In this study it is aimed to analyze the efficacy and safety of Tb-161 PSMA I&T in the 7.4 GBq activity in a large patient group of Lu-177 PSMA naïve mCRPC patients. 3 cycles of Tb-161 PSMA will be administered with 6 weeks periods. After each cycle a triple bed quantitative single photon emission CT (SPECT)-CT scan from vertex to thigh will be acquired 24 h after every treatment of Tb-161 PSMA. In the first cycle additional time points SPECT-CT acquisitions will be obtained for dosimetric calculations. Details of dosimetry acquisitions will be provided by dosimetry partner. Routine safety blood tests including full blood counts, liver function test, electrolytes, serum PSA, and assessment for adverse events were performed every 3 weeks during study treatment. Once the patient completed three cycles of Tb-161 PSMA, they will continue to undergo clinical review, assessment for adverse events, routine safety bloods, and PSA every 6 weeks for 48 weeks. OR to treatment will be assessed by Ga-68 PSMA PET/CT using RECIP 1.0 criteria.

Radionuclide treatment with Lutetium-177 (Lu-177)-labelled prostate-specific membrane antigen (PSMA) has become a standard care of treatment for patients with metastatic castration-resistant prostate cancer (mCRPC). Main advantages of Lu-177 PSMA improvement of overall survival and quality of life. Progression of disease occurs most of the patients after Lu-177 PSMA treatment. For this reason, labelling of PSMA with other radionuclides such as alfa or Auger electrons emitters have been a subject of interest. The major advantage of Terbium-161 is, besides the beta-radiation similar to Lu-177, its additional emission of Auger electron. Additional energy arising from Auger electrons has a shorter distance. Thus, higher concentration of radiation affects micrometastatic deposits of prostatic cancer due to cause of double-strand DNA damage. Preclinical studies demonstrated superior anti-tumor activity of Tb-161 PSMA compared with the Lu-177 PSMA. Furthermore, safety of Tb-161 I&T has been documented recently with VIOLET trial as the first in human study.

In this study it is aimed to analyze the efficacy and safety of Tb-161 PSMA I&T in the 7.4 GBq activity in a large patient group of Lu-177 PSMA naïve mCRPC patients.

3 cycles of Tb-161 PSMA will be administered with 6 weeks periods. After each cycle a triple bed quantitative single photon emission CT (SPECT)-CT scan from vertex to thigh will be acquired 24 h after every treatment of Tb-161 PSMA. In the first cycle additional time points SPECT-CT acquisitions will be obtained for dosimetric calculations. Details of dosimetry acquisitions will be provided by dosimetry partner.

Routine safety blood tests including full blood counts, liver function test, electrolytes, serum PSA, and assessment for adverse events were performed every 3 weeks during study treatment. Once the patient completed three cycles of Tb-161 PSMA, they will continue to undergo clinical review, assessment for adverse events, routine safety bloods, and PSA every 6 weeks for 48 weeks.

Ga-68-PSMA and F-18-FDG PET-CT will be repeated at 8 weeks after last cycle. During cycles if any progression is observed in posttreatment SPECT/CT imaging or PSA levels, additional Ga-68-PSMA and F-18-FDG PET-CT scans will be performed. If disease progression is confirmed, then treatment will be ceased.

Patient-reported outcomes will be assessed within 3 days before cycle 1 day 1, then at 6, 12, 24, 36, and 48 weeks, using the Brief Pain Inventory-Short Form for pain, the Functional Assessment of Cancer Therapy for Prostate Cancer questionnaire for quality of life, and the Functional Assessment of Cancer Therapy-Radionuclide Therapy questionnaire for treatment-specific symptoms.

PSMA-I&T will be radiolabeled with no-carrier-added Tb-161 in the onsite hospital radiopharmacy. Labelling procedure will be provided by Thertera. After labelling quality control tests for radionuclidic purity, radiochemical purity, and radiochemical identity using high-pressure liquid chromatography and radio-thin-layer chromatography, as well as endotoxin and sterility testing will be performed. 7.4 GBq Tb-161 PSMA-I&T will be administered by slow intravenous injection in an ambulatory treatment. A minimum of 500 mL of normal saline hydration over 1-2 h will be given with radiopharmaceutical therapy, unless fluids are contraindicated. All patients will receive androgen deprivation therapy continuously throughout the trial. The subsequent activities of Tb-161 PSMA-I&T will be reduced by 20% for patients who have the following toxicities from the preceding cycle: dry mouth (grade 2), dry eyes (grade 2), nadir platelet count of less than 100 × 109/L, nadir neutrophil count of less than 1.0 × 109/L, or other significant dose-related toxicities (grade 3 or worse) that are considered both attributable to Tb-PSMA-I&T and are radioactivity-related. OR to treatment will be assessed by Ga-68 PSMA PET/CT using RECIP 1.0 criteria.

Inclusion Criteria:

• Men aged 18 years or older with mCRPC (histologically or cytologically confirmed adenocarcinoma of the prostate)
• Progressive disease as defined by the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) under previous treatment with taxane chemotherapy (unless medically unsuitable) and at least one second-generation androgen receptor pathway inhibitor (ARPI)
• Adequate bone marrow, hepatic, and renal function
• Eastern Cooperative Oncology Group performance status of 0-2;
• A life expectancy of at least 6 months.
• On Ga-68 PSMA PET/CT, a maximum standardised uptake value (SUVmax) of at least 20 in at least one metastasis and SUVmax of at least 10 in measurable soft tissue metastases.
• Patient has provided written informed consent
• PSA progression: minimum of 2 rising PSA values from baseline measurement with interval of ≥1 wk between each measurement
• Soft-tissue progression: per RECIST 1.1
• Bone progression: ≥2 new lesions on bone scan
• At least 3 wk interval since completion of surgery or radiotherapy before registration

Exclusion Criteria:

• Patients with discordant metastases defined as positive on 2-[¹⁸F]fluoro-2-deoxy-D-glucose (FDG) PET-CT with minimal uptake on Ga-68-PSMA PET-CT
• Previous treatment with another radioisotope
• Other malignancies within the previous 2 years before registration other than basal cell or squamous cell carcinomas of skin or other cancers that are unlikely to recur within 24 months
• Concurrent illnesses that could jeopardise the ability of the patient to undergo the trial procedures.
• Patient has symptomatic brain metastases or leptomeningeal metastases
• Patient has symptomatic or impending cord compression unless appropriately treated beforehand and clinically stable for >4 wk