Veterans Affairs Seamless Phase II/III Randomized Trial of STAndard Systemic theRapy With or Without PET-directed Local Therapy for OligoRecurrenT Prostate Cancer

Inclusion Criteria:

Ability to provide Informed Consent for participation in the study.
ECOG Performance Status
Prior localized prostate cancer, confirmed histologically or cytologically, and defined as:

Any T-classification, Gleason Grade Group, and pre-treatment PSA at the time of initial curative-intent treatment are acceptable.
Nx, N0, or N1 N-classification at the time of curative-intent local therapy
No metastatic disease at the time of initial curative-intent treatment are acceptable
If original documentation for Criteria 5.4.1, 5.4.2, and/or 5.4.3 is unavailable, documentation of localized prostate cancer or NCCN risk group satisfies these criteria.
Prior curative-intent local therapy for localized prostate cancer with either upfront definitive radiotherapy or prostatectomy with or without post-operative radiotherapy.

PSA suspicious for biochemical recurrence after local therapy, with lab value(s) taken within 90 days prior to enrollment or prior to start of SST (if current SST has already started), and meeting one of the three below categories:

PSA >/= 0.2 ng/ml x 2 after prostatectomy +/- post-operative radiotherapy; or
Elevation of PSA >/= 2 ng/ml above the nadir after definitive radiotherapy; or
Two consecutively elevated PSAs with evidence of metastasis on the imaging studies.

Serum testosterone obtained prior to randomization and meets one of the criteria below.

For patients who have a history of prior therapy with SST agents for prostate cancer, a total testosterone >/= 100 ng/dl after completion of prior SST and either before the start of current SST or within 30 days of starting current SST is also required if the patient has already started SST for recurrence.
For patients who have no prior history of therapy with SST agents and have already started SST for recurrence, this pre-SST testosterone is not required.
CT or MRI abdomen/pelvis performed within 90 days prior to enrollment or prior to start of SST if already on SST for recurrence. The results from the CT component of the PET/CT can be used to fulfill this criterion. This is optional for patients who have a PSMA PET/CT.
Technetium (Tc99m-MDP) or sodium fluoride (NaF) bone scan (sodium fluoride preferred) performed within 90 days prior to enrollment or prior to start of SST if already on SST for recurrence. This is optional for patients who have a PSMA PET/CT.
FDA-approved standard of care PET/CT (currently PSMA, Fluciclovine, choline) performed within 90 days prior to enrollment or prior to start of SST if already on SST for recurrence.
1-5 lesions suspicious for nodal recurrence or metastasis from prostate cancer as determined by the investigator based on the above imaging studies. Per investigator determination, multiple lesions can be grouped as a single index lesion if in close proximity and considered a single treatment target.
Has already undergone NPOP sequencing or a plan is in place for NPOP sequencing for prostate cancer.

For participants on SST at the time of enrollment only:

-Has been on SST for
For participants with local recurrence on imaging:

Patients with local recurrence in the prostate, SV, or prostate bed are eligible as long as there is at least 1 nodal or distant metastatic recurrence.
Biopsy must confirm local recurrence for patients who have had prior curative-intent radiation to the prostate, SV, or prostate bed.
Candidate for salvage local therapy as determined by a urologist or radiation oncologist (depending on the respective modality to be used to treat the local recurrence).

Exclusion Criteria:

Any current or prior evidence of castration-resistant prostate cancer, defined as two consecutive rises in serum PSA, obtained at a minimum of 1-week interval, with the final PSA value >/= 1 ng/ml, while having a total testosterone < 50 ng/dl).

Prior malignancy, except the following:

Adequately treated non-melanomatous skin cancer;
Adequately treated Stage 0, I, or II cancer from which the patient is currently in complete remission; or
Any other cancer from which the patient has been disease free for three years.
Presence of a symptomatic metastasis that requires palliative radiotherapy.
Any known brain metastases, presence of leptomeningeal disease, malignant spinal cord compression, or malignant cauda equina syndrome.
Prior nodal, bone, or visceral metastasis after curative-intent therapy other than those identified on the enrollment imaging studies which make the patient ineligible for PET-directed local therapy (per investigator discretion).
Prior radiation therapy to any sites requiring PET-directed local therapy or salvage local therapy that will lead to prohibitively high risk of toxicity from subsequent local therapy, as determined by the treating radiation oncologist (if radiation is intended as the study local therapy) or surgeon/urologist (if surgery is intended as the study local therapy).
Any other previous or current condition, which, in the judgement of the Site Investigator, is likely to interfere with any STARPORT treatments or assessments.