The purpose of this study is to see whether giving a lower (de-escalated) dose of radiation therapy to some parts of the prostate can reduce side effects compared to giving the same (uniform) dose of radiation therapy to the whole prostate.

Inclusion Criteria:

• Documentation of Disease

  o Patients must have pathologically confirmed prostate adenocarcinoma.

• Definition of Disease

  • Grade Group (GG) 1, 2, or 3.
  • PSA less than 20 ng/mL prior to starting ADT, if used.
  • Clinical stage of TX, T1 or T2 on digital rectal examination. May have up to radiological stage T3a on MRI. MRI must be performed within 12 months of randomization.
  • MRI-visible tumor(s), all having PIRADS v2.1 scores of 3, 4, or 5. Each tumor should be able to be delineated on T2 and diffusion-weighted imaging (DWI) +/- dynamic contrast-enhanced imaging (DCE).
  • Tumor nodule visible on MRI should be considered able to be boosted by treating clinician (ie meet urethral constraints while maintaining mandatory GTV coverage) and <2.5cm in maximal dimension.
  • The MRI-defined lesion must be confirmed as malignant on biopsies (Grade group 1, 2, or 3).
  • Patients can be concurrently treated with androgen deprivation therapy (ADT) if this would be standard of care. LHRH analogues, LHRH agonists or Bicalutamide are permitted. ADT is not mandatory where this would usually be omitted. Patients needing greater than 6 months of ADT due to disease parameters should be excluded.
  • No high grade disease (GG3) occult to MRI-defined lesion. As a guide, any pathology for which you would consider surveillance (e.g. GG1, low volume GG2) is allowed outside of the MRI-defined area.
  • No contraindications to MRI (e.g. pacemaker, potentially mobile metal implant, claustrophobia).
  • Prostate volume less than or equal to 90mL.
  • No evidence of nodal or distant metastatic disease.

• Prior Treatment

  o No history of previous radiation to the prostate, prostate surgery (including transurethral resection of the prostate (TURP)), or other local prostate cancer treatments.

• Age ≥ 18

• ECOG Performance Status of ≤ 2 (See Appendix I for performance status criteria)

• Required Organ Function

  • Adequate hematologic function defined as follows:

    • Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3
    • Platelets ≥ 100,000 cells/mm3
    • Hemoglobin ≥ 8 g/dl

  • Adequate renal function defined as follows:

    • Creatinine clearance (CrCL) of ≥30 mL/min by the Cockcroft-Gault formula:

CrCl (mL/min) = [140 - age (years)] x weight (kg) / 72 x creatinine (mg / dL) {x 0.85 for female patients}

• Adequate hepatic function defined as follows:

  • Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (patients with known Gilbert's disease who have bilirubin level ≤ 3 x ULN may be enrolled)
  • AST and ALT ≤3 x institutional ULN

• Adequate cardiac function defined as follows:

  • Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification.

  • To be eligible for this trial, patients should be class 2B or better (see Appendix II: New York Heart Association (NYHA) Functional Classification).

    • Comorbid Conditions

• No active infection requiring parenteral antibiotic(s).

• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.

• No severe GU symptoms that would preclude extreme hypofractionation per the discretion of the treating physician.

• No IPSS Score greater than 19.

• No comorbidities which predispose to significant toxicity (e.g. inflammatory bowel disease) or preclude long term follow up.

  • Ability of the participant to understand and the willingness to sign a written informed consent form.
  • Willing to consent to contraception during and for 1 year after treatment when applicable.
  • Ability/willingness to comply with the patient reported outcome questionnaires schedule throughout the study.

Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made following one year after publication and for up to 36 months later. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.