PEACE-6 Poor Responders is an international, multicenter, open-label, controlled, randomized, phase III trial to evaluate the efficacy and safety of 177Lu-PSMA-617 when administered on top of the ongoing standard systemic treatment compared to standard systemic treatment alone in patients with de novo metastatic hormone-sensitive prostate cancer (mHSPC) who do not present with a satisfactory response characterized by a serum prostatic specific antigen (PSA) level of ≥ 0.2 ng/mL at 6 to 8 months after systemic treatment initiation for mHSPC (i.e. poor responders) in the absence of evidence of cancer progression (including a rising PSA level).

The study plans to enroll 500 patients over 63 months who will be randomized (1:1) to receive either: (i) Control arm: SoC (ADT+ ARSI (second-generation androgen receptor signaling inhibitors) +/- RT or ADT+ ARSI +/- RT) or (ii) Experimental arm: 177Lu-PSMA-617 + SoC (ADT+ ARSI +/- RT or ADT+ docetaxel + ARSI +/- RT). Response to treatment will be assessed according to the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria. Treatment will be continued at least until castration-resistant prostate cancer (CRPC) stage is reached, defined by evidence of cancer progression (either a confirmed PSA rise or a radiographic progression) with serum testosterone being at castrated levels (<0.50 ng/mL). This systemic treatment may be continued after CRPC is reached, based on patient benefit and the investigator's opinion. Treatment may also be terminated at the initiative of either the patient or the investigator for any reason that would be beneficial to the patient, including: unacceptable toxicity, intercurrent conditions that preclude continuation of treatment, or patient request. At the end of treatment period, the follow-up period will last for 102 months (8.5 years). The overall trial duration, including the follow-up, is expected to last 18.5 years.

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 of metastases at diagnosis (i.e. before any treatment started). If not available, a more recent imaging can be used

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

8. 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.

9. 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.

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 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).

14. 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.

15. Affiliated to the social security system or in possession of equivalent private health insurance (according to local regulations for participation in clinical trials).

16. 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.

Exclusion Criteria:

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

1. Any evidence of cancer progression (including a rising PSA level, clinical progression, 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 specific experimental treatments tested in the trial
5. 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
6. 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)
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 of successfully treated basal cell or squamous cell skin carcinoma
10. 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
11. Patients unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, or psychological reasons
12. Persons deprived of their liberty or under protective custody or guardianship

IPD can be shared upon request to the sponsor

After primary analysis until end of trial

Steering committee approval