A Phase 2, Open-label, Multi-cohort Study to Assess the Efficacy and Safety of ASP5541 in Participants with Advanced Prostate Cancer

The primary objectives of this study are to evaluate the efficacy and safety of ASP5541 in different cohorts of participants with advanced prostate cancer. In Cohort 1, the efficacy of ASP5541 with prednisone or prednisolone is compared with abiraterone acetate with prednisone or prednisolone in androgen receptor pathway inhibitor-naïve participants with metastatic castration-resistant prostate cancer. This comparison is clinically relevant for assessing whether ASP5541 offers therapeutic advantages in this treatment-resistant population. In Cohort 2, the study evaluates the safety of ASP5541 without steroids in a safety run-in phase and subsequently assesses the efficacy of ASP5541 without steroids compared with abiraterone acetate with prednisone or prednisolone in androgen receptor pathway inhibitor-naïve participants with metastatic hormone-sensitive prostate cancer. This objective addresses the clinical need to determine whether steroid co-administration can be eliminated while maintaining therapeutic benefit. In Cohort 3, the safety of ASP5541 with prednisone or prednisolone is evaluated specifically in Japanese participants with metastatic castration-resistant prostate cancer or metastatic hormone-sensitive prostate cancer, addressing potential population-specific safety considerations.

The secondary objectives include: • Further evaluation of the efficacy of ASP5541 with and without prednisone or prednisolone compared with abiraterone acetate with prednisone or prednisolone. • Evaluation of the safety of ASP5541 with and without prednisone or prednisolone compared with abiraterone acetate with prednisone or prednisolone. • Evaluation of the pharmacodynamic profile of ASP5541 with and without prednisone or prednisolone compared with abiraterone acetate with prednisone or prednisolone. • Evaluation of pain progression following ASP5541 with and without prednisone or prednisolone compared with abiraterone acetate with prednisone or prednisolone.

This clinical trial enrolled a total of **129 participants**, all of whom were **male** individuals aged **18 years or older**. The study population consisted of patients diagnosed with histologically or cytologically confirmed **adenocarcinoma of the prostate** without neuroendocrine differentiation or small cell features. Participants were required to have an **Eastern Cooperative Oncology Group (ECOG) performance status** of 0 or 1, or an ECOG performance status of 2 if attributable to bone pain. The trial included multiple cohorts: Cohort 1 comprised participants with **androgen receptor pathway inhibitor (ARPI)-naïve metastatic castration-resistant prostate cancer (mCRPC)**, Cohort 2 included participants with **ARPI-naïve metastatic hormone-sensitive prostate cancer (mHSPC)**, and Cohort 3 enrolled Japanese participants with either mCRPC or mHSPC. All participants were required to have documented metastatic lesions confirmed by bone scan, CT, MRI, or **prostate-specific membrane antigen positron emission tomography (PSMA-PET)**. Participants with mHSPC were required to have an estimated life expectancy of at least 12 months, while those with mCRPC needed a life expectancy exceeding 6 months. Male participants were required to agree to specific contraceptive measures throughout the treatment period and for defined periods following study intervention administration. The trial excluded vulnerable populations and required participants to be capable of understanding and complying with all study requirements and procedures.

This is a **Phase 2**, **open-label**, **multi-cohort** clinical trial evaluating the efficacy and safety of **ASP5541** in participants with advanced **prostate cancer**. The study involves multiple treatment arms across three distinct cohorts, with participants receiving either the investigational medicinal product or a comparator regimen. **Cohort 1** enrolls **androgen receptor pathway inhibitor (ARPI)-naïve** participants with **metastatic castration-resistant prostate cancer (mCRPC)** who will receive **ASP5541** with **prednisone** or **prednisolone** compared to **abiraterone acetate** with prednisone or prednisolone. **Cohort 2** includes a safety run-in phase followed by enrollment of ARPI-naïve participants with **metastatic hormone-sensitive prostate cancer (mHSPC)** who will receive ASP5541 without steroids compared to abiraterone acetate with prednisone or prednisolone. **Cohort 3** evaluates the safety of ASP5541 with prednisone or prednisolone in Japanese participants with mCRPC or mHSPC. The investigational product ASP5541, containing **abiraterone decanoate**, is administered as a **solution for injection** via **intramuscular use**, while abiraterone acetate, prednisone, and prednisolone are administered orally as tablets. The maximum treatment period is **48 months** across all cohorts.

The primary objectives vary by cohort and include evaluating the proportion of participants achieving **prostate-specific antigen (PSA) decline** of at least 90% from baseline in Cohort 1, assessing rates of no **mineralocorticoid toxicity** (defined as experiencing neither Grade ≥ 1 **hypokalemia** nor Grade ≥ 2 **hypertension**) in the Cohort 2 safety run-in, determining the proportion of participants achieving PSA levels of 0.2 ng/mL or less at 8 months in Cohort 2, and evaluating **dose-limiting toxicities (DLTs)**, **adverse events (AEs)**, **serious adverse events (SAEs)**, laboratory results, **electrocardiograms (ECGs)**, vital signs, physical examinations, and **Eastern Cooperative Oncology Group (ECOG) performance status** scores in Cohort 3. Secondary endpoints encompass **radiographic progression-free survival (rPFS)** defined as time from randomization or first dose until radiological **progressive disease (PD)** per **RECIST v1.1** and **PCWG3** criteria or death from any cause, PSA decline of at least 50% and 90% from baseline, PSA undetectable rates at thresholds of 0.2 ng/mL and 0.02 ng/mL, time to PSA progression per PCWG3 criteria, **objective response rate**, duration of response, and best overall response according to RECIST v1.1 for soft tissue disease and PCWG3 for bone disease. Additional secondary endpoints include safety assessments such as AEs, SAEs, laboratory evaluations including chemistry, hematology, urinalysis, and spot urine potassium and creatinine in Cohort 2, ECGs, vital signs, physical examinations, ECOG performance status scores, **testosterone suppression** to 1 ng/dL or less or achieving at least 90% reduction from baseline, mean testosterone values by time point, and time to pain progression using pain scores from the **Brief Pain Inventory-Short Form (BPI-SF)** and opiate analgesic use.

