A Phase III Randomised, Double-Blind, Placebo-Controlled, Multicentre Study of Durvalumab in Combination with Chemotherapy and Bevacizumab, Followed by Maintenance Durvalumab, Bevacizumab and Olaparib in Newly Diagnosed Advanced Ovarian Cancer Patients (DUO-O).

The primary objective of this study is to determine the efficacy of **durvalumab** and **olaparib** assessed by progression-free survival (PFS) in the first-line treatment of non-tumor BRCA mutation (non-tBRCAm) homologous recombination deficiency (HRD) positive patients and all non-tBRCAm patients with newly diagnosed advanced ovarian cancer. This is clinically relevant as it aims to improve outcomes in a specific subset of ovarian cancer patients who may benefit from targeted therapies.

Secondary objectives include:

• Evaluating PFS in the non-tBRCAm cohort.
• Assessing overall survival (OS) in non-tBRCAm HRD positive and all non-tBRCAm cohorts.
• Determining objective response rate (ORR), ORR pre-surgery in the interval debulking surgery (IDS) group, duration of response, PFS2, time to first subsequent therapy (TFST), time to second subsequent therapy (TSST), and time to treatment discontinuation (TDT) in the non-tBRCAm cohort.
• Evaluating health-related quality of life outcomes (HRQoL), global health status, and ovarian cancer symptoms in the non-tBRCAm cohort.
• Assessing pathological complete response (pCR) in patients undergoing IDS in the non-tBRCAm cohort.
• Characterizing pharmacokinetics (PK) and immunogenicity (Ig) of durvalumab in a sampling of the population.
• Characterizing PK of olaparib in a sampling of the population.
• Evaluating the potential additional clinical benefit in the tBRCAm cohort, including PFS, PFS2, ORR, ORR pre-surgery in the IDS group, duration of response, TFST, TSST, TDT, HRQoL, and the proportion of patients with pCR in patients undergoing IDS.

The clinical trial involves a total of **582 participants** who are exclusively **female** and have been newly diagnosed with advanced (FIGO stage III-IV) high-grade epithelial ovarian, fallopian, or primary peritoneal cancer. The study population is composed of adult women aged 18 years and older, with an **ECOG performance status** of 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants were selected based on their diagnosis and must be candidates for cytoreductive surgery, either upfront primary surgery or chemotherapy with interval debulking surgery. The trial requires the provision of a tumor sample for centralized tBRCA testing, and participants must have preserved organ and bone marrow function. Additionally, all participants are either postmenopausal or have evidence of non-childbearing status, confirmed by a negative urine or serum pregnancy test. The trial does not include male subjects and involves a vulnerable population, given the nature of the disease and treatment. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** study designed to evaluate the efficacy and safety of **durvalumab** in combination with chemotherapy and **bevacizumab**, followed by maintenance therapy with durvalumab, bevacizumab, and **olaparib** in patients with newly diagnosed advanced ovarian cancer. The trial targets female patients with histologically confirmed advanced high-grade epithelial ovarian, fallopian, or primary peritoneal cancer, specifically those classified as FIGO stage III-IV. The primary objective is to assess the progression-free survival (PFS) in non-tBRCAm HRD positive patients and all non-tBRCAm patients. Secondary endpoints include overall survival (OS), second progression (PFS2), and health-related quality of life (HRQoL), among others.

The trial is expected to span from January 30, 2019, to March 17, 2026, with participants involved for a maximum treatment period of 24 months. The study includes 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. Participants must be at least 18 years old, have an ECOG performance status of 0-1, and provide a tumor sample for centralized tBRCA testing. Conditions for early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent.

Participants will be randomly assigned to receive either the investigational treatment or a placebo, with neither the participants nor the investigators aware of the group assignments, ensuring the study's double-blind nature. The trial will be conducted across multiple centers, adhering to rigorous protocols to maintain the integrity and reliability of the data collected. The study's design and methodology are structured to provide robust evidence on the potential benefits of the investigational treatment regimen in improving outcomes for patients with advanced ovarian cancer.

**Mycophenolate mofetil** is administered in the form of capsules, with a maximum daily dose of 2 grams. The route of administration is oral. This medication is used as a rescue medication or immunosuppressant in the clinical trial. The treatment period can extend up to 9999 days, indicating long-term administration. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.

**Lynparza** is available in two formulations: 150 mg and 100 mg film-coated tablets, both containing the active substance **olaparib**. The maximum daily dose for both formulations is 600 mg, administered orally. The treatment period is set for a maximum of 24 months. The commercial Lynparza tablets are identical to the investigational medicinal product (IMP) except for differences in film coating and packaging, which are designed to facilitate blinding in placebo-controlled studies.

**Infliximab** is provided as a powder for concentrate for solution for infusion, with a maximum daily dose of 5 mg/kg. It is administered intravenously and serves as a rescue medication or immunosuppressant. The treatment period can extend up to 9999 days. The administration schedule and participant compliance are closely monitored to ensure proper dosing and effectiveness.

The **placebo** used in the study is a film-coated tablet, not authorized for marketing. It is utilized to maintain the double-blind nature of the trial. The placebo is administered in a manner consistent with the active treatments to ensure blinding is maintained throughout the study.

**Bevacizumab** is administered as a concentrate for solution for infusion, with the route of administration being intravenous. It acts as a vascular endothelial growth factor inhibitor. The treatment period is limited to 15 months. The administration schedule is designed to align with the study protocol, and participant adherence is monitored to ensure compliance.

**Imfinzi**, containing the active substance **durvalumab**, is provided as a 50 mg/mL concentrate for solution for infusion. The maximum daily dose is 1120 mg, administered intravenously. The treatment period is set for a maximum of 24 months. The administration and dosing schedules are carefully monitored to ensure participant compliance and the integrity of the study results.

The efficacy of the clinical trial will be assessed primarily through **Progression Free Survival (PFS)**, which is defined as the time from randomization to the date of objective disease progression or death from any cause in the absence of progression. This endpoint will be evaluated regardless of whether the patient withdraws from assigned therapy or receives another anticancer therapy prior to progression. Secondary efficacy endpoints include Overall Survival (OS), Second Progression (PFS2), Objective Response Rate (ORR), Duration of Response (DoR), Time to First Subsequent Therapy (TFST), Time to Second Subsequent Therapy (TSST), Time to Discontinuation or Death (TDT), Pathological Complete Response (pCR), Health-related Quality of Life (HRQoL), and Pharmacokinetic and Immunogenicity assessments.

The trial is designed to determine the efficacy of durvalumab and olaparib in the first-line treatment of non-tBRCAm HRD positive patients and all non-tBRCAm patients with newly diagnosed advanced ovarian cancer. The study will involve a randomized, double-blind, placebo-controlled, multicenter approach. The schedule for measuring and collecting these efficacy parameters will be aligned with the trial protocol, ensuring systematic and consistent data collection throughout the study duration. The analysis of these endpoints will be conducted using appropriate statistical methods to ensure robust and reliable results.