A study comparing Pluvicto® plus Standard of Care treatment with ADT and Nubeqa® vs. Standard of Care treatment with ADT and Nubeqa® in Patients with mHSPC

Prior treatment

• Rapidly progressing tumor that requires urgent exposure to taxane-based chemotherapy.
• 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; • participants with an active documented COVID-19 infection (any grade of disease severity) at time of informed consent may only be included when completely recovered (in accordance with local guidance).
• Unmanageable concurrent bladder outflow obstruction or urinary incontinence.Note: participants with bladder outflow obstruction or urinary incontinence, which is manageable and controlled with best available standard of care (incl. pads, drainage) are allowed.
• Inability to swallow oral medication.
• Any prior systemic anti-prostate cancer therapy (with the exception of the drugs listed on inclusion criteria), including chemotherapy, Poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors, immunotherapy or biological therapy (including monoclonal antibodies) or any other radiation therapy.
• Known or persistent abuse of medication, drugs or alcohol.
• Any prior radiation to the pelvic region.
• Concurrent cytotoxicity chemotherapy, immunotherapy, radioligand therapy, PARP inhibitor, biological therapy or investigational therapy.
• Previous treatment with any of the following within 6 months of start of treatment: Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223, hemi-body irradiation. Previous PSMA-targeted radioligand therapy is not allowed.
• Participants with CNS metastases that • are neurologically unstable, symptomatic, or receiving corticosteroids for the purpose of maintaining neurologic integrity; • Participants with epidural disease, canal disease and prior spinal cord involvement are allowed if those areas have been treated, are stable, and not neurologically impaired; • Participants with parenchymal CNS metastasis (or a history of CNS metastasis), that have received prior therapy and are neurologically stable, asymptomatic and not receiving steroids for CNS metastases, are allowed, baseline and subsequent radiological imaging must include evaluation of the brain (magnetic resonance imaging (MRI) preferred or CT with contrast).

Other illness

• Diagnosed with other locally advanced or metastatic malignancies that are expected to alter life expectancy or may interfere with disease assessment due to pre-existing metastases or previous or ongoing cancer treatment. However, participants with a prior history of malignancy that has been adequately treated and who have been disease free, treatment free for more than 3 years prior to start of treatment, or participants with adequately treated non-melanoma skin cancer, or superficial bladder cancer are eligible.
• History of somatic or psychiatric disease/ condition that may interfere with the objectives and assessments of the study.
• Any condition that precludes raised arms position.

Lab values

• Active clinically significant cardiac disease defined as any of the following: • NYHA class 3/4 congestive heart failure within 6 months prior to ICF signature unless treated with improvement and echocardiogram or MUGA demonstrates EF > 45% with improvement in symptoms to class < 3; • History or current diagnosis of ECG abnormalities indicating significant risk of safety for participants in the study such as: Concomitant clinically significant cardiac arrhythmias, e.g. sustained ventricular tachycardia, complete left bundle branch block, high-grade atrioventricular (AV) block (e.g., bifascicular block, Mobitz type II and third degree AV block); • History of familial long QT syndrome or known family history of torsades de pointes • Cardiac or cardiac repolarization abnormality, including any of the following: History of myocardial infarction (MI), angina pectoris, or coronary artery bypass graft (CABG) within 6 months prior to ICF signature.
• Hypersensitivity to the active substance, darolutamide, or to any of the other ingredients (calcium hydrogen phosphate (E 341), croscarmellose sodium, lactose monohydrate, magnesium stearate (E 470b), povidone (E 1201), hypromellose, lactose monohydrate, macrogol (E 1521), titanium dioxide (E 171)) or hypersensitivity to the active substance of Pluvicto® or to any of the excipients (acetic acid, sodium acetate, gentisic acid, sodium ascorbate, pentetic acid, water for injections).

Other

• Symptomatic spinal cord compression, or clinical or radiologic findings indicative of impending cord compression
• Sexually active males unwilling to use a condom during intercourse while taking study treatment and for 14 weeks after stopping study treatment. • A condom is required for all sexually active male participants to prevent them from fathering a child AND to prevent delivery of study treatment via seminal fluid to their partner. • In addition, male participants must not donate sperm for the time period specified above. • If local regulations deviate from the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the ICF.
• Patient without legal capacity who is unable to understand the nature, significance and consequences of the trial.
• Person who is in a relationship of dependence/employment with the sponsor or the investigator.
• All patients must abstain from donating blood or semen/sperm during participation in the study.
• A patient is excluded if the screening 68Ga-PSMA-11 PET/CT or 18F-PSMA-1007 scan performed as part of routine clinical care shows at least one exclusionary PSMA-negative lesion. A PSMA-negative lesion is exclusionary if, measured on diagnostic CT (short-axis diameter), it meets any of the following size criteria: • Lymph node: short-axis diameter ≥ 2.5 cm, at any site in the body; or • Bone metastasis with a soft-tissue component: soft-tissue component ≥ 1 cm in short-axis diameter; or • Solid-organ metastasis (e.g., liver, lung): ≥ 1 cm in short-axis diameter.
• Ongoing participation in any other clinical trial including a medicinal intervention.
• Transfusion for the sole purpose of making a participant eligible for study inclusion.

• Written informed consent obtained according to international guidelines and local laws
• HIV-infected patients who are healthy and have a low risk of acquired immune deficiency syndrome (AIDS)-related outcomes can participate in this trial.
• Ability to understand the nature of the trial and the trial related procedures and to comply with them.
• Male patients aged ≥ 18 years without upper age limit
• Patients with synchronous metastatic hormone-sensitive prostate cancer with histologically confirmed adenocarcinoma (current or prior biopsy of the prostate).
• Patients who have received Androgen Deprivation Therapy (ADT) + Nubeqa® at randomization for a maximum of 12 weeks.
• PSMA-positive lesions as seen on a 68Ga-PSMA-11 PET/CT or 18F-PSMA-1007 scan. PSMA-Positivity is based on VISION criteria, defined as at least one lesion showing uptake higher than liver on ⁶⁸Ga-PSMA-11 PET/ higher than spleen on 18F-PSMA-1007 PET. PSMA PET/CT should be performed not more than 28 days prior to randomisation.
• At least one documented metastatic bone and/or soft tissue/visceral lesion documented as part of routine clinical care in the following manners within 28 days prior to randomisation: • Metastatic disease to the bone (in any distribution) visible on 99Tc-MDP/DPD bone scintigraphy on either pre-ADT scans or other standard-of-care bone scan performed within 28 days prior to randomisation AND/OR; • Lymph node metastases of any size or distribution. If lymph nodes are the only site of metastasis, then at least one must be at least 1.5 cm in short axis AND outside of the pelvis AND/OR; • Visceral metastases of any size or distribution. If a participant has a history of visceral metastases at any time prior to start of treatment, he should be coded as having visceral metastases at baseline (i.e., patients with visceral metastases prior to ADT that disappear at baseline will be counted as having visceral metastases and would therefore have high volume disease for stratification purposes).
• ECOG Performance Status ≤2.
• Adequate bone marrow, liver and renal function • Bone marrow reserve: ANC ≥1.5 x 109/L, Platelets ≥100 x 109/L, Hemoglobin ≥9 g/dL; • Hepatic: Total bilirubin ≤2 x the institutional upper limit of normal (ULN); for patients with known Gilbert's Syndrome ≤3 x ULN is permitted. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤3.0 x ULN OR ≤5.0 x ULN for patients with liver metastases; • Renal: eGFR ≥ 50 mL/min/1.73m2 using the Modification of Diet in Renal Disease (MDRD) equation.
• Albumin ≥2.5 g/dL.