Efficacy and Safety Evaluation of Olaparib Monotherapy and Olaparib-Durvalumab Combination in Neoadjuvant Treatment of HER2-Negative BRCA-Mutated Breast Cancer

The primary objective of this study is to evaluate the **efficacy** of olaparib monotherapy and olaparib plus durvalumab combination therapy in patients with BRCA mutations and early-stage HER2-negative breast cancer. This is measured by the pathological complete response (pCR) rate, as assessed by central pathology review. The pCR rate is a critical endpoint in neoadjuvant therapy for breast cancer, as it is associated with improved long-term outcomes and can serve as a surrogate marker for survival benefits.

Secondary objectives include:

• Evaluating the efficacy, measured by residual cancer burden (RCB), of both therapies as assessed by central and local pathology reviews.
• Assessing the change from baseline in tumor volume to determine the efficacy of the treatments.
• Evaluating event-free survival (EFS) as a measure of efficacy.
• Assessing the safety and tolerability profile of olaparib monotherapy and the combination therapy.
• Evaluating the safety and tolerability of olaparib monotherapy when administered as adjuvant therapy to participants who achieve pCR.

The clinical trial involves a total of **10 participants** diagnosed with **BRCA Mutations and Early Stage HER2-Negative Breast Cancer**. The study population includes both male and female subjects aged 18 years and older, with a minimum body weight of 30 kg. Participants are required to have a histologically confirmed, newly diagnosed, primary, operable, non-metastatic invasive breast cancer, characterized as ER-negative or ER-low and HER2-negative. The trial population was selected based on specific criteria, including documented deleterious or suspected deleterious mutations in BRCA1 or BRCA2, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Participants must demonstrate adequate organ and bone marrow function and be willing to undergo a baseline research core needle biopsy prior to the start of study treatment. The trial includes individuals from a vulnerable population, and both genders are represented. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **Phase II**, multicenter, open-label study to evaluate the efficacy and safety of **olaparib** monotherapy and olaparib plus **durvalumab** combination therapy as neoadjuvant treatment in patients with **BRCA mutations** and early-stage **HER2-negative breast cancer**. The trial aims to assess the efficacy, measured by the pathological complete response (pCR) rate, as determined by central pathology review. The study is expected to commence recruitment on October 18, 2022, and conclude by April 15, 2027.

The trial involves a sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, body weight, and histologically confirmed diagnosis of non-metastatic invasive breast cancer. Participants must also have a documented deleterious or suspected deleterious mutation in **BRCA1** or **BRCA2**. Following the screening, participants will undergo a baseline research core needle biopsy before the initiation of study treatment. The study treatment period will include regular follow-up visits to monitor safety and efficacy, with assessments such as MRI to measure changes in tumor volume after 3 and 6 cycles of treatment. The end-of-study visit will evaluate the primary endpoint of pCR, defined as no invasive residual in the breast and axillary lymph nodes post-treatment.

Participants are expected to be involved in the study for a maximum treatment period of 336 days. Conditions that may lead to early termination from the study include disease progression that precludes surgery, local or distant recurrence after surgery, the occurrence of a second primary malignancy, or any adverse events that compromise participant safety. The study will adhere to rigorous safety monitoring, including assessments of adverse events, physical examinations, vital signs, and laboratory evaluations.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Mycophenolate mofetil** is provided in a hard capsule form and is administered orally. The maximum daily dose is 2 grams, and the treatment period is extensive, allowing for long-term administration. This medication is not a pediatric formulation and is classified as a chemical substance.

**Infliximab** is supplied as a powder for concentrate for solution for infusion. It is administered intravenously with a maximum daily dose of 5 mg/kg. The treatment period is also extensive, similar to mycophenolate mofetil. Infliximab is not a pediatric formulation and is categorized as a chemical substance.

**Durvalumab**, marketed as Imfinzi, is provided as a 50 mg/mL concentrate for solution for infusion. It is administered intravenously with a maximum daily dose of 1500 mg and a total dose limit of 9000 mg over a treatment period of 168 days. Durvalumab is a protein-based substance and is not formulated for pediatric use.

**Olaparib** is available in two formulations: 100 mg and 150 mg film-coated tablets. Both formulations are administered orally with a maximum daily dose of 600 mg and a total dose limit of 201600 mg over a treatment period of 336 days. The tablets are chemically based and not intended for pediatric use. The 100 mg tablet has a green film coat and is unmarked, while the 150 mg tablet is unmarked and packed in HDPE bottles to facilitate blinding in placebo-controlled studies.

Throughout the trial, participant compliance with the dosing schedules is monitored to ensure adherence to the prescribed treatment regimens. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments. The focus is on evaluating the efficacy and safety of the experimental medications in patients with BRCA mutations and early-stage HER2-negative breast cancer.

The efficacy of the clinical trial will be assessed primarily through the evaluation of the **pathological complete response (pCR)** rate. The pCR is defined as the absence of invasive residuals in the breast and axillary lymph nodes, specifically ypT0/Tis ypN0, following the completion of neoadjuvant systemic therapy. This assessment will be conducted via a central pathology review. Secondary endpoints include the Residual Cancer Burden (RCB) index, which categorizes response into four classes: RCB 0 (pCR), I (minimal RCB), II (moderate RCB), and III (extensive RCB). Additionally, the percentage change in tumor volume from baseline will be measured using MRI after 3 and 6 cycles of treatment. Event-free survival (EFS) will also be evaluated, defined as the time from the first dose of study intervention to events such as disease progression that precludes surgery, local or distant recurrence after surgery, second primary malignancy, or death from any cause. Safety and tolerability will be monitored through adverse events (AEs) and serious adverse events (SAEs), alongside physical examinations, vital signs, clinical laboratory assessments, and ECGs.