This is a phase II study of ultrahypofractionated whole pelvis proton therapy with brachytherapy boost for patients with high risk or unfavorable intermediate risk prostate with elevated risk of lymph node involvement.

Inclusion Criteria:

• Pathologic evidence of prostate cancer

• Risk group: high or intermediate risk as defined below

  • High risk: T3a or Gleason Grade Group 4/5 or PSA >20
  • Unfavorable intermediate risk disease: at least one or more of the following: T2b-T2c, Gleason Grade Group 2/3, PSA 10-20, >50% of cores positive

• Must be appropriate for whole pelvis per the treating oncologist or based on lymph node predicting nomogram

• Patient is a candidate for definitive external beam radiotherapy:

  • No prior radiotherapy in the region of study
  • No inflammatory bowel disease, active collagen/vascular/connective tissue disorders

• Age ³18 years

• ECOG performance status: 0-2

• Patients may initiate androgen deprivation therapy up to 3 months prior to radiation start, concurrently, or up to 3 months after completion of radiation therapy start. Patients may have received androgen deprivation therapy for the following months: unfavorable intermediate risk patients for 6 months; high-risk patients for 24 months. Patients will be allowed to discontinue ADT at physician and patient discretion.

• Pretreatment evaluation

  • History & Physical by a radiation oncologist within 6 weeks of enrollment
  • MRI prostate
  • PSMA PET
  • PSA level

• Eligible for rectal spacer procedure as determined by treating physician

• Informed consent: Patients must have the ability to understand and be willing to sign the study-specific informed consent indicating their understanding of the investigational nature and the risks of this study before any of the protocol related studies are performed (this does not include routine laboratory testing or imaging studies required to establish study eligibility);

Exclusion Criteria:

• Evidence of distant metastatic disease

• History of inflammatory bowel or active collagen/vascular/connective tissue disorders

• Prior radiation to the pelvis

• Prior or concurrent second invasive malignancy other than non-melanoma skin cancers, unless disease free for minimum of five years

• Known severe, active co-morbidity, defined as follows:

  o Any clinically significant unrelated systemic illness, medical condition, or other factor, which at the discretion of the Principal Investigators, would interfere in the safe and timely completion of study procedures, compromise the patient's ability to tolerate the protocol therapy, or is likely to interfere with the study procedures or results.

• Patients should not have a prior history of TURP

• Patients should not have pre-treatment IPSS >20 or on maximum alpha-blocker medications at baseline

• Patients should not be on therapeutic anticoagulation