An International Prospective Open-label, Randomized, Phase III Study Comparing 177Lu-PSMA-617 in Combination With SoC, Versus SoC Alone, in Adult Male Patients With mHSPC

Inclusion Criteria:

Participants eligible for inclusion in this study must meet all of the following criteria:

1. Signed informed consent must be obtained prior to participation in the study

2. Patients must be adults ≥18 years of age

3. Patients must have an ECOG performance status of 0 to 2

4. Patients must have a life expectancy >9 months as determined by the studyinvestigator

5. Patients must have metastatic prostate cancer with histologically or cytologicallyconfirmed adenocarcinoma (current or prior biopsy of the prostate and/or metastaticsite)

6. Patients must have evidence of PSMA-positive disease as seen on a 68Ga-PSMA-11PET/CT scan, and eligible as determined by the sponsor's central reader

7. Patients must have at least one documented metastatic bone and/or softtissue/visceral lesion documented in the following manners within 28 days priorrandomization:

8. Metastatic disease to the bone (in any distribution) visible on 99Tc-MDP bonescintigraphy on either pre-ADT scans or baseline scans AND/OR

9. Lymph node metastases of any size or distribution. If lymph nodes are the onlysite of metastasis, then at least one must be at least 1.5 cm in short axis ANDoutside of the pelvis AND/OR

10. Visceral metastases of any size or distribution. If a participant has a historyof visceral metastases at any time prior to randomization, he should be codedas having visceral metastases at baseline (i.e., patients with visceralmetastases prior to ADT that disappear at baseline will be counted as havingvisceral metastases and would therefore have high volume disease forstratification purposes).

11. Patients must have adequate organ function:

• Bone marrow reserve ANC ≥1.5 x 109/L Platelets ≥100 x 109/L Hemoglobin ≥9 g/dL

• Hepatic Total bilirubin ≤2 x the institutional upper limit of normal (ULN). Forpatients with known Gilbert's Syndrome ≤3 x ULN is permitted Alanineaminotransferase (ALT) or aspartate aminotransferase (AST) ≤3.0 x ULN OR ≤5.0 xULN for patients with liver metastases

• Renal eGFR ≥ 50 mL/min/1.73m2 using the Modification of Diet in Renal Disease (MDRD) equation

9. Albumin ≥2.5 g/dL

10. Human immunodeficiency virus (HIV)-infected patients who are healthy and have a lowrisk of acquired immune deficiency syndrome (AIDS)-related outcomes can participatein this trial

11. Patients must be:

Treatment naïve OR minimally treated with:

• Up to 45 days of luteinizing hormone-releasing hormone (LHRH) agonist /antagonistsor bilateral orchiectomy with or without first generation anti-androgen (e.g.bicalutamide, flutamide) for metastatic prostate cancer is allowed prior to ICFsignature. If given, first generation anti-androgen must be discontinued prior tostart of study therapy or after 45 days whatever happens first.

• If received, prior LHRH agonist/antagonist with or without first generationanti-androgen use in the adjuvant/neo-adjuvant setting must have been discontinued > 12 months prior to ICF signature AND must not have exceeded 24 months of therapy ANDmust not have shown disease progression within 12 months of completingadjuvant/neo-adjuvant therapy.

• Up to 45 days of CYP17 inhibitor or ARDT exposure for metastatic prostate cancer isallowed prior to ICF signature. No CYP17 inhibitor or ARDT exposure for earlierstages of prostate cancer is allowed.

Exclusion Criteria:

Participants meeting any of the following criteria are not eligible for inclusion in this study.

1. Participants with rapidly progressing tumor that requires urgent exposure totaxane-based chemotherapy

2. Any prior systemic anti-prostate cancer therapy (with the exception of the drugslisted on inclusion criteria 11), including chemotherapy, Poly (adenosinediphosphate-ribose) polymerase (PARP) inhibitors, immunotherapy or biologicaltherapy (including monoclonal antibodies).

3. Concurrent cytotoxicity chemotherapy, immunotherapy, radioligand therapy, PARPinhibitor, biological therapy or investigational therapy

4. Previous treatment with any of the following within 6 months of randomization:Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223, hemi-bodyirradiation. Previous PSMA-targeted radioligand therapy is not allowed

5. Ongoing participation in any other clinical trial

6. Use of other investigational drugs within 30 days prior to day of randomization

7. Known hypersensitivity to any of the study treatments or its excipients or to drugsof similar chemical classes

8. Transfusion for the sole purpose of making a participant eligible for studyinclusion

9. Participants with CNS metastases that are neurologically unstable, symptomatic, orreceiving corticosteroids for the purpose of maintaining neurologic integrity.Participants with epidural disease, canal disease and prior cord involvement areallowed if those areas have been treated, are stable, and not neurologicallyimpaired. Participants with parenchymal CNS metastasis (or a history of CNSmetastasis), that have received prior therapy and are neurologically stable,asymptomatic and not receiving steroids for CNS metastases, are allowed, baselineand subsequent radiological imaging must include evaluation of the brain (magneticresonance imaging (MRI) preferred or CT with contrast).

10. Diagnosed with other malignancies that are expected to alter life expectancy or mayinterfere with disease assessment. However, participants with a prior history ofmalignancy that has been adequately treated and who have been disease free,treatment free for more than 3 years prior to randomization, or participants withadequately treated non-melanoma skin cancer, superficial bladder cancer areeligible.

11. Concurrent serious (as determined by the Principal Investigator) medical conditions,including, but not limited to, uncontrolled infection, known active hepatitis B orC, or other significant co-morbid conditions that in the opinion of the investigatorwould impair study participation or cooperation. Participants with an activedocumented COVID-19 infection (any grade of disease severity) at time of informedconsent may be included only when completely recovered (in accordance with localguidance).

12. Active clinically significant cardiac disease defined as any of the following:

• NYHA class 3/4 congestive heart failure within 6 months prior to ICF signatureunless treated with improvement and echocardiogram or MUGA demonstrates EF > 45% with improvement in symptoms to class < 3.

• History or current diagnosis of ECG abnormalities indicating significant riskof safety for participants in the study such as: Concomitant clinicallysignificant cardiac arrhythmias, e.g. sustained ventricular tachycardia,complete left bundle branch block, high-grade atrioventricular (AV) block (e.g., bifascicular block, Mobitz type II and third degree AV block)

• History of familial long QT syndrome or known family history of Torsades dePointes

• Cardiac or cardiac repolarization abnormality, including any of the following:History of myocardial infarction (MI), angina pectoris, or coronary arterybypass graft (CABG) within 6 months prior to ICF signature

13. History of somatic or psychiatric disease/condition that may interfere with theobjectives and assessments of the study

14. Symptomatic cord compression, or clinical or radiologic findings indicative ofimpending cord compression

15. Any condition that precludes raised arms position

16. Unmanageable concurrent bladder outflow obstruction or urinary incontinence. Note:participants with bladder outflow obstruction or urinary incontinence, which ismanageable and controlled with best available standard of care (incl. pads,drainage) are allowed.

17. Sexually active males unwilling to use a condom during intercourse while takingstudy treatment and for 14 weeks after stopping study treatment. A condom isrequired for all sexually active male participants to prevent them from fathering achild AND to prevent delivery of study treatment via seminal fluid to their partner.In addition, male participants must not donate sperm for the time period specifiedabove. If local regulations deviate from the contraception methods listed above toprevent pregnancy, local regulations apply and will be described in the ICF