Randomized, Double-Blind, Placebo-Controlled Phase III Study of Olaparib Maintenance Monotherapy in BRCA-Mutated Advanced Ovarian Cancer Post-Platinum Chemotherapy

The primary objective of this study is to evaluate the **efficacy** of olaparib maintenance monotherapy compared to placebo in patients with BRCA mutated advanced ovarian cancer, specifically those in clinical complete response or partial response following first-line platinum-based chemotherapy. This is assessed by progression-free survival (PFS) using investigator assessment according to modified Response Evaluation Criteria in Solid Tumours (RECIST 1.1). The clinical relevance of this objective lies in its potential to improve management strategies for high-risk advanced ovarian cancer, potentially extending the duration of remission and delaying disease progression.

Secondary objectives include:

• Determining the efficacy of olaparib maintenance monotherapy compared to placebo by assessing overall survival, time to earliest progression by RECIST or Cancer Antigen-125 or death, and time from randomization up to second progression.
• Comparing the effects of olaparib maintenance monotherapy with placebo on health-related quality of life (HRQoL) assessed by the Trial Outcome Index (TOI) of the Functional Assessment of Cancer Therapy-Ovarian (FACT-O).
• Assessing the efficacy of olaparib in patients identified as having a deleterious or suspected deleterious variant in either of the BRCA genes using variants identified with current and potential future BRCA mutation assays.
• Determining the efficacy of olaparib maintenance monotherapy compared to placebo by assessing time from randomization to first subsequent therapy, second subsequent therapy, and study treatment discontinuation or death.
• Assessing the safety and tolerability of olaparib maintenance monotherapy.

The clinical trial involves a total of **222 participants** who are exclusively female, as the study focuses on patients with **BRCA Mutated Advanced (FIGO Stage III-IV) Ovarian Cancer**. The age range of the participants falls within categories 3 and 4, which typically correspond to adult and older adult populations. Participants were selected based on their diagnosis of high-risk advanced ovarian cancer, specifically those with a histologically confirmed BRCA mutation. The trial population includes individuals who have completed first-line platinum-based chemotherapy and are in clinical complete or partial response, with no evidence of disease progression. The study does not include male subjects and involves a vulnerable population, given the advanced stage of the disease. Lifestyle factors such as diet and physical activity are not specified in the available data. The selection criteria emphasize the completion of optimal debulking surgery for Stage III patients and either biopsy or debulking surgery for Stage IV patients, ensuring a specific focus on those with a documented deleterious BRCA1 or BRCA2 mutation.

The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** study designed to evaluate the efficacy of **olaparib** maintenance monotherapy in patients with **BRCA mutated advanced ovarian cancer** following first-line platinum-based chemotherapy. The trial aims to assess progression-free survival (PFS) as the primary endpoint, with secondary endpoints including overall survival, time to progression, and safety assessments. The study is expected to commence recruitment on February 9, 2024, and conclude by September 30, 2029.

Participants will be randomly assigned to receive either **Lynparza** (olaparib) or a placebo, both administered as film-coated tablets for oral use. The maximum daily dose of olaparib is 600 mg, with a treatment period of up to 36 months. The trial will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess final outcomes. The inclusion criteria specify that participants must be female patients with newly diagnosed, high-risk advanced ovarian cancer, confirmed to have a deleterious **BRCA1** or **BRCA2** mutation, and have completed first-line platinum-based chemotherapy with a clinical complete or partial response.

The expected duration of participant involvement is up to 36 months, depending on individual response and progression. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent. The trial will adhere to rigorous standards to ensure the validity and reliability of the results, contributing valuable data to the understanding of olaparib's efficacy in this patient population.

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 150 mg of the active substance **olaparib**. The pharmaceutical form is a film-coated tablet, and the route of administration is oral. The maximum daily dose is 600 mg, and the treatment period can extend up to 36 months. The tablets are manufactured by AstraZeneca AB and are identified by the marketing authorization number EU/1/14/959/004. The chemical origin of the active substance is confirmed, and the tablets are intended for use in patients with BRCA mutated advanced ovarian cancer.

Additionally, **Lynparza 100 mg film-coated tablets** are included in the study. Each tablet contains 100 mg of **olaparib**. Similar to the 150 mg tablets, the pharmaceutical form is a film-coated tablet, and the administration is oral. The maximum daily dose remains at 600 mg, with a treatment period of up to 36 months. These tablets are also produced by AstraZeneca AB, with the marketing authorization number EU/1/14/959/003. Notably, the investigational medicinal product (IMP) version of the 100 mg tablet has a green film coat and is unmarked, differing from the commercial version, which has a yellow film coat and commercial debossing. This modification facilitates blinding in placebo-controlled studies.

The study also employs a **placebo** in the form of film-coated tablets. The placebo is designed to match the appearance of the experimental medication to maintain the double-blind nature of the trial. The placebo tablets do not contain any active substance and are used as a comparator to evaluate the efficacy of **olaparib** in the study population. The placebo administration follows the same oral route and dosing schedule as the active treatment to ensure consistency in the trial protocol.

The efficacy of the clinical trial will be assessed primarily through **Progression Free Survival (PFS)**, as determined by investigator review using the modified Response Evaluation Criteria in Solid Tumours (RECIST 1.1). This primary endpoint will evaluate the duration during which patients with BRCA mutated advanced ovarian cancer remain free from disease progression following treatment with olaparib maintenance monotherapy compared to placebo. Secondary endpoints will include overall survival, time to earliest progression by RECIST or Cancer Antigen-125 (CA-125), and time from randomisation to second progression. Additionally, the Trial Outcome Index (TOI) of the Functional Assessment of Cancer Therapy - Ovarian Cancer (FACT-O) will be utilized to assess changes from baseline in TOI score and the proportion of patients showing improvement.

Further efficacy assessments will involve the evaluation of olaparib's impact on time to first subsequent therapy or death (TFST), time to second subsequent therapy or death (TSST), and time from randomisation to study treatment discontinuation or death (TDT). The development and delivery of a BRCA mutation companion diagnostic will also be part of the efficacy evaluation. Adverse events, physical examination, vital signs including blood pressure, pulse, electrocardiogram, and laboratory findings such as clinical chemistry and haematology will be monitored to support the assessment of efficacy and safety. The trial is designed as a Phase III, randomised, double-blind, placebo-controlled, multicentre study, with an estimated end date of September 30, 2029.