This phase II trial evaluates an imaging technique (rhPSMA-7.3 positron emission tomography [PET]/computed tomography [CT]) for detecting prostate cancer in patients who have increasing prostate-specific antigen levels following prior treatment (biochemical recurrence) but who were prostate specific membrane antigen negative on their most recent PET scan. Contrast agents like rhPSMA-7.3 (also called POSLUMA) circulate in the blood until they find their intended target. Once they are taken up by the target tumor cells, they can be visualized using PET/CT cameras. A PET scan is a procedure in which a small amount of radioactive tracer (in this case rhPSMA-7.3) is injected into a vein, and a scanner is used to make detailed, computerized pictures of areas inside the body where the tracer is taken up. Because tumor cells often take up more tracer than normal cells, the pictures can be used to find tumor cells in the body. A CT scan is a procedure that uses a computer linked to an x-ray machine to make a series of detailed pictures of areas inside the body. The pictures are taken from different angles and are used to create 3-dimensional views of tissues and organs. Combining a PET scan with a CT scan can help make the image easier to interpret. PET/CT scans are hybrid scanners that combine both modalities into a single scan during the same examination. The researchers want to determine whether the rhPSMA7.3 PET/CT scan is useful for detecting biochemically recurrent prostate cancer in patients who were negative on prior non-POSLUMA PET imaging.

PRIMARY OBJECTIVE:

I. Determine consensus detection rate by flotufolastat F-18 gallium (rhPSMA-7.3)-PET (POSLUMA) scan in men with recent negative non-POSLUMA PET prostate specific membrane antigen (PSMA) scans.

SECONDARY OBJECTIVES:

I. Determine patient level verified detection rates (by histopathology or a surrogate standard of truth [second contemporaneous imaging, treatment response/change in subsequent imaging]).

II. Determine change in management plan based on POSLUMA scan (major / minor).

EXPLORATORY OBJECTIVE:

I. Determine patient and patient disease characteristics consistent with a positive POSLUMA scan at prostate specific antigen (PSA) < 0.5ng/ml (i.e. pathological Gleason grade, PSA at scan, time to biochemical recurrence [BCR], prostate-specific antigen doubling time [PSADT]).

OUTLINE:

Patients receive rhPSMA-7.3 intravenously (IV) and undergo PET/CT 60 minutes later on day 1.

After completion of study intervention, patients are followed up at 14 days and then every 3 months for 2 years.

Inclusion Criteria:

• Men with a history of prostate adenocarcinoma treated with local therapy (including radical prostatectomy or radical prostatectomy and secondary therapy [i.e. salvage radiation])
• Men must have biochemical recurrence (defined as PSA >= 0.1ng/ml) after therapy
• PSA < 0.5ng/ml (within 90 days of enrollment)
• Men must have had negative or equivocal PET PSMA based imaging with 90 days of enrollment with an Food and Drug Administration (FDA) approved non-POSLUMA tracer
• Non-castrate testosterone (testosterone [T] > 50ng/dL) within 90 days of study entry
• Institutional Review Board (IRB)-/Independent Ethics Committee (IEC)-approved written informed consent and privacy language as per national regulations must be obtained from the subject or legally authorized representative prior to any study-related procedures
• Patients must have the ability to understand and the willingness to sign a written informed consent prior to registration on the study
• Concurrent diseases and malignancies are permitted

Exclusion Criteria:

• Most recent PSA not between 0.1ng/ml and 0.5ng/ml
• Men with non-metastatic castrate resistant prostate cancer (defined as rising PSA and T < 50ng/dl)
• Patients receiving 5-alpha reductase inhibitors, androgen deprivation therapy and androgen receptor antagonists within 3 months of enrollment (men may start these therapies at physician discretion immediately following POSLUMA PET PSMA scan)

Reads will be completed by three trained radiologists blinded to each other's reads.