The hypotheses of this study are:

1. Delivery of single fraction Lattice Extreme Ablative Dose (LEAD) radiotherapy (RT) to the dominant tumor lesion(s) in the prostate as identified by multiparametric functional Magnetic Resonance Imaging is safe and feasible when given prior to standard prostate radiotherapy.
2. Biomarker expression levels differ in the functional MRI identified suspicious tumor regions and unsuspicious tumor regions. The investigators hypothesize that a significant source of variation in biomarker levels is due to tumor heterogeneity and that it is molecular abnormalities in the dominant tumor areas that are angiogenic and determine outcome.

Inclusion Criteria:

1. Biopsy confirmed adenocarcinoma of the prostate.

2. T1-T3a disease based on digital rectal exam (DRE).

   • T3a disease based on MRI is acceptable (no evidence of frank (clear cut) seminal vesicle (SV) involvement or invasion of bladder or rectum).

3. Gleason score 6-10.

4. Patients with Gleason score ≥8 must be offered long term androgen deprivation therapy (ADT) and refuse such treatment because only 4-6 months (+/- 2 months) (short term ADT) is permitted (not required) on this protocol. The ADT is recommended to begin after fiducial marker placement; however, ADT is permitted to have been started up to two months prior to the signing of consent. All patients in this protocol may (not required) be treated with 4-6 months (+/- 2 months) of ADT, at the discretion of the treating physician.

   • Gleason ≥ 8 must have < 40% of the tissue involved with Gleason 8 in the biopsy specimen.

5. Prostate-specific antigen (PSA) ≤ 30 ng/mL within 3 months of enrollment. If PSA was above 30 and dropped to ≤ 30 with antibiotics, this is acceptable for enrollment.

6. No previous pelvic radiotherapy.

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

8. 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.

9. Identifiable multiparametric-MRI tumor lesion or lesions, that total in volume < 33% of the prostate

   • Multiparametric MRI of prostate and pelvis is required prior to protocol consideration.
   • If contrast not given, the point dose on the apparent diffusion coefficient (ADC) map should be < 1000.

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

11. Zubrod performance status < 2.

12. Willingness to fill out quality of life forms.

13. Bone scan negative if PSA > 15 ng/mL or Gleason ≥ 8 disease. A questionable bone scan is acceptable if other imaging tests are negative for metastasis.

14. Serum testosterone is within 40% of normal assay limits (e.g., x=0.4*lower assay limit and x=.04*upper assay limit + upper assay limit), and taken within 4 months of enrollment. Patients who have been started on ADT prior to signing consent are not required to have a serum testosterone at this level prior to signing consent; but, a serum testosterone prior to fiducial marker placement is recommended.

15. Serum liver function tests (LFT) are taken within 3 months of enrollment.

16. Complete blood counts are taken within 3 months of enrollment.

17. Age ≥ 35 and ≤ 85 years.

Exclusion Criteria:

1. > T3a disease on digital rectal exam or >T3a disease clearly identified by MRI.
2. Gleason score < 6.
3. ≥ 40% Gleason 8-10 tumor, over the total tissue including other tumor and normal tissue. For example: (Gleason 8-10 tumor length/other biopsy tissue length)*100 = ≥ 40%.
4. Androgen deprivation therapy longer than 8 months. Androgen deprivation timing is for the Luteinizing hormone-releasing hormone (LHRH) agonist portion only and not when anti-androgen is started beforehand with the purpose of counteracting the surge in testosterone from the LHRH agonist - PSA > 30 ng/mL within 3 months of enrollment.
5. PSA > 30 ng/mL within 3 months of enrollment
6. Unable to obtain a 1.5T or 3.0T multiparametric MRI of the pelvis and prostate with contrast.
7. Unidentifiable multiparametric MRI tumor lesion.
8. Identifiable multiparametric-MRI tumor lesions, that total in volume ≥ 33% of the prostate.
9. Previous pelvic radiotherapy.
10. Previous history of radical prostatectomy.
11. Concurrent, active malignancy, which is not 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 not eligible.
12. Zubrod performance status ≥ 2.
13. Inability to understand or unwilling to sign a written informed consent document
14. Unwilling to fill out quality of life/psychosocial forms.
15. Bone scan is positive and other imaging tests confirm a suspicion of metastasis from prostate cancer.
16. Serum testosterone is not within 40% of normal assay limits taken within 4 months of enrollment (only applicable to patients not started on ADT prior to signing consent).
17. Serum liver function tests (LFTs) are not taken within 3 months of enrollment.
18. Complete blood counts are not taken within 3 months of enrollment.
19. Age < 35 and > 85 years.

Up to 6 years