The University of Miami Adapt (UAdapt) Trial

Inclusion Criteria:

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

2. T1-T3 disease based on digital rectal exam (DRE), informed by mpMRI. Prostate MRImay aid in the staging evaluation by verifying organ-confined status6,7. The abilityto distinguish between organ-confined tumors (≤T2c) and those that extend beyond theprostate (≥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. Aquestionable bone scan is acceptable if additional imaging studies; eg, plainx-rays, CT, MRI, prostate specific membrane antigen (PSMA) positron emissiontomography (PET)/CT do not confirm for metastasis.

4. No evidence of metastasis by clinical criteria or available radiographic tests (N0M0by clinical or imaging criteria).

5. Gleason score 6-10.

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

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

8. Peripheral zone: Distinct lesion on dynamic contrast enhanced (DCE)-MRI withearly enhancement and later washout (Note: contrast not required forenrollment), and/or distinct lesion on the apparent diffusion coefficient (ADC)map (Value <1000).

9. Central gland: A suspicious central gland lesion on mpMRI must have a distinctlesion on the ADC map (Value <1000).

10. No previous pelvic radiotherapy.

11. No previous history of radical/total prostatectomy (suprapubic prostatectomy isacceptable).

12. No concurrent, active malignancy, other than nonmetastatic skin cancer orearly-stage chronic lymphocytic leukemia (well-differentiated small cell lymphocyticlymphoma). If a prior malignancy is in remission for ≥5 years, then the patient iseligible.

13. Ability to understand and the willingness to sign a written informed consentdocument.

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

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

16. Serum testosterone is within 40% of normal assay limits (eg, x=0.4lower assay limitand x=0.4upper assay limit + upper assay limit), taken within (≤) 3 months ofsigning of consent.

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

18. Anti-androgen therapy and ADT must be started after 3-week post-LEAD RTgradient biopsy.

19. Anti-androgen therapy and ADT are recommended to be started prior to orconcurrent with start of moderately hypofractionated RT course and must bestarted before the end of the hypofractionated RT course.

20. The total length planned must be ≤ 30 months.

21. Patient unable to receive iodine or gadolinium contrast due to allergy or poor renalfunction 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 metastaticdisease with the following specifications: PSMA-PET or Fluciclovine PET: Patientswith subclinical (<1.5 cm) pelvic lymph nodes that are suspicious on such PET scanswill be ineligible for FTLEAD, however will still be eligible for HypoLEAD. In thelatter case the treating physician may boost such nodes to a higher dose.

5. Concurrent, active malignancy, other than nonmetastatic skin cancer or early-stagechronic 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 anddrops 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 understandand voluntarily sign a written informed consent document.

10. Patients unable to tolerate diagnostic MRI acquisition. Note: inability to toleratecontrast agents is not exclusionary.