Eligible participants must be male and at least 18 years of age at the time of consent. Participants must have histologically or cytologically confirmed **adenocarcinoma** of the prostate without **neuroendocrine differentiation** or small cell features. ECOG performance status must be 0 or 1, or 2 if due to bone pain. Participants with mHSPC must have an estimated life expectancy of at least 12 months, while those with mCRPC must have an estimated life expectancy greater than 6 months. Cohort 1 participants must have mCRPC documented by metastatic lesions on bone scan, **computed tomography (CT)**, **magnetic resonance imaging (MRI)**, or **prostate-specific membrane antigen positron emission tomography (PSMA-PET)**. Cohort 2 participants must have mHSPC documented by metastatic lesions on bone scan, CT, MRI, or PSMA-PET. Cohort 3 participants must have mCRPC or mHSPC documented by metastatic lesions on bone scan, CT, MRI, or PSMA-PET. Participants must be able to understand and comply with all study requirements and procedures, including completion of patient-reported outcome questionnaires. Male participants must agree to use defined forms of contraception with female partners of childbearing potential throughout the treatment period and for 7 months after final ASP5541 administration or for 3 months after abiraterone acetate administration, remain abstinent or use a condom with pregnant partners for the duration of pregnancy throughout the investigational period and for 7 months after final ASP5541 or 3 months after abiraterone acetate administration, and must not donate sperm during the treatment period and for 7 months after final ASP5541 or 3 months after abiraterone acetate administration. Participants must provide informed consent and agree not to participate in another interventional study while receiving ASP5541.

The estimated recruitment start date is October 2025, with an estimated study completion date of May 2032. The maximum daily dose of ASP5541 is 1260 mg, with a maximum total dose of 20160 mg over the treatment period. For abiraterone acetate, the maximum daily dose is 1000 mg with a maximum total dose of 1440000 mg. Prednisone and prednisolone are administered at a maximum daily dose of 10 mg each, with maximum total doses of 14400 mg over the treatment period. Participant involvement may extend up to 48 months depending on treatment response and tolerability. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, withdrawal of consent, or investigator decision based on participant safety or protocol non-compliance.

The experimental medication **ASP5541** contains **abiraterone decanoate** as the active substance of chemical origin. ASP5541 is formulated as a **solution for injection** administered via the **intramuscular** route. The maximum daily dose is **1260 mg**, with a maximum total dose of **20160 mg** over a treatment period of up to **48 months**. This investigational product is manufactured by Astellas Pharma Global Development, Inc. and is also identified by the synonym PRL-02.

**Abiraterone acetate** serves as a comparator treatment in this clinical trial. The active substance is abiraterone acetate of chemical origin. This medicinal product is supplied as a **tablet** for **oral use**. The maximum daily dose is **1000 mg**, with a maximum total dose of **1440000 mg** administered over a treatment period of up to **48 months**.

**Prednisolone** is utilized as a test medication in combination with other treatments. The active substance is prednisolone of chemical origin. Prednisolone is formulated as a tablet for oral administration. The maximum daily dose is **10 mg**, with a maximum total dose of **14400 mg** over a treatment period of up to 48 months.

**Prednisone** is also employed as a test medication in this study. The active substance is prednisone of chemical origin. Prednisone is provided as a tablet for oral use. The maximum daily dose is 10 mg, with a maximum total dose of 14400 mg administered over a treatment period of up to 48 months. The study protocol includes different treatment regimens across multiple cohorts, with some participants receiving ASP5541 with prednisone or prednisolone, others receiving ASP5541 without steroids, and comparator groups receiving abiraterone acetate with prednisone or prednisolone.

Efficacy will be assessed through multiple parameters specific to each cohort. For androgen receptor pathway inhibitor-naïve metastatic castration-resistant prostate cancer participants in Cohort 1, the primary efficacy endpoint is the proportion of participants achieving prostate-specific antigen decline of at least 90% from baseline. For metastatic hormone-sensitive prostate cancer participants in Cohort 2, the primary efficacy endpoint is the proportion of participants with prostate-specific antigen levels at or below 0.2 ng/mL at 8 months. Secondary efficacy endpoints across cohorts include radiographic progression-free survival, defined as the time from randomization or first dose date until radiological progressive disease per RECIST v1.1 and PCWG3 criteria as determined by investigator or death from any cause. Additional secondary endpoints include prostate-specific antigen decline of at least 50% from baseline, prostate-specific antigen undetectable rates at 0.2 ng/mL and 0.02 ng/mL thresholds, time to prostate-specific antigen progression per PCWG3 criteria, objective response rate per RECIST v1.1 for soft tissue disease and PCWG3 for bone disease, duration of response per RECIST v1.1 for soft tissue disease and PCWG3 for bone disease, and best overall response per RECIST v1.1 for soft tissue disease and PCWG3 for bone disease. Testosterone suppression to levels at or below 1 ng/dL or achievement of at least 90% reduction from baseline level, mean testosterone values by time point, and time to pain progression defined using pain scores from the Brief Pain Inventory-Short Form and opiate analgesic use will also be evaluated as secondary endpoints.