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

Prior treatment

• Prior or concurrent PSMA-based radioligand therapy or other PSMA target treatments
• Any of the following within 6 months before randomization: stroke, myocardial infraction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, congestive heart failure New York Heart Association (NYHA) Class III or IV
• Severe or uncontrolled concurrent disease, infection or co-morbidity
• Ongoing participation in another clinical trial involving an investigational product.. Treatment with an investigational product must have ended within 28 days prior to the day of randomization

Other illness

• Any evidence of cancer progression (including a rising PSA level, clinical progression, or radiological progression)
• Known hypersensitivity to the components of the study therapy or its analogs
• Any condition preventing the use of the standard of care and/or specific experimental treatments tested in the trial
• Hypertension not controlled by an anti-hypertensive treatment (systolic blood pressure \[sBP\] ≥ 160 mmHg or diastolic blood pressure \[dBP\] ≥ 95 mmHg, 3 consecutive measures taken 5 minutes apart)
• History of malignancy within 3 years of the current diagnosis with the exception of successfully treated basal cell or squamous cell skin carcinoma

Other

• Patients presenting with any of the following criteria are not eligible:
• Pathological findings consistent with small cell carcinoma of the prostate
• Patients unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, or psychological reasons
• Persons deprived of their liberty or under protective custody or guardianship

• All of the following criteria must be met ahead of randomization to satisfy trial eligibility requirements:
• 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.
• Aged ≥18 years old
• Life expectancy \> 6 months as per investigator estimate
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• Men with histologically or cytologically confirmed adenocarcinoma of the prostate
• De novo metastatic disease defined by clinical or radiographic evidence of metastases at diagnosis (i.e. before any treatment started). If not available, a more recent imaging can be used
• Measurable disease or bone lesions evaluable according to PCWG3 criteria. Patients with doubtful bone metastases are not eligible
• A pre-randomization 68Ga-PSMA-11 PET/CT scan performed within 4 weeks prior to randomization in the trial.
  • FDG PET scan is not required for this protocol. All patients will be treated independently from the results of pre-randomization PSMA PET scan: patients with PSMA-positive or PSMA-negative disease according to PROMISE 2.0 criteria are eligible.
• Have 6 to 8 months of previous AND ongoing standard systemic treatment for prostate cancer 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), or darolutamide,) ± 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 accepted as long as it was not PSMA-based and must has been completed at least 4 weeks ahead of randomization.
• Stable or declining PSA level but not a rising one
• Serum PSA of ≥ 0.2 ng/mL at 6 to 8 months after systemic treatment initiation
• Testosterone level \< 50 ng/dl or \< 1.7 nmol/L
• Be fit enough for 177Lu-vipivotide tetraxetan treatment:
  • Adequate bone marrow function: hemoglobin ≥90 g/L (in absence of red blood cell transfusion 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 alanine aminotransferase (ALT) ≤2.0 x upper limit of normal (ULN), or ≤ 5.0 x ULN in the presence of liver metastases; bilirubin \<1.5 x ULN (unless known or suspected Gilbert syndrome, then \<3 x ULN is permitted)
  • Adequate renal function: calculated creatinine clearance ≥ 50 ml/min (using the MDRD or CKD EPI method).
• For sexually active men with female partners of reproductive potential or with pregnant women, agreement to use a condom with another effective contraceptive method during trial participation and up to 14 weeks after study treatment completion.
• Affiliated to the social security system or in possession of equivalent private health insurance (according to local regulations for participation in clinical trials).
• Willing and able to comply with the protocol for the duration of the trial including undergoing treatment and scheduled visits, and examinations including follow-up.