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* Participants will receive the standard of care. Standard systemic therapy (SST) and definitive local therapy (radiotherapy \[RT\] or radical prostatectomy \[RP\]) are the standard of care for de novo oligometastatic prostate cancer. This arm will be used to compare to the experimental arm.
* SST will begin 6 weeks of randomization and occur for 12 months. The definitive local therapy will be RT, with a small portion undergoing RP. Local therapy should be completed by the end of Week 20.

* Participants will receive the standard of care. Standard systemic therapy (SST) and definitive local therapy (radiotherapy \[RT\] or radical prostatectomy \[RP\]) are the standard of care for de novo oligometastatic prostate cancer. This arm will be used to compare to the experimental arm.
* SST will begin 6 weeks of randomization and occur for 12 months. The definitive local therapy will be RT, with a small portion undergoing RP. Local therapy should be completed by the end of Week 20.
* MDRT should be completed by the end of Week 24. Depending on the participant, there are different approaches to MDRT dosing and fraction size.

Standard androgen deprivation therapy (ADT) will be administered at the discretion of treating physician.

Androgen deprivation therapy (ADT)

Standard androgen receptor signaling inhibitors (ARSI) will be administered at the discretion of the treating physician.

Androgen receptor signaling inhibitor (ARSI)

Local therapy will either be radiotherapy (RT) or radical prostatectomy (RP).

* Prostate +/- pelvic nodal radiation
* Radical prostatectomy + pelvic lymph node dissection

Local Therapy: Radical Prostatectomy (RP) or Radiotherapy (RT)

In participants randomized to the MDRT arm, MDRT to all lesions will be performed by the end of Week 24. Selection of a particular regimen (the dose and fractionation) will based on the size and location of the participant's metastatic site and the surrounding normal tissue constraints.

Metastasis directed radiotherapy (MDRT)

Angela Y Jia, MD, PhD

Daniel E Spratt, MD

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.

Phase II non-blinded randomized study evaluating men with de novo oligometastatic prostate cancer randomized (1:1) to standard of care (SOC) versus SOC plus MDRT.

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

Metastasis-directed Radiotherapy (MDRT) for Men With De-novo Oligometastatic Prostate Cancer Treated With Long-term Androgen Deprivation Therapy in the STAMPEDE Trial (METANOVA)

All IPD that underlie results in publication.

Failure-free survival, defined as time from randomization to first evidence of at least one of: biochemical failure; progression either locally in lymph nodes, or in distant metastases; any salvage intervention (local or systemic) required after 12m of planned SOC therapy; or death from prostate cancer. Biochemical failure, based on the PSA nadir in the first 24 weeks after randomization, is defined as at least one of:

1. PSA nadir by 24 wks post-randomization remains \>50% of pre-treatment PSA, will be considered biochemical failure at time zero;
2. post-radiation therapy (RT):

   1. serum PSA 50% above nadir and at least 4 ng/mL if PSA nadir is less than 4 ng/mL, requiring confirmation ≥ 4 weeks later
   2. PSA 50% above nadir if PSA nadir is at least 50% lower than the last pre-treatment PSA but remaining greater than 4 ng/mL, , requiring confirmation ≥ 4 weeks later
3. post-radical prostatectomy (RP): serum PSA nadir + 0.5 ng/mL

Overall Survival (OS) is defined as the time from randomization until death due to any cause. For participants who survive, time to death will be censored at the time of last contact. The distributions of OS for each treatment arm will be plotted using the Kaplan-Meier method, and median values for each will be estimated and reported with 95% CIs for each treatment arm and compared using stratified log-rank tests. Univariable Cox proportional hazard models will be used to estimate the effect of MDRT on OS.

Radiographic progression-free survival (rPFS) is defined as the time from randomization until clinical progression, detection of at least one new metastatic lesion on CT, MRI, bone scan or Prostate Specific Membrane Antigen (PSMA) PET, or death from prostate cancer. The distributions of rPFS for each treatment arm will be plotted using the Kaplan-Meier method, and median values for each will be estimated and reported with 95% CIs for each treatment arm and compared using stratified log-rank tests. Univariable Cox proportional hazard models will be used to estimate the effect of MDRT on rPFS.

TTNI is defined as time-to-next-intervention. TTNI will be summarized in each arm and compared using Chi-square tests, as well as time-to-event analyses using cumulative incidence methods.

The rate of time-to-castration-resistant prostate cancer will be summarized in each arm and compared using Chi-square tests, as well as time-to-event analyses using cumulative incidence methods.

Prostate cancer specific mortality (PCSM) is defined the time from randomization to death directly attributable to prostate cancer, death from treatment complications, or death from unknown causes in participants with active prostate cancer or previously documented clinical or biochemical relapse.

EPIC-26 is the validated short version of "The Expanded Prostate Cancer Index Composite". EPIC-26 will be administered as a health related quality of life questionnaire for participants with prostate cancer. EPIC-26 consists of 26 items under 5 domains. This study will analyze 4 of the domains, including the urinary, bowel, sexual, and hormonal domain. Each domain will be scaled, scored, and compared by arm.

EPIC-26 assess participant function and bother on a qualitative scale which is then normalized on a scale of 0 to 100 (worst to best) to calculate individual domain scores.

The "International Prostate Symptom Score" (IPSS) is an eight-question questionnaire that will be administered as a health related quality of life measure for participants with prostate cancer. The IPSS score is reported on a scale of 0 to 35. Scores are broken down as: "Mild" (0 to 7 points), "Moderate" (8 to 19 points), and "Severe" (20 to 35 points). The change in IPSS score from baseline prior to treatment to one year after treatment will be measured.

The "International Prostate Symptom Score" (IPSS) is an eight-question questionnaire that will be administered as a health related quality of life measure for participants with prostate cancer. The IPSS score is reported on a scale of 0 to 35. Scores are broken down as: "Mild" (0 to 7 points), "Moderate" (8 to 19 points), and "Severe" (20 to 35 points). The change in IPSS score from baseline prior to treatment to three years after treatment will be measured.

Time to the first skeletal-related event is defined as the time from randomization to the first new pathological bone fracture, spinal cord compression, tumor-related orthopedic surgery, and radiation therapy for bone pain. The SRE will be summarized in each arm and compared using Chi-square tests, as well as time-to-event analyses using cumulative incidence methods. The univariable generalized linear models (e.g., Poisson or negative binomial model) will be used to quantify the MDRT effect on the frequency of SRE.

Spots Global Cancer Trial Database for secondary malignant neoplasm of prostate