovine PET: Patients with subclinical (<1.5 cm) pelvic lymph nodes that are suspicious on such PET scans will be ineligible for FTLEAD, however will still be eligible for HypoLEAD. In the latter case the treating physician may boost such nodes to a higher dose.
5. Concurrent, active malignancy, other than nonmetastatic skin cancer or early-stage chronic lymphocytic leukemia (well-differentiated small cell lymphocytic lymphoma). If a prior malignancy is in remission for > 5 years, then the patient is eligible.
6. Zubrod status >2.
7. Pretreatment PSA >100 ng/ml or Gleason score <6. If PSA was above 100 ng/mL and drops to ≤100 ng/mL with antibiotics, this is acceptable for enrollment.
8. Thyroxine (T4) disease.
9. Patients with impaired decision-making capacity who lack the ability to understand and voluntarily sign a written informed consent document.
10. Patients unable to tolerate diagnostic MRI acquisition. Note: inability to tolerate contrast agents is not exclusionary.