Study Evaluating mCRPC Treatment Using PSMA [Lu-177]-PNT2002 Therapy After Second-line Hormonal Treatment

Inclusion Criteria:

1. Male aged 18 years or older.

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

3. Ineligible or averse to chemotherapeutic treatment options.

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

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

6. 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 alltarget lesions based on the smallest SOD since treatment started or theappearance of one or a new lesion.

7. Progression of bone disease defined as the appearance of two or more newlesions by bone scan.

8. Progression on previous treatment with one ARAT (abiraterone or enzalutamide ordarolutamide or apalutamide) in either the CSPC or CRPC setting.

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

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

11. Adequate organ function, independent of transfusion: a. Bone marrow reserve: i. White blood cell (WBC) count ≥2.5 × 10^9/L OR absoluteneutrophil count (ANC) ≥1.5 × 10^9/L. ii. Platelets ≥100 × 10^9/L. iii. Hemoglobin ≥8 mmol/L. b. Liver function: i. Totalbilirubin ≤1.5 × institutional upper limit of normal (ULN). For patients with knownGilbert's syndrome, ≤3 × ULN is permitted. ii. ALT or AST ≤3.0× ULN. c. Renal function: i. Serum/plasma creatinine ≤1.5 × ULNor creatinine clearance ≥50 mL/min based on Cockcroft-Gault formula (for patients inFrance, serum/plasma creatinine ≤1.5 × ULN or CrCl ≥60 mL/min based onCockcroft-Gault formula). d. Albumin ≥30 g/L.

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

13. For patients who have partners who are pregnant or of childbearing potential: acondom is required along with a highly effective contraceptive method during thestudy and for 6 months after last study drug administration. Such methods deemedhighly effective include a) combined (estrogen and progestogen containing) hormonalcontraception associated with inhibition of ovulation, b) progestogen-only hormonalcontraception associated with inhibition of ovulation, c) intrauterine device (IUD),d) intrauterine hormone-releasing system (IUS), e) bilateral tubal occlusion, f)vasectomy, g) true sexual abstinence: when this is in line with the preferred andusual lifestyle of the subject [periodic abstinence (e.g., calendar, ovulation,symptothermal, post-ovulation methods), declaration of abstinence for the durationof exposure to IMP, and withdrawal are not acceptable methods of abstinence].

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

15. ECOG performance status 0 to 1.

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

17. Signed informed consent.

Exclusion Criteria:

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

1. If noted in pathology report, prostate cancer with known significant (>10% presentin cells) sarcomatoid or spindle cell or neuroendocrine components. Any small cellcomponent in the cancer should result in exclusion.

2. Prior treatment for prostate cancer ≤28 days prior to randomization, with theexclusion of first-line local external beam, ARAT, luteinizing hormone-releasinghormone (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 lastdose 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 progressed on 2 or more lines of ARATs.

9. Patients receiving bone-targeted therapy (e.g. denosumab, zoledronic acid) not onstable doses for at least 4 weeks prior to randomization.

10. Administration of an investigational agent ≤60 days or 5 half-lives, whichever isshorter, 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 increasedskeletal radioisotope uptake relative to soft tissues in association with absent orfaint genitourinary tract activity.

15. Dose escalation or initiation of opioids for cancer-related pain ≤30 days prior toconsent up to and including randomization.

16. Known presence of central nervous system metastases.

17. Contraindications to the use of planned ARAT therapy, [Ga-68]-PSMA-11, [F-18]-DCFPyLor [Lu-177]-PNT2002 therapy, including but not limited to the following:

• Hypersensitivity to [Ga-68]-PSMA-11, [F-18]-DCFPyL or [Lu-177]-PNT2002excipients (Diethylenetriaminepentaacetic acid (DTPA), Sodium ascorbate,Lascorbic acid, Sodium gentisate, HCl, Sodium hydroxide).

• Recent myocardial infarction or arterial thrombotic events (in the past 6months) or unstable angina (in the past 3 months), bradycardia or leftventricular ejection fraction measurement of < 50%.

• History of seizures in patients planned to receive enzalutamide.

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

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

20. Serious psychological, familial, sociological, or geographical condition that mighthamper compliance with the study protocol and follow-up schedule. Patients thattravel 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 ofimpending 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 congestiveheart failure (see 12.1 Appendix 1), unstable ischemia, uncontrolled symptomaticarrhythmia, history of congenital prolonged QT syndrome, uncontrolled infection,known active hepatitis B or C, or other significant co-morbid conditions that in theopinion of the investigator would impair study participation or cooperation.