(21492 ARASTEP) A randomized, double-blind, placebo-controlled Phase 3 study of darolutamide plus androgen deprivation therapy (ADT) compared with placebo plus ADT in patients with high-risk biochemical recurrence (BCR) of prostate cancer

The primary objective of this Phase 3 study is to determine if **darolutamide** plus androgen deprivation therapy (ADT) administered for a duration of 24 months improves radiographic progression-free survival (rPFS) as assessed by PSMA PET/CT, compared with placebo plus ADT given for the same period. This is clinically relevant as it aims to establish the efficacy of darolutamide in delaying disease progression in patients with high-risk biochemical recurrence of prostate cancer, potentially offering a more effective treatment option.

Secondary objectives include:

• To further evaluate the efficacy of the treatment and measure its impact on participants' quality of life, providing insights into the broader benefits of the therapy beyond disease control.
• To assess the safety profile of darolutamide plus ADT compared with placebo plus ADT, ensuring that the treatment is not only effective but also safe for long-term use in this patient population.

The clinical trial involves a total of **336 male participants** diagnosed with **biochemically recurrent prostate cancer**. The study population consists of males aged **18 years and older**, with a confirmed diagnosis of adenocarcinoma of the prostate. Participants were selected based on specific health criteria, including a high-risk biochemical recurrence characterized by a prostate-specific antigen doubling time of less than 12 months. All participants have undergone prior treatments such as radical prostatectomy, adjuvant radiotherapy, or primary radiotherapy. The trial excludes female subjects and does not involve a vulnerable population. Participants are required to maintain certain lifestyle considerations, such as the use of contraception during the treatment period and refraining from sperm donation. The general health status of participants is assessed through various screening values, including liver function tests and blood counts, ensuring they meet the necessary health standards for trial inclusion. The trial does not include any specific dietary or physical activity requirements.

The clinical trial is a **randomized, double-blind, placebo-controlled Phase 3 study** designed to evaluate the efficacy of **darolutamide** in combination with androgen deprivation therapy (ADT) compared to placebo plus ADT in patients with high-risk biochemical recurrence of **prostate cancer**. The primary objective is to assess whether darolutamide plus ADT improves radiographic progression-free survival (rPFS) as measured by PSMA PET/CT over a 24-month treatment period. The trial is expected to conclude by February 2029, with recruitment starting in September 2023.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on specific inclusion criteria, such as confirmed adenocarcinoma of the prostate and high-risk biochemical recurrence. The screening process includes a PSMA PET/CT scan to identify PSMA PET positive lesions. Following successful screening, participants will be randomized to receive either the study drug or placebo, both in combination with ADT, for a duration of 24 months. Regular follow-up visits will be scheduled to monitor safety, efficacy, and compliance with the study protocol. These visits will include assessments such as blood tests, imaging studies, and evaluations of prostate-specific antigen (PSA) levels.

The end-of-study visit will occur after the 24-month treatment period, where final assessments will be conducted to evaluate the primary and secondary endpoints, including time to castration-resistant prostate cancer (CRPC), overall survival (OS), and time to symptomatic progression. Participant involvement is expected to last approximately 24 months, with conditions for early termination including significant adverse events, withdrawal of consent, or non-compliance with study procedures. The trial aims to provide comprehensive data on the potential benefits of darolutamide in managing high-risk biochemical recurrence of prostate cancer.

The clinical trial involves the administration of **Pylclari**, a **solution for injection** containing the active substance **piflufolastat (18F)**. This radiopharmaceutical is provided at a concentration of 1,000 MBq/mL and is administered via **intravenous injection**. The maximum daily dose is 1.83 MBq, with a total dose not exceeding 2,640 MBq over a treatment period of up to 46 days. The administration of Pylclari is monitored to ensure compliance with the dosing schedule and to assess any potential adverse reactions.

Another experimental treatment in the study is **BAY 1841788**, a **film-coated tablet** containing **darolutamide**. This medication is administered orally, with a maximum daily dose of 1,200 mg and a total dose of 876 g over a 24-month period. The trial aims to evaluate the efficacy of darolutamide in combination with androgen deprivation therapy (ADT) compared to a placebo plus ADT. Participant compliance is monitored through regular assessments and pill counts to ensure adherence to the dosing regimen.

The study also includes a **placebo** for BAY 1841788, which is used as a comparator treatment. The placebo is designed to match the appearance of the BAY 1841788 tablets but does not contain any active pharmaceutical ingredients. It is administered orally in the same manner and frequency as the active treatment to maintain the double-blind nature of the trial.

Additionally, the trial utilizes **Gallium (68Ga) PSMA-11 (gozetotide)**, prepared using a PSMA-11 Sterile Cold Kit, as a **solution for injection**. This radiopharmaceutical is administered via **intravenous bolus use**. The maximum daily dose is 1.03 MBq, with a total dose not exceeding 1,480 MBq over a treatment period of up to 46 days. The administration of Gallium (68Ga) PSMA-11 is carefully monitored to ensure accurate dosing and to evaluate its role in improving radiographic progression-free survival (rPFS) in patients.

Efficacy in this clinical trial will be assessed primarily through the evaluation of **rPFS** (radiographic progression-free survival) using PSMA PET/CT scans, which will be assessed by a blinded independent central review (BICR). Secondary endpoints include MFS (metastasis-free survival) assessed by BICR, time to CRPC (castration-resistant prostate cancer) assessed by the investigator, time to initiation of first subsequent systemic antineoplastic therapy, time to loco-regional progression by PSMA PET/CT, time to first SSE (symptomatic skeletal event), overall survival (OS), PSA undetectable rates (<0.2 ng/mL) at 12 months, time to deterioration in the FACT-P total score, number of participants with TEAEs (treatment-emergent adverse events) and TESAEs (treatment-emergent serious adverse events) categorized by severity, number of participants who discontinue study treatment due to a TEAE, and time to symptomatic progression.

The trial will involve the administration of darolutamide plus androgen deprivation therapy (ADT) compared with placebo plus ADT in patients with high-risk biochemical recurrence of prostate cancer. The efficacy parameters will be measured at various timepoints throughout the study, including at 12 months for PSA undetectable rates. The use of PSMA PET/CT scans will provide a baseline reference for identifying PSMA PET positive lesions of prostate cancer, which will be crucial for assessing progression and response to treatment. The trial is designed to determine if the combination of darolutamide and ADT improves outcomes compared to placebo and ADT over a 24-month treatment period.