This study is a phase I dose escalation clinical trial aims to evaluate 161Tb-PSMA-I&T, a new generation prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) using Terbium-161 to replace Lutetium-177, its safety, dosimetry, biodistribution, pharmacokinetics, and preliminary efficacy in Taiwanese men with metastatic castration-resistant prostate cancer, and to inform future clinical trials.

Metastatic castration-resistant prostate cancer (mCRPC) represents the most advanced and treatment-refractory form of prostate cancer, where disease progression continues despite hormone-suppressing therapies and multiple lines of systemic treatment. Radioligand therapy (RLT) targeting prostate-specific membrane antigen (PSMA) has emerged as a promising treatment strategy, delivering targeted radiation to cancer cells using PSMA-binding ligands labeled with therapeutic radioisotopes. While Lutetium-177 (177Lu)-labeled compounds such as 177Lu-PSMA-617 have demonstrated meaningful clinical benefit, their effectiveness may be limited in cases of micrometastatic disease or heterogeneous PSMA expression, due to the physical characteristics of longer-range β particle radiation.

Terbium-161 (161Tb) is a next-generation radionuclide that emits not only β particles but also short-range, high-linear energy transfer Auger electrons. This dual emission profile enables more effective cell killing in small or poorly perfused tumor sites, with potentially enhanced tumor-to-normal tissue selectivity. Preclinical studies and early case reports suggest that 161Tb-labeled PSMA agents may offer superior tumor dosimetry and cytotoxicity compared to 177Lu analogs. Most notably, the recently published VIOLET Phase I/II trial-the largest clinical experience with 161Tb-PSMA-I&T to date-demonstrated favorable safety across escalating doses (up to 7.4 GBq) and promising therapeutic activity. These findings confirm that 161Tb-PSMA RLT is both safe and clinically active, even in patients previously treated with 177Lu-based agents.

Building on this foundation, our study aims to establish a standardized GMP-grade production process for 161Tb-PSMA-I&T and to evaluate its pharmacokinetics, biodistribution, and radiation dosimetry in a small cohort of Taiwanese patients with mCRPC. These pilot data will generate critical clinical insight and infrastructure, directly informing the design of future Phase Ib/II trials and accelerating national readiness for next-generation PSMA-targeted therapies, especially emphasizing on three specific aims: (1) to establish a GMP-compliant manufacturing process for clinical-grade 161Tb-PSMA-I&T suitable for clinical application in Taiwan; (2) to characterize 161Tb-PSMA-I&T focusing on its pharmacokinetics, biodistribution, and radiation dosimetry; (3) to explore preliminary safety data of 161Tb-PSMA-I&T using potential treatment doses in Asian population.

Inclusion Criteria:

1. Age ≥ 20 years, ability to understand and willingness to sign informed consent, cooperate with all study-related procedures and assessments including blood tests and imaging
2. Histologically confirmed adenocarcinoma of the prostate with evidence of metastatic castration-resistant prostate cancer (mCRPC)
3. Prior surgical orchiectomy or chemical castration maintained on luteinizing hormone-releasing hormone analog, with a serum testosterone level <50 ng/dL (castrate range)
4. Prior treated with at least one line of taxane-based chemotherapy unless medically unsuitable, and at least one line of androgen receptor pathway inhibitor (e.g., abiraterone, enzalutamide, apalutamide, or darolutamide)
5. Prior treated with 177Lu-labeled PSMA RLT unless medically unsuitable or declined by the patient
6. Progressive disease defined according to Prostate Cancer Clinical Trials Working Group 3: Either a PSA progression of more than 2 rising PSA values from baseline with intervals ≥ 1 week, or a soft-tissue progression on images per RECIST 1.1 criteria, or a bone progression on images with more than 2 new lesions
7. Evidence of significant PSMA-avid lesions on 68Ga- or 18F-labeled PSMA PET/CT within 12 weeks prior to screening, which defined as 68Ga-PSMA or 18F-PSMA uptake greater than that of liver or spleen parenchyma (depend on the tracer used) in at least one metastatic lesion of any size in any organ system
8. A life expectancy of ≥ 6 months and Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
9. Adequate bone marrow and organ functions 9.1 Hemoglobin ≥ 10 g/dL without RBC transfusion within 4 weeks 9.2 Absolute neutrophil count ≥ 1.5 × 109/L 9.3 Platelet count ≥ 150 × 109/L 9.4 Creatinine clearance ≥ 50 mL/min (Cockcroft-Gault) 9.5 AST and ALT ≤ 3 × ULN, total bilirubin ≤ 1.5 × ULN
10. Willingness to comply with the use of medically acceptable forms of barrier contraception if sexually active

Exclusion Criteria:

1. History of allergic reaction to PSMA-targeted compounds or radiometals
2. Prior radioligand therapy with 223Ra or 177Lu-PSMA within 6 months
3. Prior surgery or radiotherapy within 4 weeks prior to first investigational dose
4. Prior systemic therapies against prostate cancer within 4 weeks, including androgen receptor pathway inhibitor, chemotherapy, targeted therapy such as PARP inhibitors (PARPi)
5. Discordant disease on PET images: FDG-positive disease with minimal PSMA expression
6. Urinary tract obstruction causing hydronephrosis unless appropriately treated beforehand
7. Known symptomatic brain metastases or leptomeningeal disease, symptomatic or impending cord compression unless appropriately treated beforehand
8. Other active malignancy requiring systemic treatment
9. Significant cardiovascular disease (e.g., recent myocardial infarction, unstable angina)
10. Concurrent severe uncontrolled illness that may jeopardize patient safety, including uncontrolled infections