Neoadjuvant Lu-PSMA radioligand therapy and Ipilimumab in men with very high-risk prostate cancer (NEPI)

Prior treatment

• Distant metastasis (clinical stage M1) on conventional imaging. Oligometastatic (maximum 3 bone lesions ) patients on exclusively PSMA PET imaging will not be excluded. Patients with PSA values below 20ng/ml and no evidence of nodal disease are excluded.
  • Other concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, or investigational therapy
  • Lack of availability for clinical follow‐up assessments
  • Other potential life‐threatening malignancies within the past five years requiring treatment
  • Serious cardiac, gastrointestinal, hepatic or pulmonary disease reducing life expectancy to less than five years
  • Patients with serious intercurrent illness, requiring hospitalization
  • Other serious illnesses, e.g., serious infections requiring antibiotics or bleeding disorders
  • Patients carrying organ transplants and/or receiving continuous immunosuppressive medication (other than steroid therapy of up to 10 mg prednisone per day)
  • The patient is known to be positive for Human Immunodeficiency Virus (HIV) or other chronic infections (HBV, HCV) or has another confirmed or suspected immunosuppressive or immunodeficient condition
  • Known hypersensitivity reaction to any of the components of study treatment
  • Known alcohol or drug abuse
  • Prior treatment with androgen receptor antagonists. Treatment with GnRH analogs prior to ICF signature
  • Participation in another clinical study and use of any investigational or non‐registered product (drug or vaccine) other than the study treatment within the 30 days before registration
  • Significant disease or condition which, in the investigator’s opinion, would exclude the patient from the study
  • Legal incapacity or limited legal capacity
  • Bilateral orchiectomy
  • History of prior systemic or local therapy for prostate cancer, including pelvic radiation for prostate cancer
  • Use of any investigational agent ≤4 weeks prior to randomization or any therapeutic procedure for prostate cancer at any time
  • Major surgery ≤4 weeks prior to randomization
  • Prior therapy with CTLA4 antibodies
  • Previous treatment with any of the following within 6 months of randomization:  Strontium‐89, Samarium‐153, Rhenium‐186, Rhenium‐188, Radium‐223,  Previous PSMA‐targeted radioligand therapy
  • Any immunosuppressive therapy given within the past 30 days prior to study drug administration (excluding physiologic steroid hormone replacement and / or steroid therapy up to a maximum dose of 10 mg prednisone or equivalent per day)

• Must be ≥18 years of age
• Sexually active patients must use a condom to prevent them from fathering a child and to prevent delivery of study treatment via seminal fluid to their partner for at least 14 weeks after the last dose of [177Lu]Lu‐PSMA‐617
• Tumor tissue of both prostate biopsy and radical prostatectomy specimen available for local histology review and reference pathology by Professor Henning Reis (Department of Pathology, University Hospital Frankfurt)
• Signed an informed consent form (ICF) indicating that the participant understands the purpose of and procedures required for the study and is willing to participate in the study; participants must be willing and able to adhere to the prohibitions and restrictions specified in this protocol
• Histologically confirmed adenocarcinoma of the prostate including following criteria: Very High‐risk defined by a total Gleason‐Score ≥4+4 (ISUP‐GG 4+5) and clinical stage cT3 (digital rectal examination or imaging based) plus clinical nodal status cN+ or Serum‐PSA level >20ng/ml
• Exclusion of metastases (M0) on conventional imaging and maximum oligometastatic status (maximum 3 bone lesions) on PSMA PET imaging
• Treatment naïve patients
• Eastern Cooperative Oncology Group ECOG 0‐1
• Candidate for radical prostatectomy with pelvic lymph node dissection as per the investigator
• Patients must be PSMA Positron Emission Tomography (PET) scan positive with a prostatic SUVmax > 12 (PRIMARY Score: 5) .
• Following laboratory criteria must be obtained within 14 days prior to randomization:  Bone Marrow reserve • White blood cells, WBC ≥ 2000/μL • Neutrophils ≥ 1500/μL • Platelets ≥ 100 x103/μL • Hemoglobin ≥ 9.0 g/dL  Hepatic • AST/ALT ≤ 3 x ULN • Total Bilirubin ≤ 1.5 x ULN (except participants with Gilbert Syndrome, who may have total bilirubin < 3.0 mg/dL)  Renal • Serum creatinine ≤ 1.5xULN  Endocrine • TSH 0,4 ‐ 4,0 mU/l = 0,4 ‐ 4,0 μU/ml o If TSH is not in normal range, fT3 and fT4 must be determined o fT3 2,3 ‐ 4,5 pg/ml = 3,5 ‐ 7,0 pmol/l o fT4 0,8 ‐ 1,8 ng/dl = 8 ‐ 18 ng/l = 10 ‐ 23 pmol/l  Albumin >3.0 g/dL (3.0 g/dL is equivalent to 30 g/L)  Electrolytes: • Potassium: 3.5‐5 mmol/L • Sodium: 135‐145 mmol/L  Pancreatic: • amylase, lipase ≤ 3 x ULN  alkaline phosphatase (range to be assessed in context of oligometastatic disease)  blood sugar < 200 mg/dL (11.1 mmol/L)