An Open-label Study Comparing Lutetium (177Lu) Vipivotide Tetraxetan Versus Observation in PSMA Positive OMPC. (PSMA-DC)

Inclusion Criteria: Signed informed consent must be obtained prior to participation in the study Participants must be adults ≥18 years of age at the time of informed consent ECOG performance status of 0 or 1 at screening Participants must have a life expectancy ≥24 months as determined by the Investigator at screening Histologically confirmed prostate cancer prior to randomization Participants must have biochemically recurrent disease after definitive treatment to prostate by RP, (alone or with post-operative radiation to prostate bed/pelvic nodes) or XRT, (prostate alone or prostate with seminal vesicle and/or pelvic nodes) and/or brachytherapy prior to randomization. Biochemical recurrence is defined as: nadir PSA + 2 ng/mL post XRT (if participant received-radiation therapy to intact prostate) and PSA > 0.2 ng/mL and rising post RP (with or without post-operation RT) Participants must have OMPC with ≤5 PSMA-positive metastatic lesions on screening PSMA PET/CT scan (with either gallium (68Ga) gozetotide or piflufolastat (18F)) as visually assessed by BIRC based on the methodology proposed in the Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) (Eiber et al 2018); for further details, please refer to Section 8.1 and Imaging Manual. Metastatic lesions may include regional/pelvic lymph nodes (N1), distant lymph nodes (M1a), bone (M1b), lung and others visceral (M1c) except liver and brain classified using AJCC 8. When counting the number of oligometastatic lesions, each lesion is counted as distinct metastasis irrespective of its anatomical location (e.g., one pelvic and one extra-pelvic lymph node will be counted as two metastatic lesions) At least 1 PSMA-positive lesion should be a distant metastasis (M1) per AJCC8 classification at screening. For AJCC M staging, PSMA PET information should be used Participants must have a negative conventional imaging for M1 disease at screening. Note: For a participant not to be eligible, CI positive M1 lesions should be unequivocal in CI scans, i.e., potentially not attributable to findings thought to represent something other than tumor (e.g., degenerative, or post-traumatic changes or Paget's disease in bone lesions). Prior knowledge of PSMA PET positivity should not influence the radiologist (reader) in determination of CI positivity. Two different readers will be involved, one reader for PSMA PET scan and one reader for CI: Reader will be blinded to PSMA PET scan results while reading CI scans. Readers should not modify their assessment of CI scans (e.g. changing a lesion previously identified as equivocal in CI to unequivocal) after reading the PSMA PET scan. Similarly, biopsy positivity should not influence the reader in the assessment of CI positivity. More details on the reading paradigm will be provided in the imaging charter. MRI for radiation treatment planning may show M1 disease but this will not exclude the participant from the study if the lesion is deemed negative per baseline CT or bone scans. Participants with pelvic disease (N1) seen in conventional imaging are allowed if the local spread is below common iliac bifurcation (per AJCC 8 definition of local disease). Distant lymph node disease (M1a) that is visible per CI and less than 10mm in the short axis are not exclusionary irrespective of PSMA PET positivity. All metastatic lesions detected at screening should be amenable to SBRT If participants previously received SBRT for OMPC, progressive disease must be demonstrated prior to randomization (e.g., a new PSMA PET lesion). Previously treated lesions must be stable in baseline imaging scans and will not be counted towards 1-5 lesions required in this study. If a previously treated lesion was unequivocal for M1 by bone scan or CT before the previous SBRT, the participant is not eligible. Confirmation of Controlled primary tumor at screening: If local recurrence is suspected, MRI is required to rule out local relapse. Participants with MRI or PET positive local lesions require biopsy to rule out local progression. These locally recurrent participants (with biopsy proven local disease or with MRI or PET positive local lesions without biopsy) may be eligible for the study after salvage therapy to local disease. Note: Participants who previously undergone pelvic RT (salvage pelvic RT) at local