Lutetium-177 Ludotadipep for advanced prostate cancer

Inclusion Criteria:

1. Adult male aged ≥19 years at the time of written informed consent.
2. Histologically, pathologically, or cytologically confirmed prostate adenocarcinoma without small cell features.
3. Patients with progressive metastatic castration-resistant prostate cancer (mCRPC) meeting at least one of the following criteria:

   1. PSA progression: Minimum PSA level of ≥2.0 ng/mL with at least two consecutive increases at intervals of ≥1 week.
   2. Soft tissue progression:

   i. ≥20% increase in the sum of diameters (SOD)\* of target lesions compared to the smallest SOD since treatment initiation, or ii. Appearance of one or more new lesions.

   \*Short axis for lymph nodes and long axis for non-nodal lesions. (c) Bone progression: Appearance of ≥2 new lesions on bone scan.
4. At least one metastatic lesion documented by CT, MRI, or bone scan within 4 weeks prior to baseline.
5. Castration-resistant status with serum testosterone ≤50 ng/dL (≤1.7 nmol/L), achieved by surgical or medical castration.

   Patients without bilateral orchiectomy receiving LHRH analogs must continue such therapy throughout the study.
6. Prior therapy meeting all of the following:

   1. At least one novel anti-androgen drug (NAAD) (e.g., enzalutamide and/or abiraterone).

      (First-generation anti-androgens such as bicalutamide, flutamide, and nilutamide are not counted.)
   2. At least one, but no more than two, prior taxane regimens. Patients who have not received docetaxel may be enrolled if deemed unsuitable, refused treatment, or lack access.
7. COG performance status ≤2.
8. Life expectancy of at least 24 weeks.
9. PSMA-positive mCRPC confirmed by \[18F\]PSMA PET/CT at screening by independent central review, meeting all of the following:

   1. At least one PSMA-positive metastatic lesion§.

      §Defined as uptake greater than liver background, regardless of organ system or lesion size.
   2. No PSMA-negative lesions∥. ∥Defined as metastatic lesions with uptake equal to or lower than liver background and measurable on CT¶.

      * i. Bone lesions with soft tissue component ≥1 cm (short axis) ii. Solid organ metastases ≥1 cm (short axis) iii. Lymph nodes ≥2.5 cm (short axis)
10. Adequate bone marrow, hepatic, and renal function at screening (one repeat test allowed during screening).
11. Agreement to avoid fathering a child and to use effective contraception from screening until 24 weeks after the last dose of study drug, and to refrain from sperm donation.

    Acceptable contraception methods include hormonal contraception, intrauterine device/system, surgical sterilization, double-barrier methods, or complete abstinence.
12. Planned best supportive care/standard of care (BSC/SoC) must be permitted in this study, and both investigator and patient agree that disease management with BSC/SoC alone is appropriate.
13. Ability to understand the study and provision of written informed consent prior to any study-specific procedures.

Exclusion Criteria:

1. Prior treatment with any of the following therapies:

   1. PSMA-targeted radioligand therapy
   2. Systemic radionuclide therapy within 24 weeks prior to the first dose of study intervention (e.g., strontium-89, samarium-153, rhenium-186, rhenium-188, radium-223, or hemi-body irradiation)
   3. Any other anticancer therapy (including cytotoxic chemotherapy, immunotherapy, biologic therapy, or targeted therapy) within 4 weeks prior to randomization
2. History of any of the following:

   1. Hypersensitivity to the active substance or any component of the investigation
   2. History of another primary malignancy within 3 years prior to screening, except for adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, superficial bladder cancer, papillary thyroid cancer, or carcinoma in situ with no recurrence for at least 2 years, as judged by the investigator
   3. Clinically significant cardiovascular disease within 24 weeks prior to screening, including but not limited to:

   i. Myocardial infarction or severe/unstable angina ii. Congestive heart failure (NYHA Class III or IV) iii. QTcF \>480 msec on ECG iv. Clinically significant seizures or conditions predisposing to seizures v. Symptomatic or impending spinal cord compression (d) Known human immunodeficiency virus (HIV) infection
3. Presence of any of the following comorbidities:

   1. Uncontrolled hypertension (SBP ≥160 mmHg or DBP ≥90 mmHg)
   2. Symptomatic or uncontrolled central nervous system metastases (Patients may be eligible if clinically and radiologically stable for ≥4 weeks and off anticonvulsants and corticosteroids for ≥2 weeks prior to study treatment)
   3. Immunocompromised status (including splenectomy or hematopoietic stem cell transplantation) or active autoimmune disease (e.g., myasthenia gravis, Hashimoto's thyroiditis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, scleroderma)
   4. Severe infection or other uncontrolled active infection that may interfere with study assessments, as judged by the investigator
   5. Active hepatitis B or C infection:

   Hepatitis B: Defined as HBsAg positive at screening; however, patients may be eligible if HBV DNA \<500 IU/mL and on stable antiviral therapy for ≥2 weeks prior to first dose, with intent to continue during the study and for ≥24 weeks after the last dose Hepatitis C: Defined as HCV antibody positive; patients are eligible if HCV RNA is negative
4. Presence of a superscan on bone scan at baseline.
5. Failure to recover to baseline or ≤ Grade 1 from prior anticancer therapy-related toxicities (except for alopecia of any grade or other conditions deemed acceptable per eligibility criteria).
6. Participation in another clinical study with administration of an investigational product or device within 4 weeks prior to the first dose of study intervention.
7. Any other condition that, in the opinion of the investigator, would make the subject unsuitable for participation in the study.