This phase I trial studies the safety, side effects, and treatment cycle 1 best dose of Lu-177-PSMA-617 in patients with prostate cancer that keeps growing even when the amount of testosterone in the body is reduced to very low levels (castration-resistant) and has spread from where it first started (primary site) to other places in the body (metastatic). Lu-177-PSMA-617 is a radioactive drug. It binds to a protein called prostate-specific membrane antigen (PSMA), which is found on prostate cancer tumor cells. Lu-177-PSMA-617 gives off radiation that may kill these tumor cells. It is a type of radioconjugate. Lu-177-PSMA-617 is currently used in a series of 6 intravenous infusions of the standard dosage, each separated by 6 weeks from the previous infusion. Investigators have observed that the first therapy administration (cycle 1) delivers better radiation treatment to the cancer than each of the following 5 infusions. Giving an increased dosage of Lu-177-PSMA-617 in treatment cycle 1 may have a better effect on metastatic castration-resistant prostate cancer than the standard dosage. The study does not change the total cumulative activity from what is used in the standard dosage treatment but gives an increased dosage in cycle 1 and reduces the total number of cycles.

Inclusion Criteria:

• Patients must be eligible for standard Lu-177-PSMA617 RLT for mCRPC, including PSMA PET/CT scan positive (lesion uptake > liver uptake by visual assessment)
• Patients must have recovered to ≤ Grade 2 from all clinically significant toxicities related to prior therapies (i.e., prior chemotherapy, external beam radiation, brachytherapy, immunotherapy, etc.)
• Patients must be ≥18 years of age
• Patients must have an ECOG performance status of 0 or 1
• Absolute neutrophil count (ANC) ≥ 1500/mm^3
• Platelet count ≥ 150,000/mm^3
• Hemoglobin ≥ 10.0 g/dL
• Estimated glomerular filtration rate (EGFR) ≥ 60ml/min
• Bilirubin ≤ 1.5 x the institutional upper limit of normal (ULN). For patients with known Gilbert's Syndrome ≤ 3 x ULN is permitted
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 3.0 x ULN OR ≤ 5.0 x ULN for patients with liver metastases
• Albumin > 3.0 g/dL
• Use effective birth control methods during the treatment and for 14 weeks after the last Lu-177-PSMA-617 dose
• Ability to understand and the willingness to sign a written informed consent

Exclusion Criteria:

• Does not meet criteria for standard Lu-177-PSMA-617 RLT
• Diffuse marrow involvement evident on Ga-68-PSMA PET/CT as assessed by study treating clinician
• Prior RLT
• Unmanageable concurrent bladder outflow obstruction or urinary incontinence
• Concurrent serious (as determined by the Principal Investigator) medical conditions, including, but not limited to, New York Heart Association class III or IV congestive heart failure, history of congenital prolonged QT syndrome, uncontrolled infection, active hepatitis B or C, or other significant co-morbid conditions that in the opinion of the investigator would impair study participation or cooperation
• Plan to start any additional anti-cancer therapy or investigational agents during study therapy. Anti-cancer therapies include chemotherapy and endocrine therapy
• Exclusion criteria for participation in other investigational trials: should not participate during RLT or 30 days prior to start of RLT