Phase 3 Randomized, Double-Blind Study of Niraparib, Abiraterone Acetate, and Prednisone in HRR Gene-Mutated Metastatic Castration-Sensitive Prostate Cancer

The primary objective of this Phase 3 randomized, placebo-controlled, double-blind study is to evaluate the efficacy of **niraparib** in combination with **abiraterone acetate** and **prednisone** compared to abiraterone acetate and prednisone alone in participants with deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-sensitive prostate cancer (mCSPC). The study aims to determine if the combination therapy provides superior efficacy in improving radiographic progression-free survival (rPFS). This is clinically relevant as it may offer a more effective treatment option for patients with this specific genetic mutation, potentially delaying disease progression and improving patient outcomes.

The clinical trial involves a total of **487 participants** diagnosed with **metastatic castration-sensitive prostate cancer** (mCSPC) with deleterious germline or somatic homologous recombination repair (HRR) gene mutations. The study population is exclusively male, with participants falling within the age categories of 18 to 64 years and 65 years and older. Participants were selected based on specific inclusion criteria, including a pathological diagnosis of prostate adenocarcinoma, documented metastatic disease through conventional imaging, and the initiation of androgen deprivation therapy at least 14 days prior to randomization. The trial does not include individuals with lymph node-only disease. The participants are not considered a vulnerable population, and lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The trial aims to evaluate the efficacy of niraparib and abiraterone acetate (AA), plus prednisone, compared to AA plus prednisone in improving radiographic progression-free survival (rPFS) in this specific patient group.

The clinical trial is designed as a **randomized**, **double-blind**, placebo-controlled study to evaluate the efficacy of **niraparib** in combination with **abiraterone acetate** and **prednisone** compared to abiraterone acetate and prednisone alone in participants with deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-sensitive prostate cancer (mCSPC). The primary objective is to assess the improvement in radiographic progression-free survival (rPFS). The trial is expected to run until May 7, 2027, with recruitment having commenced on October 16, 2020.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a pathological diagnosis of prostate adenocarcinoma, documented metastatic disease, and prior initiation of androgen deprivation therapy. Following randomization, participants will attend regular follow-up visits to monitor treatment efficacy and safety. The end-of-study visit will conclude the participant's involvement, which is anticipated to last up to 78 weeks, depending on individual response and progression.

Participant involvement may be terminated early if there is evidence of disease progression, unacceptable toxicity, or withdrawal of consent. The trial will adhere to rigorous methodological standards to ensure the reliability and validity of the findings, contributing valuable insights into the treatment of mCSPC.

The clinical trial involves the administration of several experimental and non-experimental treatments. **Abiraterone acetate** is provided in tablet form, with each tablet containing 250 mg of the active substance. The maximum daily dose is 1000 mg, administered orally. The treatment period extends up to 78 weeks. This medication is produced by Janssen-Cilag International N.V. and is not a paediatric formulation.

**Niraparib** is administered in capsule form, with each capsule containing 100 mg of the active substance. The maximum daily dose is 200 mg, also administered orally, over a treatment period of 78 weeks. This product is also manufactured by Janssen-Cilag International N.V.

Another experimental treatment involves a combination of **Niraparib tosylate monohydrate** and **Abiraterone acetate** in film-coated tablet form. Two formulations are used: one containing 159.40 mg of Niraparib (equivalent to 100 mg base) and 500 mg of Abiraterone acetate, and another containing 79.90 mg of Niraparib (equivalent to 50 mg base) and 500 mg of Abiraterone acetate. The maximum daily doses are 1200 mg and 1100 mg, respectively, administered orally for up to 78 weeks.

**Prednisone** is used as a non-experimental treatment in the study. It is provided in tablet form, with each tablet containing 5 mg of the active substance. The maximum daily dose is 10 mg, administered orally, over a treatment period of 78 weeks. This product is manufactured by Acis Arzneimittel GmbH.

Placebos are also utilized in the trial, including a placebo for Niraparib, a placebo for Abiraterone acetate, and placebos for the combination of Niraparib and Abiraterone acetate in both 100/500 mg and 50/500 mg fixed-dose combinations. These placebos are used to maintain the double-blind nature of the study.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to evaluate the efficacy of these treatments in improving radiographic progression-free survival in participants with metastatic castration-sensitive prostate cancer with deleterious germline or somatic homologous recombination repair gene mutations.

The efficacy of the clinical trial will be assessed primarily through the endpoint of **radiographic progression-free survival (rPFS)**. This endpoint is designed to evaluate the time during and after the treatment that a participant lives with the disease without it getting worse, as determined by radiographic imaging. The trial involves the administration of **niraparib** in combination with **abiraterone acetate** and **prednisone**, compared to a control group receiving only abiraterone acetate and prednisone, in participants with metastatic castration-sensitive prostate cancer (mCSPC) with deleterious germline or somatic homologous recombination repair (HRR) gene mutations.

The measurement of rPFS will be conducted using conventional imaging techniques such as computed tomography (CT) or magnetic resonance imaging (MRI) for soft tissue lesions, and 99mTc bone scans for bone lesions. The trial is structured as a Phase 3, randomized, placebo-controlled, double-blind study, ensuring that neither the participants nor the investigators know which treatment the participants are receiving, thus minimizing bias. The trial is expected to run until May 2027, with the recruitment having started in October 2020. The maximum treatment period for participants is set at 78 weeks.