Evaluation of Apalutamide Addition to Radiotherapy and LHRH Agonist in High-Risk Hormone-Sensitive Prostate Cancer Assessed by PSMA-PET

The primary objective of this study is to evaluate whether the addition of **apalutamide** to radiotherapy (RT) and luteinizing hormone-releasing hormone agonist (LHRHa) therapy can delay metastatic progression or death in patients with high-risk hormone-sensitive prostate cancer, as assessed by PSMA-PET imaging, compared to treatment with RT and LHRHa alone. This is clinically relevant as it may provide insights into improving treatment strategies for patients with high-risk recurrent prostate cancer who have previously undergone radical prostatectomy, potentially enhancing survival outcomes and quality of life.

The clinical trial involves a total of **183 participants** who are exclusively male, as the study focuses on individuals with **high-risk recurrent prostate cancer** previously treated with radical prostatectomy. The age range of participants includes adults aged 18 years and older. Participants were selected based on specific criteria, including a histologically confirmed diagnosis of adenocarcinoma of the prostate and a high risk of developing metastasis. The trial does not include a vulnerable population. Participants are required to have adequate organ function and must be able to adhere to the study's prohibitions and restrictions. Lifestyle considerations such as diet and physical activity are not specified, but participants must be on stable doses of bone-sparing agents if receiving bone-loss prevention treatment. The study does not include female subjects, and the selection process ensures that participants are capable of complying with the study's requirements, including the ability to swallow the study drug tablets or follow instructions for admixing with apple sauce.

The clinical trial is designed to evaluate the efficacy and safety of adding **apalutamide** to radiotherapy and LHRH agonist in patients with high-risk hormone-sensitive prostate cancer. This study is a randomized, controlled, multicenter, open-label trial. The primary objective is to determine if the addition of apalutamide delays metastatic progression as assessed by PSMA-PET or death compared to radiotherapy and LHRH agonist alone. The trial is expected to run from November 17, 2020, to January 28, 2030, with a maximum treatment period of 108 weeks for certain interventions.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, organ function, and previous treatment history. Following randomization, participants will receive the assigned treatment and attend regular follow-up visits to monitor safety and efficacy outcomes. The end-of-study visit will conclude the participant's involvement, assessing final outcomes and any adverse events. The expected length of participant involvement varies, with some treatments lasting up to 108 weeks.

Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with study procedures. The trial employs a rigorous methodology to ensure the reliability of results, with endpoints including PSMA-PET metastatic progression-free survival. The study is not classified as low intervention and is conducted under a Phase 3 trial category, focusing on adult participants with prostate cancer. The trial's design and procedures are structured to provide comprehensive data on the potential benefits of apalutamide in this patient population.

The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. The **experimental medication** is JNJ-56021927, which contains the active substance **apalutamide**. This medication is provided in the form of a film-coated tablet and is administered orally. The dosing schedule for apalutamide is not specified in terms of daily or total dose amounts, but the maximum treatment period is set at 6 months. Apalutamide is a chemical substance and is not formulated for pediatric use. Participant compliance with the oral administration will be monitored throughout the trial.

In addition to the experimental medication, the trial includes the use of **technetium (99mTc) compounds**. These compounds are administered intravenously and are classified under the ATC code V09IA0X, which pertains to diagnostic radiopharmaceuticals. The pharmaceutical form is denoted as PHF00126MIG. The maximum treatment period for these compounds is 108 months, with no specified daily or total dose amounts. These compounds are used as auxiliary treatments in the trial.

Another auxiliary treatment in the study is a product classified under the ATC code V09IX, which includes **other diagnostic radiopharmaceuticals for tumor detection**. This product is also administered intravenously and has a pharmaceutical form of PHF00231MIG. Similar to the technetium compounds, the maximum treatment period is 108 months, with no specified dosing amounts.

The trial also incorporates **gonadotropin-releasing hormone analogues** as part of the standard-of-care therapy. These analogues are administered subcutaneously and are classified under the ATC code L02AE. The pharmaceutical form is PHF00243MIG, and the treatment period is limited to 6 months. This therapy is part of the androgen deprivation therapy regimen used in the trial.

The efficacy of the clinical trial will be assessed by evaluating the primary endpoint of **PSMA-PET metastatic progression-free survival (ppMPFS)**. This is defined as the time from randomization to the date of metastatic progression as determined by PSMA PET or death from any cause. The assessment will be conducted using PSMA-PET imaging, which will be evaluated by a blinded independent central review (BICR). The trial aims to determine if the addition of apalutamide to radiotherapy and LHRH agonist delays metastatic progression in high-risk patients with hormone-sensitive prostate cancer compared to radiotherapy and LHRH agonist alone.