Prostate cancer is the third leading cause of cancer-related death in men in the United States and Europe. The treatment of metastatic castration-resistant prostate cancer (mCRPC) has evolved with the arrival of the radioligand [177Lu]Lu-PSMA-617, which specifically targets PSMA-expressing cancer cells.

The randomized phase III VISION study showed that [177Lu]Lu-PSMA-617 significantly improved progression-free survival and overall survival with an acceptable toxicity profile.

The ReaLuP study will evaluate the efficacy of a re-treatment of [177Lu]Lu-PSMA-617 in patients with progressive PSMA-positive mCRPC and who have been previously treated with [177Lu]Lu-PSMA without evidence of progression during this first course of treatment.

Patients will be treated until disease progression, unacceptable toxicity or death, or alternatively up to 9 months after the last dose of treatment.

At the end of this follow up period, patients will enter the " long term follow up ", at least for 2 years after the end of the last active follow-up.

Inclusion Criteria:

• Males ≥ 18 years of age

• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 assessed within 7 days of study treatment initiation

• Histologically or cytologically confirmed adenocarcinoma of prostate (Patients with small cell carcinoma of the prostate may be included)

• Metastatic disease documented by at least one lesion on bone scan or abdominal/pelvic/chest computed tomography (CT) or magnetic resonance imaging (MRI) scan assessed by investigator. Patients without bone metastasis must have measurable lesions in extra-pelvic lymph nodes or in soft-tissues as defined by RECIST 1.1 criteria

• Confirmed progression mCRPC despite ongoing androgen deprivation with serum testosterone < 50ng/dl (1.7nM) within 3 months prior to screening. Progression is defined by the presence of at least one of the following criteria :

  • PSA progression using local laboratory values as defined by a minimum of 2 consecutive rising PSA levels with an interval of ≥1 week between each assessment where the PSA value at screening should be ≥1 ng/mL
  • Radiographic disease progression in bone based on PCWG3 criteria defined as the appearance of 2 or more new bone lesions on bone scan, with or without PSA progression
  • Radiographic disease progression in extra-pelvic lymph nodes based or soft-tissues on RECIST1.1 criteria with or without PSA progression

• PSMA positive metastatic lesions on [68Ga]-PSMA-PET/CT without PSMA negative lesion (The presence of PSMA-positive lesions is defined as [68Ga]-PSMA-11 uptake greater than that of liver parenchyma in one or more metastatic lesions of any size in any organ system. The presence of PSMA-negative lesions is defined as PSMA uptake equal to or lower than that of liver parenchyma in any lymph node with a short axis of at least 2.5 cm, in any metastatic solid-organ lesions with a short axis of at least 1.0 cm, or in any metastatic bone lesion with a soft-tissue component of at least 1.0 cm in the short axis. Patients with any PSMA negative metastatic lesion meeting these criteria are ineligible).

• Participants must have been previously treated with at least 4 consecutive cycles of [177Lu]Lu-PSMA with no evidence of progression during this first course of treatment (including radiological, clinical but also PSA progression).

• Participants must have been previously treated with at least one ARSI - Androgen Receptor Signaling Inhibitors - (including enzalutamide, apalutamide, abiraterone or darolutamide) initiated for mCSPC, nmCRPC or mCRPC. (ARSI may be also administered together with [177Lu]Lu-PSMA-617 provided that the patient has not received an identical ARSI in the past and that this ARSI was initiated at least 15 days before the first cycle of [177Lu]Lu-PSMA-617 and less than 2 months ago. The ARSI administrated in association with LuPSMA should not be considered as a prior therapy. A previous ARSI treatment is mandatory for patient eligibility)

• Patients must have been previously treated with at least one taxane based chemotherapy (with docetaxel or cabazitaxel) (The number of previously administrated lines of taxane-based therapy is not limited ; patients can have received a taxane-based chemotherapy before or after the first sequence of [177Lu]Lu-PSMA)

• Patients must have been progressed at least 120 days after the last injection of the first course of [177Lu]Lu-PSMA therapy. (Patients with a radiological or clinical progressive disease during the first 120 days after the last cycle of the first course of [177Lu]Lu-PSMA are not eligible. PSA progression is defined by a ≥ 25% increase in PSA and an absolute increase of 2 ng/mL or more from the NADIR and confirmed by a second consecutive value obtained 3 or more weeks later. Patients treated with chemotherapy, ARSI or PARP inhibitors between the first 117LuPSMA course and screening are also eligible).

• Be abstinent from heterosexual intercourse OR must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary medical cause) until 98 days (14 weeks) post-treatment.

• Adequate organ functions :

  • Bone marrow reserve :

    • ANC ≥ 1.5 X 109/L
    • Platelets ≥ 100 X 109/L
    • Hemoglobin ≥ 10 g/dL

  • Hepatic :

    • Total bilirubin ≤ 2 x ULN. For patients with known Gilbert's syndrome ≤ 3 x ULN.
    • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤3 x ULN

  • Renal :

    • Clearance ≥40 ml/mn

• Patients must have signed informed consent prior to participating in any study related procedures

• Willing and able to comply with the protocol, including follow-up visits and examinations

• Patients have to be affiliated to the French social security system, or equivalent

Exclusion Criteria:

• History of a [177Lu]Lu-PSMA serious adverse event (SAE) or CTCAE Grade 3 or 4 AE during the initial course of [177Lu]Lu-PSMA that led to the discontinuation of treatment
• More than one course of [177Lu]Lu-PSMA therapy
• Less than 120 days from the last dose administrated in the initial course of [177Lu]Lu-PSMA treatment and the radiological or clinical disease progression, or the initiation of a subsequent therapy.
• Any history of treatment with radium-223 dichloride or other systemic radiotherapy (including strontium-89, samarium-153, actinium-PSMA...)
• Transfusion of red blood cells within 30 days prior to the first injection of the re-treatment of [177Lu]Lu-PSMA-617
• Current central nervous system (CNS) metastases
• Hypersensitivity to the active substance (Lutetium [177Lu] vipivotide tetraxetan or Gallium [68Ga] gozetotide) or to any of the excipients
• Prior > hemibody external radiotherapy
• Imminent or established spinal cord compression based on clinical findings and / or MRI that has not yet been treated
• Other malignancy treated within the last 3 years (except non-melanoma skin cancer or low-grade superficial bladder cancer)
• Chronic conditions associated with non-malignant abnormal bone growth (e.g., confirmed Paget's disease of bone)
• Ongoing participation in any other clinical trial who may interfere with the present study in the judgment of the investigator
• Concurrent serious (as determined by the Principal Investigator) medical conditions, including, but not limited to, uncontrolled infection, known active hepatitis B or C, or other significant co-morbid conditions that in the opinion of the investigator would impair study participation or cooperation.
• Active clinically significant cardiac disease
• History of somatic or psychiatric disease/condition that may interfere with the objectives and assessments of the study
• Patients under tutorship or guardianship