Phase 3 Randomized, Double-blind, Placebo-controlled Study of Apalutamide and GnRH Agonist in High-risk Localized or Locally Advanced Prostate Cancer with Primary Radiation Therapy

The primary objective of this randomized, double-blind, placebo-controlled Phase 3 study is to evaluate the efficacy of **apalutamide** in combination with a GnRH agonist in subjects with high-risk localized or locally advanced **prostate cancer** undergoing primary radiation therapy. The study aims to determine if this combination results in an improvement in metastasis-free survival (MFS) as assessed by conventional or PSMA-PET imaging, evaluated by blinded independent central review (BICR). This is clinically relevant as improving MFS can potentially delay disease progression and improve patient outcomes in this high-risk population.

The clinical trial involves a total of **680 participants** diagnosed with **high- or very-high risk, localized or locally advanced prostate cancer**. The study population is exclusively male, with an age range of 18 years and older. Participants were selected based on specific criteria, including a histologically confirmed adenocarcinoma of an intact prostate and a Charlson comorbidity index (CCI) of 3 or less. The trial does not include a vulnerable population. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) Performance Status Grade of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Adequate organ function is a prerequisite, as determined by central laboratory values. Lifestyle considerations include the requirement for sexually active participants to use a condom and agree not to donate sperm during the trial. The trial population was selected to ensure participants are indicated and planned to receive primary radiation therapy for prostate cancer. The sponsor has not provided additional information regarding specific lifestyle factors such as diet or physical activity.

The clinical trial is a **randomized, double-blind, placebo-controlled** Phase 3 study designed to evaluate the efficacy and safety of JNJ-56021927 in subjects with high-risk, localized or locally advanced **prostate cancer** receiving primary radiation therapy. The trial aims to determine if the addition of apalutamide plus GnRH agonist improves metastasis-free survival (MFS) based on conventional or PSMA-PET imaging evaluated by blinded independent central review (BICR). The study is expected to run from February 2016 to August 2025, with participant involvement lasting up to 840 days.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, planned radiation therapy, histologically confirmed adenocarcinoma, and adequate organ function. Following randomization, participants will receive either the investigational product or placebo, administered orally or subcutaneously, depending on the treatment arm. Regular follow-up visits will be scheduled to monitor safety, efficacy, and compliance with the study protocol. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, withdraw consent, or if the investigator deems it in their best interest. The primary endpoint is the time from randomization to the first occurrence of radiographic bone or soft tissue distant metastasis, histopathologic diagnosis of distant metastasis, or death from any cause. The trial's design ensures rigorous evaluation of the investigational product's impact on disease progression and overall survival in the target population.

The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **Bicalutamide placebo** is utilized as a comparator in the study. It is administered orally, although specific details regarding its pharmaceutical form and active substance are not provided. The maximum treatment period for this placebo is 112 days, with no active daily or total dose specified.

**Other hormone antagonists and related agents** are used as part of the androgen deprivation therapy. These agents are administered subcutaneously, with a maximum daily dose of 240 mg and a total dose of 2560 mg over a treatment period of 840 days. The specific pharmaceutical form is not detailed, but the agents are classified under the ATC code L02BX.

**Bicalutamid PUREN 50 mg Filmtabletten** is another treatment used in the trial. This medication is a film-coated tablet containing the active substance **bicalutamide**. It is administered orally, with a treatment period of 112 days. The product is of chemical origin and is manufactured by PUREN PHARMA GMBH & CO. KG.

**Tumour detection** agents are employed for diagnostic purposes and are administered intravenously. The maximum daily dose is 0.02 Sv, with a total dose of 0.23 Sv over 840 days. These agents are categorized under the ATC code V09I.

**Gonadotropin releasing hormone analogues** are also part of the androgen deprivation therapy, administered subcutaneously. The maximum daily dose is 22.5 mg, with a total dose of 225 mg over 840 days. The pharmaceutical form is identified as PHF00243MIG, and these analogues are classified under the ATC code L02AE.

**Apalutamide placebo** is used as a comparator in the study. Specific details regarding its administration route, pharmaceutical form, and active substance are not provided. The treatment period for this placebo is unspecified.

**JNJ-56021927**, containing the active substance **apalutamide**, is the primary experimental medication in the trial. It is administered orally in the form of a film-coated tablet. The treatment period extends up to 840 days. This product is of chemical origin and is produced by JANSSEN-CILAG INTERNATIONAL N.V.

Efficacy in this clinical trial will be assessed primarily through the evaluation of **metastasis-free survival (MFS)**. MFS is defined as the time from randomization to the first occurrence of radiographic bone or soft tissue distant metastasis, as determined by conventional imaging or PSMA-PET imaging, histopathologic diagnosis of distant metastasis, or death from any cause, whichever occurs first. The imaging evaluations will be conducted by a blinded independent central review (BICR) to ensure objectivity and consistency in the assessment of metastasis. The trial aims to determine if the combination of apalutamide plus a GnRH agonist in subjects with high-risk localized or locally advanced prostate cancer receiving primary radiation therapy results in an improvement of MFS. The schedule for measuring and collecting these efficacy parameters will be aligned with the trial's protocol, ensuring systematic data collection and analysis throughout the study duration.