A Phase II Study of AAA617 Alone and AAA617 in Combination With ARPI in Patients With PSMA PET Scan Positive CRPC

An International Prospective Open-label, Multi-center, Randomized, Non-comparative Phase II Study of Lutetium [177Lu] Vipivotide Tetraxetan (AAA617) Alone and Lutetium [177Lu] Vipivotide Tetraxetan (AAA617) in Combination With Androgen Receptor Pathway Inhibitors in Patients With PSMA PET Scan Positive Castration-Resistant Prostate Cancer

The purpose of this study is to evaluate the efficacy and safety of AAA617 alone (Lutetium [177Lu] vipivotide tetraxetan) and in combination with an Androgen Receptor Pathway Inhibitors (ARPI) in participants with PSMA-positive, castration-resistant prostate cancer and no evidence of metastasis in conventional imaging (CI) (i.e., CT/MRI and bone scans).

All participants will be assessed for eligibility and will undergo baseline disease assessments including a mandatory gallium [68Ga] gozetotide (hereinafter referred to as AAA517) or piflufolastat (18F) (also known as[18F]DCFPyL) PET/CT scan and conventional imaging (i.e., CT/MRI and bone scans). Piflufolastat- (18F) PET/CT scan will be performed in US only.

The treatment duration will be up to 6 cycles of AAA617, treatment will be administered once every 6 weeks (duration of 1 cycle). Participants randomized to Arm B may continue to receive ARPI after second end of treatment (EOT2) outside the study protocol at the investigator's discretion and in accordance with local guidelines.

The visit frequency will be every week 1 and week 4 of each of the 6 cycles and every 16 weeks thereafter (for both arms) until the first event of disease progression (RECIST 1.1) or until global end of study (EOS), whichever comes first. After cycle 1 the safety visit at week 4 is optional onsite and could be paired with efficacy assessments or handled remotely. No biomarker collections are expected after the last end of trial (EOT) visit is completed. The study duration will be approximately 36 months.

Key Inclusion criteria

• Participants must be adults ≥ 18 years of age with signed informed consent prior to participation to study
• Histologically or cytologically confirmed prostate cancer
• Participants must have ongoing androgen deprivation therapy with a GnRH agonist/antagonist or prior bilateral orchiectomy at the time of randomization. Intermittent administration of ADT is accepted before randomization if criterion for serum testosterone is met
• Castrate level of serum testosterone (< 1.7 nmol/l [50 ng/dl]) on GnRH agonist or antagonist therapy (continuous/intermittent) or after bilateral orchiectomy prior to randomization
• Participants must have evidence of PSMA-positive disease (N1 or M1) as seen on a AAA517 or piflufolastat F 18 PET/CT scan at baseline as determined by Blinded Independent Central Review (BICR) based on the methodology proposed in the Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) (Eiber et al 2018). Participants with M1 disease only on PSMA PET scan are allowed to participate
• Participants must have a negative conventional imaging for M1 disease.
• Participants must have adequate organ functions: bone marrow reserve, hepatic & renal

Key Exclusion criteria

• Prior or present evidence of metastatic disease as assessed by CT/MRI locally for soft tissue disease and whole-body radionuclide bone scan for bone disease. Exception: Participants with pelvic disease may be eligible (e.g., participants with enlarged lymph nodes below the bifurcation of common iliac arteries (N1))
• Unmanageable concurrent bladder outflow obstruction or urinary incontinence. Note: participants with bladder outflow obstruction or urinary incontinence, which is manageable with best available standard of care (incl. pads, drainage) are allowed
• Active clinically significant cardiac disease; history of seizure or condition that may pre-dispose to seizure which may require treatment with surgery or radiation therapy
• Prior therapy with: second generation anti-androgens (e.g., enzalutamide, apalutamide and darolutamide) < 3 months before randomization; CYP17 inhibitors (e.g., abiraterone acetate, orteronel, galeterone) < 3 months before randomization; ketoconazole (short duration ketoconazole treatment (<28 days) is permitted); radiopharmaceutical agents (e.g., Strontium-89) if wash-out period of at least 3 months is not completed, PSMA-targeted radioligand therapy; immunotherapy (e.g., sipuleucel-T); chemotherapy, except if administered in the adjuvant/neoadjuvant setting, completed > 2 years before randomization; any other investigational agents for CRPC; use of estrogens, 5-α reductase inhibitors (finasteride, dutasteride), other steroidogenesis inhibitors (aminoglutethimide) or first-generation anti-androgens (bicalutamide, flutamide, nilutamide, cyproterone) within 28 days before randomization; radiation therapy (external beam radiation therapy [EBRT] and brachytherapy within 28 days before randomization
• Other concurrent cytotoxicity chemotherapy, immunotherapy, radioligand therapy, poly adenosine diphosphate-ribose polymerase (PARP) inhibitor, biological therapy or investigational therapy

Other protocol-defined inclusion/exclusion criteria may apply.