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.