Phase II Study of Lutetium (177Lu) Vipivotide Tetraxetan with Androgen Receptor Pathway Inhibitors in PSMA PET Positive Castration-Resistant Prostate Cancer

The primary objective of this study is to evaluate the **prostate-specific antigen (PSA) response** in participants with castration-resistant prostate cancer (CRPC) receiving lutetium [177Lu] vipivotide tetraxetan (AAA617) alone and in combination with androgen receptor pathway inhibitors (ARPIs). This is clinically relevant as PSA response is a critical marker in assessing the efficacy of treatments in CRPC, providing insights into the potential benefits of AAA617 in managing this condition.

Secondary objectives include evaluating:

• Investigator-assessed metastasis-free survival (MFS) and radiographic progression-free survival (rPFS).
• Overall survival (OS) and second progression-free survival (PFS2) in participants with CRPC.
• Time to symptomatic progression, initiation of cytotoxic chemotherapy, and first symptomatic skeletal event (SSE).
• Time to distant metastasis development and local radiological progression in participants with CRPC.
• Time to next therapy or change in therapy, PSA progression, and PSA response (PSA50 and PSA90) in participants with CRPC.
• Health-related quality of life (HRQoL) and safety and tolerability of AAA617 (CTCAE version 5.0) administered alone and in combination with ARPIs.

The clinical trial involves a total of **75 participants** diagnosed with **Castration-Resistant Prostate Cancer (CRPC)**, confirmed through histological or cytological methods. The study population consists exclusively of male adults aged 18 years and older, who have provided informed consent. Participants are required to have ongoing androgen deprivation therapy with a GnRH agonist or antagonist, or have undergone prior bilateral orchiectomy, ensuring a castrate level of serum testosterone. The trial specifically includes individuals with evidence of PSMA-positive disease as determined by a PSMA PET scan, with a PSA Doubling Time of 10 months or less. Participants must also demonstrate adequate organ function, including bone marrow reserve, hepatic, and renal function. The selection criteria exclude females and vulnerable populations, focusing on those with a negative conventional imaging for M1 disease. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed as an international, prospective, open-label, multi-center, randomized, non-comparative phase II study. The primary objective is to evaluate the **PSA response** in participants with **castration-resistant prostate cancer** (CRPC) who are receiving **lutetium (177Lu) vipivotide tetraxetan** alone or in combination with androgen receptor pathway inhibitors. The trial is expected to commence recruitment on January 5, 2024, and conclude by November 10, 2028. Participants will be involved in the study for a maximum treatment period of 60 months, depending on their assigned treatment group and response to therapy.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, histological confirmation of prostate cancer, ongoing androgen deprivation therapy, and evidence of PSMA-positive disease. Following randomization, participants will attend regular follow-up visits to monitor treatment efficacy and safety, including assessments of PSA levels, imaging studies, and evaluations of organ function. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination from the study.

Early termination from the study may occur if participants experience unacceptable toxicity, disease progression, or withdrawal of consent. The trial will employ a rigorous methodology to ensure the reliability of results, including the use of blinded independent central review for imaging assessments. The primary endpoint is the PSA response rate, defined as the proportion of participants achieving a post-baseline PSA nadir value of ≤0.2 ng/mL, confirmed by a subsequent measurement at least four weeks later. Secondary endpoints include measures of metastasis-free survival, radiographic progression-free survival, overall survival, and time to symptomatic progression, among others.

The clinical trial involves the administration of several experimental and non-experimental treatments. **Relugolix** is an experimental medication used in this study. It is administered in the form of a tablet, with a maximum daily dose of 360 mg. The route of administration is oral, and the treatment period can extend up to 60 days. Relugolix functions as a **gonadotropin releasing antagonist**.

**Pluvicto** (1,000 MBq/mL solution for injection/infusion) is another experimental treatment in the trial. The active substance is **lutetium (177Lu) vipivotide tetraxetan**. It is administered intravenously, with a maximum daily dose of 7.4 GBq and a total dose limit of 44.4 GBq over a treatment period of up to 36 days. This treatment is categorized under various therapeutic radiopharmaceuticals.

**Enzalutamide** is included in the study as both a tablet and a capsule form. The maximum daily dose is 160 mg, administered orally, with a total dose limit of 291,200 mg over a 60-day period. Enzalutamide acts as an **androgen receptor inhibitor**.

**Degarelix Acetate** is administered as a solution for injection. The maximum daily dose is 240 mg, with a total dose limit of 4,960 mg over a 60-day period. The route of administration is oral, and it functions as a **gonadotropin releasing antagonist**.

**Locametz** (25 micrograms kit for radiopharmaceutical preparation) contains the active substance **gozetotide**. It is administered intravenously, with a maximum daily dose of 259 MBq and a total dose limit of 4,208.75 MBq over a 60-day period. This preparation is used for radiopharmaceutical purposes.

**Darolutamide** is administered as a film-coated tablet, with a maximum daily dose of 1,200 mg and a total dose limit of 2,184,000 mg over a 60-day period. The route of administration is oral, and it serves as an **androgen receptor inhibitor**.

**Apalutamide** is also administered as a film-coated tablet, with a maximum daily dose of 240 mg and a total dose limit of 436,800 mg over a 60-day period. The route of administration is oral, and it functions as an **androgen receptor inhibitor**.

Additionally, the study includes a non-experimental treatment categorized under **gonadotropin releasing hormone analogues**. The specific pharmaceutical form and active substance are not specified, and the route of administration is unknown. This treatment is included to provide a standard-of-care comparator within the trial.

The efficacy of the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the **PSA response rate**, defined as the proportion of participants achieving a post-baseline PSA nadir value of ≤0.2 ng/mL, confirmed by a subsequent PSA measurement at least four weeks later. Secondary endpoints include several time-to-event measures: Metastasis-Free Survival (MFS), Radiographic Progression-Free Survival (rPFS), Overall Survival (OS), and Progression-Free Survival 2 (PFS2). These endpoints will be evaluated from the date of randomization to various events such as radiographic disease progression, symptomatic progression, initiation of cytotoxic chemotherapy, and first symptomatic skeletal event (SSE), among others.

Additional secondary endpoints include time to distant metastasis development, time to local radiological progression, and time to initiation or change in therapy. PSA progression will be assessed according to the PCWG3 guideline criteria, with specific criteria for PSA50 and PSA90 responses, defined as ≥50% and ≥90% decreases in PSA from baseline, respectively, confirmed by a second measurement at least four weeks later. Health-related quality of life (HRQoL) will be evaluated using the Functional Assessment of Cancer Therapy Prostate (FACT-P), Brief Pain Inventory Short Form (BPI-SF), and Functional Assessment of Cancer Therapy (FACT-RNT).

Safety and tolerability will also be monitored, including the incidence and severity of adverse events (AEs) and serious adverse events (SAEs), changes in laboratory values, vital signs, and ECGs. Clinically significant abnormalities will be recorded as AEs. The trial will employ validated scales and conventional imaging techniques such as CT/MRI and bone scans, assessed by investigators using RECIST 1.1 criteria, to measure these endpoints. The schedule for these assessments will be aligned with the trial's protocol, ensuring systematic data collection and analysis throughout the study duration.