Efficacy and Safety of Olaparib as Adjuvant Therapy in Germline BRCA1/2 Mutated High-Risk HER2-Negative Primary Breast Cancer: A Phase III Randomized Study

The primary objective of this study is to evaluate the **efficacy** of adjuvant treatment with olaparib on **Invasive Disease Free Survival (IDFS)** in patients with germline BRCA1/2 mutations and high-risk HER2-negative primary breast cancer. This is clinically relevant as improving IDFS can potentially lead to better long-term outcomes and reduce the risk of cancer recurrence in this high-risk population.

Secondary objectives include:

• Assessing the efficacy of adjuvant treatment with olaparib on **overall survival (OS)**.
• Evaluating the efficacy on **Distant Disease Free Survival (DDFS)**.
• Investigating the impact on the incidence of new primary contralateral breast cancers, as well as new primary ovarian, fallopian tube, and peritoneal cancers.
• Determining the efficacy of olaparib on patient-reported outcomes using the FACIT Fatigue and EORTC QLQ-C30 QoL questionnaires.
• Assessing the efficacy in patients with a deleterious or suspected deleterious variant in the **BRCA genes** using current and future mutation assays.
• Determining the exposure to olaparib in plasma in patients receiving it as adjuvant therapy.

The clinical trial involves a total of **936 participants** diagnosed with **Breast Cancer**. The study population includes both male and female subjects aged **18 years and older**. Participants have a histologically confirmed non-metastatic primary invasive adenocarcinoma of the breast, with specific phenotypes such as TNBC ER and PgR negative and HER2 negative, or ER and/or PgR positive and HER2 negative. All participants have a documented germline mutation in BRCA1 or BRCA2, which is predicted to be deleterious. The trial population was selected based on the completion of adequate breast and axilla surgery and at least six cycles of neoadjuvant or adjuvant chemotherapy containing anthracyclines, taxanes, or both. The study includes individuals with an ECOG performance status of 0-1. The trial also considers vulnerable populations, ensuring a comprehensive evaluation of the treatment's efficacy on **Invasive Disease Free Survival (IDFS)**. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is a **randomized**, **double-blind**, parallel group, placebo-controlled, multi-center Phase III study designed to evaluate the efficacy and safety of **olaparib** as an adjuvant treatment in patients with germline BRCA1/2 mutations and high-risk HER2-negative primary **breast cancer**. The trial aims to assess the impact of olaparib on Invasive Disease Free Survival (IDFS) as the primary endpoint, with secondary endpoints including overall survival, distant disease-free survival, and the incidence of new primary cancers. The study will also evaluate patient-reported outcomes and the safety profile of olaparib.

The trial is expected to commence recruitment on February 9, 2024, and is estimated to conclude by May 28, 2029. Participants will be involved in the study for a maximum treatment period of 12 months, during which they will receive either olaparib or a placebo in the form of film-coated tablets administered orally. The study will include several key visits: an initial screening visit to confirm eligibility based on criteria such as age, histological confirmation of non-metastatic primary invasive adenocarcinoma of the breast, and completion of prior chemotherapy. Follow-up visits will be scheduled to monitor the participants' health status, adherence to the treatment regimen, and any adverse events. The end-of-study visit will assess the final outcomes and gather data on the primary and secondary endpoints.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, withdraw consent, or if the investigator deems it necessary for their safety. The trial will adhere to rigorous blinding procedures to ensure unbiased results, with the investigational medicinal product (IMP) being indistinguishable from the commercial product except for specific packaging modifications to maintain blinding. The study will be conducted in compliance with ethical standards and regulatory requirements, ensuring the integrity and reliability of the data collected.

The clinical trial involves the administration of **Lynparza** (olaparib) in two different dosages as the experimental medication. **Lynparza 150 mg film-coated tablets** are utilized, with each tablet containing the active substance **olaparib**, a chemical compound. The pharmaceutical form is a film-coated tablet, and the medication is administered orally. The maximum daily dose is 600 mg, and the treatment period extends up to 12 months. The tablets used in the trial are unmarked and packed in HDPE bottles to maintain blinding in placebo-controlled studies. The commercial version of the tablet differs only in its debossing and packaging.

Additionally, **Lynparza 100 mg film-coated tablets** are used, also containing the active substance **olaparib**. These tablets are similarly administered orally, with a maximum daily dose of 600 mg and a treatment period of up to 12 months. The investigational medicinal product (IMP) is distinguished from the commercial version by its green film coat and lack of commercial debossing, facilitating blinding in the study. The commercial version has a yellow film coat due to the absence of black iron oxide.

The study also includes a **placebo** in the form of film-coated tablets, which serve as a comparator treatment. The placebo tablets are designed to match the appearance of the experimental medication to ensure blinding. The placebo does not contain any active pharmaceutical ingredient and is used to assess the efficacy and safety of the experimental treatment in a controlled manner.

The efficacy of the clinical trial will be assessed primarily through the measurement of **Invasive Disease Free Survival (IDFS)**. This endpoint will evaluate the effectiveness of olaparib as an adjuvant treatment in patients with germline BRCA1/2 mutations and high-risk HER2-negative primary breast cancer. Secondary endpoints include overall survival (OS), distant disease-free survival (DDFS), and the incidence of new primary cancers such as contralateral invasive breast cancer, non-invasive breast cancer, ovarian cancer, fallopian tube cancer, and peritoneal cancer. Additionally, patient-reported outcomes will be collected using the FACIT Fatigue and EORTC QLQ-C30 quality of life questionnaires. The determination of BRCA mutation status will be conducted using current and future BRCA mutation assays, including gene sequencing and large rearrangement analysis. The exposure to olaparib in plasma will also be monitored in patients receiving the drug as adjuvant therapy.