A PHASE IV TRIAL TO CONFIRM THE EFFICACY OF OLAPARIB IN COMBINATION WITH BEVACIZUMAB AS MAINTENANCE FRONTLINE TREATMENT OF HRD POSITIVE OVARIAN TUMOURS (IOLANTHE)

The primary objective of this study is to define the proportion of patients with advanced high-grade epithelial **ovarian cancer** (EOC) who are homologous recombination deficiency (HRD)-positive and will be treated with **olaparib** in combination with **bevacizumab** as maintenance therapy. This objective is clinically relevant as it aims to confirm the efficacy of this combination treatment in a real-world setting, following first-line chemotherapy in patients with advanced high-grade EOC who have received bevacizumab. Understanding the proportion of patients who benefit from this treatment can guide clinical decision-making and optimize therapeutic strategies for HRD-positive ovarian cancer.

Secondary objectives include: 1) describing the compliance to olaparib administered with bevacizumab in terms of treatment modifications and duration; 2) describing the safety profile of olaparib added to bevacizumab; and 3) evaluating its efficacy in terms of progression-free survival 2 (PFS2) and overall survival (OS). These objectives are crucial for assessing the practical aspects of treatment administration, safety, and long-term outcomes, which are essential for comprehensive patient management and improving survival rates in this patient population.

The clinical trial involves **female** participants diagnosed with advanced, high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. The study population is exclusively female, with an age range of **18 years and older**. Participants are required to have a confirmed diagnosis of advanced disease, specifically FIGO stage III-IV, and must be suitable for a chemotherapy regimen that includes platinum-taxane and bevacizumab. The trial does not include vulnerable populations. Participants must have normal organ and bone marrow function, as well as controlled blood pressure, with an ECOG performance status of 0-1, and a life expectancy of at least 16 weeks. The sponsor has not provided information regarding the total number of participants. The selection criteria emphasize the availability of tumor samples for HRD status evaluation and the ability to undergo standard chemotherapy plus bevacizumab. Lifestyle factors such as diet and physical activity are not specified in the trial data.

The clinical trial is designed to evaluate the efficacy of **olaparib** in combination with **bevacizumab** as a maintenance therapy for patients with advanced high-grade epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. This is a phase IV, randomized, double-blind, controlled trial. The trial will span approximately three years, with an estimated end date in June 2026. Participants will be involved in the study from the start of their treatment regimen, which includes a frontline platinum-based chemotherapy plus bevacizumab, followed by maintenance therapy with olaparib and bevacizumab for those who achieve a complete or partial response and have HRD-positive tumors.

The sequence of study visits begins with an inclusion (screening) visit, where eligibility criteria are confirmed, including the availability of tumor samples for HRD status evaluation. Following the screening, participants will undergo surgery and start the chemotherapy regimen. After completing chemotherapy, patients who meet the response criteria will transition to the maintenance phase with olaparib and bevacizumab. Follow-up visits will occur every 12 weeks during the maintenance phase to monitor treatment compliance, safety, and efficacy, including progression-free survival (PFS) rates. The end-of-study visit will occur at the conclusion of the maintenance therapy or upon disease progression or death, whichever occurs first.

Participant involvement is expected to last up to 24 months, depending on individual response and disease progression. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or any medical condition that contraindicates continued participation. The primary endpoint of the trial is the PFS rate at 24 months, while secondary endpoints include treatment compliance, safety profile, and PFS2, defined as the time from starting olaparib to the second progression or death. The trial aims to confirm the efficacy of the treatment regimen in a setting close to clinical practice, ensuring that patients receive the best standard therapies according to international guidelines.

The clinical trial involves the administration of several **experimental medications** and non-experimental treatments. **Carboplatin** is utilized as a concentrate for solution for infusion. It is a chemical substance with a maximum daily dose of 440 mg and a total dose limit of 3500 mg. The treatment period for carboplatin is up to 24 weeks. The administration route is intravenous infusion, and it is categorized under chemotherapy agents.

**Bevacizumab** is another experimental medication used in this trial. It is a monoclonal antibody provided as a concentrate for solution for infusion. The dosing is calculated based on body weight, with a maximum daily dose of 15 mg/kg and a total dose limit of 300 mg/kg. The treatment duration for bevacizumab is up to 15 weeks. It is administered intravenously and is used in combination with chemotherapy.

**Paclitaxel** is also included in the trial as a concentrate for solution for infusion. This chemical substance has a maximum daily dose of 175 mg/m² and a total dose limit of 1400 mg/m². The treatment period extends up to 24 weeks. Paclitaxel is administered via intravenous infusion and is classified as a chemotherapy agent.

**Olaparib** is administered in two different formulations: Lynparza 150 mg and Lynparza 100 mg film-coated tablets. Both formulations are taken orally. Olaparib is a chemical substance and a PARP inhibitor, with a maximum daily dose of 300 mg and a total dose limit of 219000 mg. The treatment period for olaparib is up to 24 weeks. The tablets are manufactured by AstraZeneca AB and are used as part of the maintenance therapy in combination with bevacizumab.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to confirm the efficacy of olaparib in combination with bevacizumab as a maintenance treatment for HRD-positive ovarian tumors.

The efficacy of the clinical trial will be assessed primarily through the evaluation of **Progression-Free Survival (PFS)** rate at 24 months. PFS is defined as the time from the initiation of olaparib therapy until disease progression or death, whichever occurs first. This primary endpoint will provide a measure of the treatment's effectiveness in delaying disease progression in patients with advanced high-grade epithelial ovarian cancer (EOC) who are HRD-positive.

Secondary efficacy assessments will include the evaluation of **PFS2**, which is the time from the start of olaparib treatment to the second progression or death, whichever comes first. Additionally, compliance with treatment, including any modifications and the duration of treatment with olaparib, will be monitored. The safety profile of olaparib will also be assessed, focusing on the maximum toxicity grade experienced by each patient, the occurrence of grade 3-4 toxicities, and the type, frequency, and nature of serious adverse events (SAEs), serious adverse drug reactions (SADRs), and suspected unexpected serious adverse reactions (SUSARs).