ADT De-escalation in Selected High-Risk Prostate Cancer Patients (ADaPPt Trial) a GROUQ Led PCS Study (PCS XIV)

Inclusion Criteria:

* • Able to understand and sign informed consent form (ICF);

  * Males aged ≥ 18 years;
  * Histologically confirmed adenocarcinoma of the prostate;
  * Participants with high-risk prostate cancer according to either of the following:

    a) High-risk disease - at least one of the following: i. T3a ii. Gleason 8 or less iii. PSA ≤ 30 ng/mL

iv. Gleason 9 (4+5) not more than 30% of the biopsy (e.g. a 10-needle biopsy can only have a maximum of 3 x 9 \[4+5\]);

* PTEN-proficient tumor confirmed by CLIA-certified immunohistochemistry (IHC);
* PSMA-PET within 90 days prior to randomization: negative for nodal or distant disease.
* Candidate for definitive radiation to prostate and pelvis;
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 or Karnofsky performance status of ≥70%;
* Testosterone ≥150 ng/dL or 5 nmol/L;
* Adequate hematologic, renal, liver function (Hemoglobin ≥10 g/dL, Absolute Neutrophil Count ≥1.5x10⁹/L, Platelets ≥100x10⁹/L);
* Judged to be medically fit for ADT and RT;
* Participants must be accessible for treatment and follow-up. Investigators must assure themselves the participants enrolled on this trial will be available for complete documentation of the treatment, adverse events, and follow-up.
* Sexually active patients, unless surgically sterile, must agree to use condoms as an effective barrier method and refrain from sperm donation during the study treatment and for 3 months after the end of the study treatment.

Exclusion Criteria:

* • Prior local or systemic therapy for prostate cancer (e.g. ADT, chemotherapy or novel Androgen Receptor Inhibitors \[ARIs\]);

  * PSMA-PET positive nodal or distant metastases;
  * PTEN loss or equivocal by IHC (at least more than 50%);
  * Evidence of nodal or distant metastases on conventional imaging;
  * Prior pelvic radiation or prostate surgery interfering with RT (except biopsy/TURP);
  * Life expectancy \<5 years regardless of the prostate cancer;
  * Severe concurrent disease, infection, or co-morbidity that would make the patient inappropriate for enrollment (e.g. cardiovascular disease, hypertension, diabetes, etc);
  * Uncontrolled cardiovascular disease including:

    * Myocardial infarction within 6 months;
    * Unstable angina;
    * Congestive Heart Failure: New York Heart Association (NYHA) class III or IV;
    * Severe arrhythmia;
  * Active severe infection or immunocompromised;
  * Active second malignancy within 5 years with the exception of:

    * Non-melanoma skin cancer;
    * Chronic Lymphocytic Leukemia (CLL) that is stable and not actively treated;
  * Any condition compromising adherence to the protocol.