Study Evaluating mCRPC Treatment Using PSMA [Lu-177]-PNT2002 Therapy After Second-line Hormonal Treatment
Study Evaluating mCRPC Treatment Using PSMA [Lu-177]-PNT2002 Therapy After Second-line Hormonal Treatment
The purpose of this study is to evaluate the efficacy and safety of [Lu-177]-PNT2002 in
 patients with metastatic castration-resistant prostate cancer who have progressed following
 treatment with androgen receptor axis-targeted therapy (ARAT).
The primary objective of the study is to determine the efficacy of [Lu-177]-PNT2002
 ([Lu-177]-PSMA-I&T) versus abiraterone or enzalutamide in delaying radiographic progression
 in patients with mCRPC.

 The study consists of 3 phases: Dosimetry, Randomized Treatment, and Long term Follow up.

 The study will commence with a 25-patient safety and dosimetry lead-in (Part 1) and proceed
 to a randomization treatment phase in approximately 390 patients (Part 2). Patients in Part 2
 will be randomized in a 2:1 ratio to receive either [Lu-177]-PNT2002 (Arm A), or enzalutamide
 or abiraterone (Arm B). Patients in Arm B who experience radiographic progression per central
 review and meet protocol defined eligibility, may crossover to receive [Lu-177]-PNT2002. All
 patients will be followed in long-term follow-up for at least 5 years from the first
 therapeutic dose, death, or loss to follow up (Part 3).

 Only patients that meet PSMA PET avidity criteria per central review will be eligible for
 this study.
Inclusion Criteria:

 1. Male aged 18 years or older.

 2. Histological, pathological, and/or cytological confirmation of adenocarcinoma of the
 prostate.

 3. Ineligible or averse to chemotherapeutic treatment options.

 4. Patients must have progressive mCRPC at the time of consent based on at least 1 of the
 following criteria:

 1. Serum/plasma PSA progression defined as increase in PSA greater than 25% and >2
 ng/mL above nadir, confirmed by progression at 2 time points at least 3 weeks
 apart.

 2. Soft-tissue progression defined as an increase ≥20% in the sum of the diameter
 (SOD) (short axis for nodal lesions and long axis for non-nodal lesions) of all
 target lesions based on the smallest SOD since treatment started or the
 appearance of one or a new lesion.

 3. Progression of bone disease: evaluable disease or one new bone lesion by bone
 scan

 5. Previous treatment with one ARAT (abiraterone or enzalutamide or darolutamide or
 apalutamide) in either the CSPC or CRPC setting.

 6. PSMA-PET scan (i.e., 68Ga-PSMA-11 or 18F-DCFPyL) positive as determined by the
 sponsor's central reader.

 7. Castrate circulating testosterone levels (<1.7 nmol/L or <50 ng/dL).

 8. Adequate organ function, independent of transfusion:

 a. Bone marrow reserve: i. White blood cell (WBC) count ≥2.5 × 109/L OR absolute
 neutrophil count (ANC) ≥1.5 × 109/L.

 ii. Platelets ≥100 × 109/L. iii. Hemoglobin ≥8 mmol/L. b. Liver function: i. Total
 bilirubin ≤1.5 × institutional upper limit of normal (ULN). For patients with known
 Gilbert's syndrome, ≤3 × ULN is permitted.

 ii. ALT or AST ≤3.0× ULN. c. Renal function: i. Serum/plasma creatinine ≤1.5 × ULN or
 creatinine clearance ≥50 mL/min based on Cockcroft-Gault formula.

 d. Albumin ≥30 g/L.

 9. Human immunodeficiency virus-infected patients who are healthy and have a low risk of
 acquired immunodeficiency syndrome-related outcomes are included in this trial.

 10. For patients who have partners of childbearing potential: Partner and/or patient must
 use a method of birth control with adequate barrier protection, deemed acceptable by
 the principal investigator during the study and for 6 months after last study drug
 administration.

 11. Willing to initiate ARAT therapy (either enzalutamide or abiraterone), pre-specified
 by investigator, if randomized to Treatment Arm B.

 12. ECOG performance status 0 to 1.

 13. Willing and able to comply with all study requirements and treatments (including 177Lu
 PNT2002) as well as the timing and nature of required assessments.

 14. Signed informed consent.

 Exclusion Criteria:

 Patients are excluded from the study if any of the following criteria apply:

 1. Prostate cancer with known significant (>10%) sarcomatoid or spindle cell or
 neuroendocrine components. Any small cell component in the cancer should result in
 exclusion.

 2. Prior treatment for prostate cancer ≤28 days prior to randomization, with the
 exclusion of first-line local external beam, ARAT, luteinizing hormone-releasing
 hormone (LHRH) therapy, or non-radioactive bone-targeted agents.

 3. Any prior cytotoxic chemotherapy for CRPC (e.g., cabazitaxel or docetaxel);
 chemotherapy for hormone-sensitive prostate cancer (HSPC) is allowed if the last dose
 was administered >1 year prior to consent.

 4. Prior treatment with systemic radionuclides (e.g. radium-223, rhenium-186, strontium
 89).

 5. Prior immuno-therapy, except for sipuleucel-T.

 6. Prior PSMA-targeted radioligand therapy, e.g., Lu-177-PSMA-617, I 131-1095.

 7. Prior poly ADP ribose polymerase (PARP) inhibitor for prostate cancer.

 8. Patients who have had 2 or more lines of ARATs.

 9. Patients receiving bone-targeted therapy (e.g. denosumab, zoledronic acid) must be on
 stable doses for at least 4 weeks prior to randomization.

 10. Administration of an investigational agent ≤60 days or 5 half-lives, whichever is
 shorter, prior to randomization.

 11. Major surgery ≤30 days prior to randomization.

 12. Estimated life expectancy <6 months as assessed by the principal investigator.

 13. Presence of liver metastases >1 cm on abdominal imaging.

 14. A superscan on bone scan defined as a bone scan that demonstrates markedly increased
 skeletal radioisotope uptake relative to soft tissues in association with absent or
 faint genitourinary tract activity71.

 15. Use of opioids for cancer-related pain ≤30 days prior to consent.

 16. Known presence of central nervous system metastases.

 17. Contraindications to the use of planned ARAT therapy.

 18. Active malignancy other than low-grade non-muscle-invasive bladder cancer and non
 melanoma skin cancer.

 19. Concurrent illness that may jeopardize the patient's ability to undergo study
 procedures.

 20. Serious psychological, familial, sociological, or geographical condition that might
 hamper compliance with the study protocol and follow-up schedule. Patients that travel
 need to be capable of repeated visits even if they are on the control arm.

 21. Symptomatic cord compression, or clinical or radiologic findings indicative of
 impending cord compression.

 22. Concurrent serious (as determined by the investigator) medical conditions, including,
 but not limited to, New York Heart Association class III or IV congestive heart
 failure (see 12.1 Appendix 1), unstable ischemia, uncontrolled symptomatic arrhythmia,
 history of congenital prolonged QT syndrome, uncontrolled infection, known active
 hepatitis B or C, or other significant co-morbid conditions that in the opinion of the
 investigator would impair study participation or cooperation.