Strategic Endocrine Therapy and Targeted Radiotherapy for Prostate Cancer

Inclusion Criteria:

1. Histologically confirmed adenocarcinoma of the prostate.
2. High-risk localized prostate cancer, defined as ≥1 of the following (per National Comprehensive Cancer Network or D'Amico criteria):

   1. Prostate specific antigen ≥ 20 ng/mL
   2. Gleason score 8-10
   3. Clinical stage T3a or higher; imaging can be used to determine T stage if there is macroscopic (gross) extraprostatic extension or invasion of the seminal vesicles or other non-prostate organs
3. No evidence of distant metastasis, confirmed by:

   a. Prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) or equivalent staging imaging
4. Planning to receive definitive external beam radiotherapy and hormone therapy as standard of care (on label or medically accepted) treatment
5. Eastern Cooperative Oncology Group performance status 0-1.
6. Age ≥ 18 years.
7. Willingness to use adequate contraception if sexually active and of reproductive potential
8. Ability to understand and willingness to sign informed consent.
9. Stated willingness to comply with all study procedures and availability for the duration of the study.

Exclusion Criteria:

1. Evidence of metastatic disease, including nodal disease beyond the pelvis or distant metastases on imaging.
2. Clear evidence of regional nodal disease on conventional imaging.
3. Prior prostatectomy.
4. Prior systemic therapy for prostate cancer, including:

   1. Androgen deprivation therapy (Note that participants who have started Androgen deprivation therapy within 90 days prior to randomization can be enrolled.)
   2. Androgen receptor pathway inhibitor (e.g., abiraterone, enzalutamide, apalutamide, darolutamide).
   3. Chemotherapy for prostate cancer.
5. Prior pelvic radiotherapy.
6. Any condition that, in the investigator's judgment, would compromise the patient's safety or compliance.