MDRT in Prostate Cancer Treated With Long-term Androgen Deprivation Therapy in the STAMPEDE Trial (METANOVA)

The purpose of this study is to find out if giving radiation therapy (RT) to areas of metastatic prostate cancer at the time a participant is diagnosed will help control disease better than the usual treatment. This treatment is called metastasis-directed radiotherapy (MDRT).

The usual treatment for prostate cancer that has spread to other parts of the body is to give lifelong treatment with hormone therapy (also known as androgen deprivation therapy or ADT). Participants may also be given prostate RT even if the disease is metastatic. Participants will receive hormone therapy (the standard treatment for prostate cancer) for 12 months. The hormone therapy agents may be taken by mouth or given as an injection. Participants will also have prostate RT. Up to 50 participants will have surgery to remove the prostate instead of having prostate RT. A portion of the participants will be randomized to receive MDRT to areas where the cancer has spread. For participants who have surgery to remove their prostate, they will be asked to allow tissue samples collected during the surgery to be sent to an outside lab for research tests and extra blood samples drawn for research tests before starting the study, and at the time the cancer becomes worse if applicable. Participation in the study will last approximately 12 months, and will be followed by their doctor for up to five years per standard of care.

The main goal is to compare the efficacy of the standard of care (standard systemic therapy + definitive prostate-directed local therapy) versus the standard of care with metastasis-directed radiotherapy (MDRT) for consolidation of metastatic disease.

Prostate cancer (PCa) is the most common cancer in men worldwide, with 10% diagnosed with metastatic disease at the time of presentation. The metastatic capacity of cancers behaves along a spectrum of disease progression, such that some solid tumors have spread widely before clinical detectability and others never metastasize. While metastatic disease has historically been treated with palliative intent, an oligometastatic state where metastases are limited in number and location has emerged in which participants with oligometastatic disease may benefit from effective local therapy in addition to systemic therapy. Systemic standard-of-care therapies often include androgen deprivation therapy (ADT) and Androgen receptor signaling inhibitor (ARSI). Studies have shown that administering local radiotherapy (RT) to the prostate in addition to standard of care may improve radiographic profession-free survival. It may be even more efficacious to add metastasis-directed radiotherapy (MDRT) to the treatment of oligometastatic prostate cancer cases. More research is necessary to investigate the application of MDRT to improve disease control.

Eligibility Criteria:
Inclusion Criteria:

* Participant must be ≥ 18 years of age.
* Participant must have an ECOG performance status ≤ 1.
* Histologic confirmation of prostate adenocarcinoma of the prostate gland, with evidence of metastasis on imaging by conventional imaging (MRI, CT, or 99mTc bone scan) or PSMA PET/CT. Biopsy of sites of metastasis is strongly encouraged, but not required.

  * There must be at least 10-15 unstained slides from 2 cores of the highest tumor cellularity available.
* Newly diagnosed disease with no prior treatment(surgery, radiation or systemic treatment, ie hormone therapy or chemotherapy) to the primary disease.

  * Participants may have started LHRH agonist or antagonist therapy, alone as long as it was not started more than 30 days before the participant is enrolled on this study.
* In participants who undergo only conventional imaging, oligometastatic disease is defined as 1-5 discrete metastatic sites in the bone and/or extra-pelvic lymph node (LN) stations.

  * Extra-pelvic LN stations are superior to the regional/pelvic LN stations. Pelvic LN stations commence at the bifurcation of the aorta and bifurcation of the proximal inferior vena cava to the common iliac veins.

    * Radiographic criteria for a LN to be considered a metastatic focus is defined as short-axis diameter in the axial plane of ≥ 1.0 cm, with irregular border and/or heterogeneous morphology
* In participants who undergo PSMA PET/CT (in the presence or absence of conventional imaging), oligometastatic disease is defined as 1-10 PSMA avid bone lesions and/or extra-pelvic LN stations. The MI-RADS reporting system will be followed to guide PSMA PET interpretation

  * In participants extra-pelvic nodal (M1a) disease only by PSMA PET/CT and M0 by conventional imaging (i.e. extra-pelvic LN did not meet size criteria by CT), participant must meet 2 of 3 following criteria in order to be eligible:

    * 1. PSA ≥ 40
    * 2. Evidence of cN1 disease (pelvic LN)
    * 3. Decipher score ≥ 0.89
* Adequate organ and marrow function to receive treatment per treating physician
* Medically fit for treatment and agreeable to follow-up.
* Ability to understand and the willingness to sign a written informed consent.

Exclusion Criteria:

Participants with the presence of any of the following:

* Castration resistant prostate cancer (CRPC).
* Evidence of visceral or intracranial metastases.
* Participant receiving any other investigational agents for cancer.
* Participant is participating in a concurrent treatment protocol for cancer.
* Unable to lie flat during or tolerate PET/MRI, PET/CT or SBRT.
* Prior definitive treatment to the primary prostate cancer or pelvis.
* Participant with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled diabetes (HgA1c \> 10), active pituitary or adrenal dysfunction, or psychiatric illness/social situations that would limit compliance with study requirements
* History of another active malignancy within the previous 2 years, except for non-melanoma skin cancer, non-muscle invasive bladder cancer, or a malignancy that is considered cured with minimal risk of recurrence
* Active Crohn's disease or ulcerative colitis despite medical management.
* Refusal to sign informed consent.
* Any condition that in the opinion of the investigator would preclude participation in this study