Standard of Care +/- 177Lu-PSMA-617 In de Novo mHSPC Patients With Poor PSA Response (PEACE6-Poor Responders)

Inclusion Criteria:

All of the following criteria must be met ahead of randomization to satisfy trial eligibility requirements:

1. Signed a written informed consent form prior to any trial specific procedures. Note: In case of physical incapacitation, a trusted representative of their choice,which is not the Investigator or sponsor, can sign on the behalf of the patients.

2. Aged ≥18 years old

3. Life expectancy > 6 months as per investigator estimate

4. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

5. Men with histologically or cytologically confirmed adenocarcinoma of the prostate

6. De novo metastatic disease defined by clinical or radiographic evidence ofmetastases at diagnosis (i.e. before any treatment started). If not available, amore recent imaging can be used

7. Measurable disease or bone lesions evaluable according to PCWG3 criteria. Patientswith doubtful bone metastases are not eligible

8. A pre-randomization 68Ga-PSMA-11 PET/CT scan performed within 4 weeks prior torandomization in the trial. FDG PET scan is not required for this protocol. All patients will be treatedindependently from the results of pre-randomization PSMA PET scan: patients withPSMA-positive or PSMA-negative disease according to PROMISE 2.0 criteria areeligible.

9. Have 6 to 8 months of previous AND ongoing standard systemic treatment for prostatecancer consisting in either:

• ADT with an androgen receptor signaling inhibitor (ARSI) (i.e., abiraterone (plus prednisone), or apalutamide or enzalutamide) ± radiotherapy **

• ADT with docetaxel* plus an ARSI (i.e. abiraterone (plus prednisone), ordarolutamide,) ± radiotherapy** Note:

*Docetaxel must have been stopped at least 4 weeks ahead of randomization.

** Previous radiotherapy to the primary tumor and/or to the metastases is acceptedas long as it was not PSMA-based and must has been completed at least 4 weeks aheadof randomization.

10. Stable or declining PSA level but not a rising one

11. Serum PSA of ≥ 0.2 ng/mL at 6 to 8 months after systemic treatment initiation

12. Testosterone level < 50 ng/dl or < 1.7 nmol/L

13. Be fit enough for 177Lu-vipivotide tetraxetan treatment:

• Adequate bone marrow function: hemoglobin ≥90 g/L (in absence of red blood celltransfusion within 4 weeks prior to randomization), absolute neutrophil count ≥1.5 x10⁹/L, platelet count >100 x10⁹/L

• Adequate liver function: aspartate aminotransferase (AST) and alanineaminotransferase (ALT) ≤2.0 x upper limit of normal (ULN), or ≤ 5.0 x ULN inthe presence of liver metastases; bilirubin <1.5 x ULN (unless known orsuspected Gilbert syndrome, then <3 x ULN is permitted)

• Adequate renal function: calculated creatinine clearance ≥ 50 ml/min (using theMDRD or CKD EPI method).

14. For sexually active men with female partners of reproductive potential or withpregnant women, agreement to use a condom with another effective contraceptivemethod during trial participation and up to 14 weeks after study treatmentcompletion.

15. Affiliated to the social security system or in possession of equivalent privatehealth insurance (according to local regulations for participation in clinicaltrials).

16. Willing and able to comply with the protocol for the duration of the trial includingundergoing treatment and scheduled visits, and examinations including follow-up.

Exclusion Criteria:

Patients presenting with any of the following criteria are not eligible:

1. Any evidence of cancer progression (including a rising PSA level, clinicalprogression, or radiological progression)

2. Prior or concurrent PSMA-based radioligand therapy or other PSMA target treatments

3. Known hypersensitivity to the components of the study therapy or its analogs

4. Any condition preventing the use of the standard of care and/or specificexperimental treatments tested in the trial

5. Any of the following within 6 months before randomization: stroke, myocardialinfraction, severe/unstable angina pectoris, coronary/peripheral artery bypassgraft, congestive heart failure New York Heart Association (NYHA) Class III or IV

6. Hypertension not controlled by an anti-hypertensive treatment (systolic bloodpressure [sBP] ≥ 160 mmHg or diastolic blood pressure [dBP] ≥ 95 mmHg, 3 consecutivemeasures taken 5 minutes apart)

7. Severe or uncontrolled concurrent disease, infection or co-morbidity

8. Pathological findings consistent with small cell carcinoma of the prostate

9. History of malignancy within 3 years of the current diagnosis with the exception ofsuccessfully treated basal cell or squamous cell skin carcinoma

10. Ongoing participation in another clinical trial involving an investigationalproduct.. Treatment with an investigational product must have ended within 28 daysprior to the day of randomization

11. Patients unwilling or unable to comply with the medical follow-up required by thetrial because of geographic, familial, social, or psychological reasons

12. Persons deprived of their liberty or under protective custody or guardianship