In this study the investigators will find out whether the use of a new type of boost approach called irreversible electroporation (IRE) is as effective as the standard boost approach of radiation therapy for participants with intermediate-risk prostate cancer receiving standard stereotactic body radiotherapy (SBRT).

Inclusion Criteria:

• Biopsy proven grade group 2 or 3 (GS 3+4 or GS 4+3) cancer with all pattern 4 found only in the MRI target; systematic biopsy pattern 4 that is concordant with MRI target per investigator is permissible
• Gland size ≤ 80 cc
• Prostate MRI < rT3b disease
• IPSS < 20
• No contraindication to IRE, RT, anesthesia, or transperineal procedure

Exclusion Criteria:

• Any Grade Group ≥4 disease, or any cribriform and/or intraductal carcinoma
• Evidence of nodal or /metastatic disease on MRI and/or PSMA PET/CT
• Unfit for general anesthesia, or contraindication/hypersensitivity to required neuromuscular blocking agents
• Active urinary tract infection (UTI) at the time of IRE or biopsy; must be treated and resolved prior to proceeding
• Actively bleeding, known bleeding disorder, or inability to interrupt anticoagulants/antiplatelet therapy as clinically indicated for biopsy/IRE safety
• Any history of cardiac arrhythmia or epilepsy, or recent myocardial infarction, consistent with NanoKnife contraindication statements
• Presence of an implanted pacemaker/defibrillator or other active implanted electronic device, or other device-related contraindications per current NanoKnife labeling/user manual
• Inability to undergo pelvic MRI
• Prior treatment of prostate cancer including androgen deprivation therapy, focal therapy, radiation therapy, or prostatectomy
• Current or intended use of androgen deprivation therapy

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.