Phase 3 Randomized Double-Blind Study of Niraparib Tosilate Monohydrate Versus Placebo in HER2-Negative BRCA-Mutated or Triple-Negative Breast Cancer

The primary objective of this randomized, double-blinded Phase 3 study is to assess the **safety** and **tolerability** of **niraparib** in participants with **HER2-negative** **BRCA-mutated** or **triple-negative breast cancer** who exhibit molecular disease as indicated by the presence of circulating tumor DNA (ctDNA) following definitive therapy. This includes neoadjuvant treatment, surgery, adjuvant radiotherapy, and adjuvant chemotherapy. The clinical relevance of this objective lies in determining the safety profile of niraparib, which is crucial for its potential use in this specific patient population. Efficacy endpoints are considered exploratory and are not the primary focus of this study.

The clinical trial involved a total of **351 participants** diagnosed with **breast cancer**, specifically focusing on those with tumor breast cancer susceptibility gene mutations (tBRCAmut) and human epidermal growth factor receptor 2-negative (HER2−) breast cancer, as well as those with tumor BRCA wild-type (tBRCAwt) triple-negative breast cancer (TNBC). The study population included both male and female subjects, with an age range of 18 years and older. Participants were selected based on their completion of prior standard therapy for curative intent, including neoadjuvant treatment, surgery, adjuvant radiotherapy, and adjuvant chemotherapy. The trial required participants to have detectable circulating tumor DNA (ctDNA) levels post-therapy. Lifestyle considerations such as diet and physical activity were not specified. The trial included individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they were fully active or restricted in physically strenuous activity but ambulatory. Participants were required to have adequate organ and bone marrow function and to have recovered from any prior cancer therapy-related toxicity to Grade 1, with exceptions for Grade 2 neuropathy or any grade of alopecia. The study population was selected to include a vulnerable population, ensuring comprehensive safety and tolerability assessments of the treatment under investigation.

The clinical trial is designed as a **randomized**, **double-blind**, and controlled study to evaluate the efficacy and safety of **niraparib** compared to placebo in participants with HER2-negative BRCA-mutated or triple-negative breast cancer. The trial targets individuals with molecular disease indicated by the presence of circulating tumor DNA (ctDNA) following definitive therapy. The study is expected to conclude by December 31, 2025, with recruitment having commenced on June 16, 2021. Participants will be involved in the study for a maximum treatment period of 36 months, during which they will receive either niraparib or placebo tablets administered orally.

The trial includes several key study visits. The initial visit, known as the inclusion or screening visit, is conducted to confirm eligibility based on criteria such as stage I-III breast cancer, ability to swallow oral medication, and adequate organ function. Following successful screening, participants will be randomized to receive either the active treatment or placebo. Subsequent follow-up visits will be scheduled to monitor safety and efficacy outcomes, including the incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events of special interest (AESIs). The end-of-study visit will occur after the completion of the treatment period or upon early termination.

Participants are expected to remain in the study for the full duration unless specific conditions necessitate early withdrawal. These conditions include the occurrence of unacceptable toxicity, withdrawal of consent, or any situation where continued participation is deemed not in the participant's best interest by the investigator. The primary endpoint focuses on safety and tolerability, with efficacy endpoints being exploratory. The study adheres to rigorous ethical standards, ensuring informed consent is obtained from all participants prior to enrollment.

The clinical trial involves the administration of **Niraparib Tosilate Monohydrate**, an experimental medication, in the form of tablets. The pharmaceutical form is a tablet, and the active substance is **Niraparib Tosilate Monohydrate**. The medication is administered orally. The dosage is set at a maximum daily dose of 300 mg, with a total maximum dose of 32,400 mg over a treatment period of up to 36 weeks. The medication is of chemical origin and is provided by GlaxoSmithKline under the sponsor product code GSK3985771. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol.

In addition to the experimental medication, the study includes the use of **Niraparib Placebo Tablets** as a comparator treatment. These placebo tablets are also administered orally and are designed to match the experimental medication in appearance and administration schedule. The placebo serves as a control to evaluate the efficacy and safety of the experimental treatment. The use of placebo is integral to maintaining the double-blind nature of the study, ensuring that neither the participants nor the investigators are aware of the treatment assignments.

The efficacy of niraparib in the clinical trial will be assessed through exploratory endpoints, as the primary focus of the study is on safety and tolerability. The trial involves participants with either HER2-negative BRCA-mutated or triple-negative breast cancer, who have molecular disease indicated by the presence of circulating tumor DNA (ctDNA) after definitive therapy. Although specific efficacy endpoints are not detailed, the exploratory nature suggests that various parameters related to disease progression and response to treatment may be evaluated. The study is designed as a randomized, double-blinded, Phase 3 trial comparing niraparib to placebo. The assessment of efficacy will likely involve the collection and analysis of data at predefined intervals throughout the study duration, which is estimated to conclude by the end of 2025. The trial's exploratory endpoints will be analyzed in accordance with the Statistical Analysis Plan (SAP), which will guide the evaluation of clinically relevant outcomes.