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

Key Inclusion criteria:

1. Histologically confirmed prostate cancer prior to randomization

2. Participants must have biochemically recurrent disease after definitive treatment toprostate by Radical Prostatectomy ((RP), (alone or with post-operative radiation toprostate bed/pelvic nodes)) or External beam Radiation Therapy (XRT), (prostatealone or prostate with seminal vesicle and/or pelvic nodes) and/or brachytherapyprior to randomization. Biochemical recurrence is defined as: nadir PSA + 2 ng/mLpost XRT (if participant received-radiation therapy to intact prostate) and PSA > 0.2 ng/mL and rising post RP (with or without post-operation Radiation Therapy (RT))

3. Participants must have OMPC with =< 5 PSMA-positive metastatic lesions on screeningPSMA PET/CT scan (with either gallium (68Ga) gozetotide or piflufolastat (18F)) asvisually assessed by BIRC based on the methodology proposed in the Prostate CancerMolecular Imaging Standardized Evaluation (PROMISE v2) (Seifert et al 2023); forfurther details, please refer to Section 8.1 and the Imaging Manual. Metastaticlesions may include regional/pelvic lymph nodes (N1), distant lymph nodes (M1a),bone (M1b), lung and others visceral (M1c) except liver and brain classified usingAJCC 8. When counting the number of oligometastatic lesions, each lesion is countedas distinct metastasis irrespective of its anatomical location (e.g., one pelvic andone extra-pelvic lymph node will be counted as two metastatic lesions)

4. At least 1 PSMA-positive lesion should be a distant metastasis (M1) per AJCC8classification at screening. For AJCC M staging, PSMA PET information should be used

5. 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 beunequivocal in CI scans, i.e., potentially not attributable to findings thoughtto represent something other than tumor (e.g., degenerative, or post-traumaticchanges or Paget's disease in bone lesions). For conventional imagingassessments, bone lesions must be assessed by bone scan only and soft tissuelesions must be assessed by CT/MRI scans only at screening.

• Prior knowledge of PSMA PET positivity should not influence the radiologist (reader) in determination of CI positivity. Two different readers will beinvolved, one reader for PSMA PET scan and one reader for CI: Reader will beblinded to PSMA PET scan results while reading CI scans. Reader should notmodify their assessment of CI scans (e.g. changing a lesion previouslyidentified as equivocal in CI to unequivocal) after reading the PSMA PET scan.Similarly, biopsy positivity should not influence the reader in the assessmentof CI positivity. More details on the reading paradigm will be provided in theimaging charter

• MRI for radiation treatment planning may show M1 disease but this will notexclude the participant from the study if the lesion is deemed negative perbaseline CT or bone scans

• Participants with pelvic disease (N1) seen in conventional imaging are allowedif the local spread is below common iliac bifurcation (per AJCC 8 definition oflocal disease)

• Distant lymph node disease (M1a) that is visible per CI and less than 10mm inthe short axis is not exclusionary irrespective of PSMA PET positivity.

• If a previously surgically removed lesion was unequivocal for M1 by bone scanor CT, the participant is not eligible.

6. All metastatic lesions detected at screening should be amenable to SBRT

7. Non-castration testosterone level >100 ng/dL at screening

Key Exclusion criteria:

1. Participants with de novo OMPC at screening

2. Unmanageable concurrent bladder outflow obstruction or urinary incontinence atscreening. Note: participants with bladder outflow obstruction or urinaryincontinence, which is manageable and controlled with best available standard ofcare (incl. pads, drainage) are allowed

3. Prior therapy with:

4. ADT including bilateral orchiectomy

• Participants who had XRT or RP and completed adjuvant ADT (or ADT+ARPI)prior to recurrence are eligible to participate if the last dose of ADT (or ADT+ARPI) was before 12 months from randomization. Participants whohad prior SBRT with short term ADT (3-6 months) are also allowed if theADT was stopped at least 12 months before randomization.
• Participants who discontinued ADT due to disease progression are notallowed (i.e., Castration-Resistant Prostate Cancer (CRPC) participants)

2. Other hormonal therapy. e.g.,

• Use of estrogens, 5-α reductase inhibitors (finasteride, dutasteride),other steroidogenesis inhibitors (aminoglutethimide) if used in thecontext of prostate cancer treatment. Same medications are allowed if usedfor other indications: e.g., Benign Prostatic Hyperplasia (BPH), ifstopped at least 5 half-lives before randomization.
• First-generation anti-androgens (bicalutamide, flutamide, nilutamide,cyproterone)
• Second generation anti-androgens (e.g., enzalutamide, apalutamide anddarolutamide)
• CYP17 inhibitors (e.g., abiraterone acetate, orteronel, galeterone,ketoconazole). Short term ketoconazole treatment (<28 days) is permitted

3. Radiopharmaceutical agents (e.g., Strontium-89, PSMA-targeted radioligandtherapy)

4. Immunotherapy (e.g., sipuleucel-T)

5. Chemotherapy, except if administered in the adjuvant/neoadjuvant settingcompleted > 12 months before randomization

6. Any other investigational or systemic agents for metastatic disease

7. Radiation therapy external beam radiation therapy (EBRT) and brachytherapy within 28days before randomization

8. Concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, hormonaltherapy (see ADT initiation guidance in Section 6.8.2), Poly AdenosineDiphosphate-Ribose Polymerase (PARP) inhibitor, biological therapy orinvestigational therapy

9. Diagnosed at screening with other malignancies that are expected to alter lifeexpectancy or may interfere with disease assessment. However, participants with aprior history of malignancy that has been adequately treated and who have beendisease/treatment free for more than 3 years are eligible, as are participants withadequately treated non-melanoma skin cancer and superficial bladder cancer.

10. History or current diagnosis of ECG abnormalities indicating significant risk ofsafety for participants participating in the study such as:

• Concomitant clinically significant cardiac arrhythmias, e.g. sustainedventricular tachycardia, and clinically significant second or third degreeAtrioventricular (AV) block without a pacemaker

• History of familial long QT syndrome or known family history of Torsades dePointe

8. Participants in immediate need of ADT as assessed by the investigator.

Other protocol defined Inclusion/Exclusion may apply.