Inclusion Criteria:

• Male patients aged 18 years or older.

• Signed informed consent.

• Histologically confirmed adenocarcinoma of the prostate.

• Prior treatment with radical prostatectomy or radiation therapy for localized disease is required.

• Prior treatment with ADT or ARPI or cytotoxic chemotherapy is permitted if:

  • The last treatment > 12 months from enrollment on the trial

  • The duration of treatment is less than 3 months and no evidence of disease progression on treatment.

• Disease detected on PSMA PET/CT scan (PSMA-avid LVM). Patients with SUVMax lesion/liver >1 (miPSMA score of 2) or lesion/parotid > 1 (miPSMA score of 3) would be included. PET scanners used in the study will comply with current guidelines established by the EANM Research Ltd (EARL) for harmonizing PET/CT image acquisition and reconstruction.

• Patients with hormone sensitive low volume metastatic disease (LVM); either de novo metastatic or recurrent disease. LVM, as assessed on PSMA PET/CT is defined as:

  • ≤ 10 total metastatic spots

    • Lymph nodes with short axis of ≤ 2.5 cm

    • Total Tumor Volume (TTV) < 200 mL

  • ≤ 4 bone metastases

  • No brain or liver metastases

• ECOG performance 0 – 2

• Adequate organ function as evidenced by the following laboratory criteria:

  • Hematologic: Hemoglobin ≥ 9 g/dL, platelet count ≥ 100,000/mm³, and absolute neutrophil count ≥ 1,500/mm³.

  • Hepatic: Serum bilirubin ≤ 1.5 × upper limit of normal (ULN), ALT/AST ≤ 2.5 × ULN.

  • Renal: Serum creatinine ≤ 1.5 × ULN or an estimated glomerular filtration rate (eGFR) ≥  50 mL/min/1.73m².

• Able to start therapy within 28 days of screening.

• Expected life expectancy >6 months.

Exclusion Criteria:

• PSMA-undetectable disease defined as rising PSA with absence of PSMA-positive lesions in PSMA PET/CT imaging.

• PSMA-negative disease defined as lesions detected on imaging that are deemed concerning for active cancer metastasis with PSMA SUVmax less than liver and meeting specific size criteria: lymph nodes with short axis of ≥ 2.5 cm, visceral lesions with a solid appearance (soft tissue density) ≥ 1 cm, and bone metastases with a measurable soft tissue component ≥ 1 cm.

• Patient with in-field failure (disease recurrence in prostate bed after primary definitive prostatectomy or radiotherapy)

• Patient with spinal metastatic disease-causing cord compression.

• Patient with prior disease progression on hormone therapy (CRPC)

• Prior treatment with ADT or cytotoxic chemotherapy or ARPI within less than 12 months from enrollment on the trial.

• Prior treatment with ADT or ARPI or cytotoxic chemotherapy is permitted only if more than 3 months treatment duration and no evidence of disease progression on treatment.

• Patients with severe (CTCAE grade ≥2) xerostomia.

• Patients with well documented history of myelosuppression or renal disease that might impair their participation in the trial per medical advice.

• Diagnosed with other malignancies that are expected to alter life expectancy or may interfere with disease assessment. However, participants with a prior history of malignancy that has been adequately treated non-melanoma skin cancer, superficial bladder cancer are eligible.

• Expected life expectancy <6 months.

• Concurrent serious medical co-morbidities as determined by study investigator and expected to impair participation in the study.

  • Subjects with female partners of reproductive potential are required to use effective, medically acceptable methods of birth control (e.g., spermicide in conjunction with a barrier such as a condom or sexual abstinence) while on this study, and for 14 weeks after the last dose of ¹⁷⁷Lu-PSMA-617.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 8/7/2025. Questions regarding updates should be directed to the study team contact.