Intrinsic Validity of Molecular Marker(s) Detection on Tissular Tumoral DNA to Predict the Efficacy of 177Lutetium-PSMA-617 (Lu-PSMA) Treatment for Castration-resistant Metastatic Prostate Cancer

Inclusion Criteria:

• Male >18 years of age

• ECOG ≤ 2

• Patient with histologically confirmed of metastatic castration resistant prostatic adenocarcinoma and with tumor biological material available (prostatic biopsies or prostatectomy)

• Patient who received at least one taxane line and a second generation hormone therapy line

• Patient receiving androgen deprivation therapy with serum testosterone < 50 ng/dL or < 1.7 nmol/L

• Progressive mCRPC based based on at least 1 of the following criteria :

• Serum or plasma PSA progression defined as 2 consecutive increases in PSA measured at least 1 week prior. The minimal start value is 2.0 ng/mL ; 1,0 ng/mL is the minimal start value if confirmed increase in PSA is the only indication of progress

• Soft-tissue progression by RECIST 1.1 criteria

• Progression of bone disease : two new lesions ; only the positivity of bone scan defines metastatic bone disease, according to PCWG3 criteria.

• Patients with at least one metastasis, bone and/or soft tissue and/or visceral, documented by the following methods in the 28 days prior to randomization :

• Bone metastasis (regardless of location) highlighted by bone scan AND/OR

• Lymph nodes metastasis, regardless of size and location; if the metastasis are only lymph nodes, the short axis of at least one node should be at least 1.5 cm AND outside the pelvis ; AND/OR

• Visceral metastasis, regardless of size and location; a history of visceral metastasis at any time prior to randomization should be encoded as the presence of visceral metastasis at baseline (i.e., a patient with visceral metastasis prior ADT introduction which are disappeared at baseline will be counted as having visceral metastasis and will be considered to have a high tumor volume during stratification)

• Patient with Lu-PSMA treatment indication, confirmed by PET 68Ga-PSMA-11. PET 68Ga-PSMA-11 positive lesions defined as :

• Any lesion with a higher hypermetabolism than the hepatic parenchyma

• A lymph node lesion of more than 2.5cm of small axis

• Bone metastases with soft tissue component ≥ 10 mm in largest diameter

• Metastases of solid organs (for example, lung, liver, adrenal glands, etc.) ≥ 10 mm in the largest diameter.

• Adequate organ function :

• Bone marrow reserve :

• Absolute neutrophil count ≥ 1.5 x 10^9/L

• Platelets ≥ 100 x 10^9/L.

• Hemoglobin ≥ 9 g/dL

• Hepatic function :

• Total bilirubin ≤ 2 x the upper limit of normal (ULN). For participants with known Gilbert's Syndrome ≤ 3 x ULN is permitted.

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 x ULN OR ≤ 5.0 x ULN for patients with liver metastases.

• Albumin > 2.5 g/dL

• Renal function : Glomerular Filtration Rate (GFR) ≥ 50 mL/min/1.73m2 according to MDRD equation.

• Obtaining the patient's free and informed consent

• Social security scheme or beneficiary.

Exclusion Criteria :

• Other cancer in the last 3 years likely to change life expectancy or interfere with the assessment of the disease

• Protected adult

• History of somatic or psychiatric illness/condition that may interfere with study objectives and evaluations

• Patient unable to understand and comply with study instructions and requirements

• ECOG > 2

• Dilation of pyelocalicial cavities not previously supported

• Obstruction of bladder discharge or uncontrollable and simultaneous urinary incontinence

• Symptomatic spinal cord compression or clinical or radiological findings indicating imminent spinal cord compression

• Fractured risk of bone damage

• Active and symptomatic brain injury

• Concurrent participation in a therapeutic trial and administration of any investigational agent within 28 days of inclusion

• Metastatic tumor tissue as the only material available for prostate cancer diagnosis

• Previous treatment with any of the following in the 6 months prior to randomization: Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223, hemi-cyclic irradiation

• Previous treatment with radioligands targeting PSMA

• Known hypersensitivity to one of the study treatments or its excipients or similar class drugs

• Transfusion or use of bone marrow stimulating agents for the sole purpose of making a participant eligible for inclusion in the study