recurrence after RP are allowed in the study. PSADT <10 months at screening [PSADT will be calculated using a linear regression model of the normal logarithm of PSA and time (Pound et al 1999)] Non-castration testosterone level >100 ng/dL at screening Human immunodeficiency virus (HIV)-infected participants at screening and during the study who are healthy and have a low risk of acquired immune deficiency syndrome (AIDS)-related outcomes can participate in this trial Participants must have adequate organ functions including the following laboratory values at the screening visit: Bone marrow reserve ANC ≥1.5 x 109/L Platelets ≥100 x 109/L Hemoglobin ≥9 g/dL Hepatic Total bilirubin (TBIL) ≤2 x the institutional upper limit of normal (ULN). For participants with known Gilbert's Syndrome ≤3 x ULN is permitted Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤3.0 x ULN. Albumin ≥2.5 g/dL Renal eGFR ≥ 60mL/min/1.73m2 using the Modification of Diet in Renal Disease (MDRD) equation Exclusion Criteria: Participants with de novo OMPC at screening Unmanageable concurrent bladder outflow obstruction or urinary incontinence at screening. 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 Prior therapy with: ADT including bilateral orchiectomy Participants who had XRT or RP and completed adjuvant ADT (or ADT+ Androgen Receptor Pathway Inhibitor (ARPI)) prior to recurrence are eligible to participate if the last dose of ADT (or ADT+ARPI) was before 12 months from randomization Participants who discontinued ADT due to disease progression are not allowed (i.e., CRPC participants) Other hormonal therapy. e.g., Use of estrogens, 5-α reductase inhibitors (finasteride, dutasteride), other steroidogenesis inhibitors (aminoglutethamide) First-generation anti-androgens (bicalutamide, flutamide, nilutamide, cyproterone). Second generation anti-androgens (e.g., enzalutamide, apalutamide and darolutamide) CYP17 inhibitors (e.g., abiraterone acetate, orteronel, galeterone, ketoconazole). Short term ketoconazole treatment (<28 days) is permitted. Radiopharmaceutical agents (e.g., Strontium-89, PSMA-targeted radioligand therapy) Immunotherapy (e.g., sipuleucel-T) Chemotherapy, except if administered in the adjuvant/neoadjuvant setting completed > 12 months before randomization Any other investigational or systemic agents for metastatic disease Herbal and non-herbal products that may decrease PSA levels (i.e., saw palmetto, pomegranate juice) within 28 days before randomization Use of other investigational drugs within 28 days prior to day of randomization Radiation therapy, external beam radiation therapy (EBRT), and brachytherapy within 28 days before randomization Systemic (oral/i.v./Intramuscular (IM)) corticosteroids within 28 days before randomization. Note: Short term use (≤ 4 weeks) of corticosteroids during the study is allowed if clinically indicated Concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, hormonal therapy (see ADT initiation guidance in Section 6.8.2), PARP inhibitor, biological therapy, or investigational therapy Known hypersensitivity to any of the study treatments or its excipients or to drugs of similar chemical classes Transfusion during screening procedures for the sole purpose of making a participant eligible for study inclusion Diagnosed at screening with other malignancies that are expected to alter life expectancy or may interfere with disease assessment. However, participants with a prior history of malignancy that has been adequately treated and who have been disease/treatment free for more than 3 years are eligible, as are participants with adequately treated non-melanoma skin cancer and superficial bladder cancer Concurrent serious (as determined by the 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 be included only when completely recovered (in accordance with local guidance) History or current diagnosis of ECG abnormalities indicating significant risk of safety for participants participating in the study such as: Concomitant clinically significant cardiac arrhythmias, e.g. sustained ventricular tachycardia, and clinically significant second- or third-degree AV block without a pacemaker History of familial long QT syndrome or known family history of Torsades de Pointe Resting heart rate (physical exam or 12 lead ECG) <60 bpm 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 Sexually active males unwilling to use a condom during intercourse