Phase 2 Randomized Study of Camizestrant vs. Fulvestrant in Postmenopausal Women with Advanced ER-Positive HER2-Negative Breast Cancer

The primary objective of this study is to determine the clinical efficacy of **AZD9833** compared to fulvestrant in women with advanced estrogen receptor (ER) positive, HER2 negative breast cancer, as assessed by progression-free survival (PFS). This is clinically relevant as it aims to establish whether AZD9833 can provide a more effective treatment option for this patient population, potentially improving outcomes and offering an alternative to existing therapies.

Secondary objectives include:

• Evaluating the safety and tolerability of AZD9833 compared to fulvestrant.
• Determining the anti-tumor effect of AZD9833 in comparison to fulvestrant.
• Assessing the effect of AZD9833 on survival and clinical benefit relative to fulvestrant.
• Evaluating the pharmacokinetics (PK) of AZD9833 at steady state in this patient population.
• Assessing the pharmacodynamics of AZD9833 and fulvestrant in a subgroup of patients.
• Evaluating the effect of AZD9833 and fulvestrant on health-related quality of life (HRQoL) as assessed by patient-completed HRQoL questionnaires.

These secondary objectives are crucial for understanding the broader impact of AZD9833 on patient safety, tumor response, survival outcomes, and quality of life, thereby providing a comprehensive evaluation of its potential as a therapeutic agent.

The clinical trial involved a total of **99 participants**, all of whom were **female** and aged at least 18 years, with a focus on post-menopausal women. The study population was specifically selected to include individuals with **Estrogen Receptor Positive HER2 Negative Advanced Breast Cancer**. Participants were required to have a histological or cytological confirmation of adenocarcinoma of the breast, with either metastatic disease or loco-regionally recurrent disease suitable for treatment with fulvestrant. The trial did not include any vulnerable populations. Participants were selected based on their ability to provide signed and dated informed consent, and they were required to have at least one measurable lesion or a specific type of bone lesion. The trial population was characterized by a good general health status, as indicated by an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Lifestyle considerations such as diet and physical activity were not specified in the trial data provided.

The clinical trial is designed as a **randomized**, open-label, parallel-group, multicenter Phase 2 study. It aims to compare the efficacy and safety of oral **camizestrant** (AZD9833) versus **fulvestrant** in women with advanced estrogen receptor-positive (ER-positive), HER2-negative breast cancer. The trial is expected to run from January 6, 2020, to March 28, 2025. Participants will be randomly assigned to receive either camizestrant in the form of a film-coated tablet for oral use or fulvestrant as a solution for injection. The primary endpoint is progression-free survival, with secondary endpoints including objective response rate, duration of response, and overall survival, among others.

The study involves several key visits, starting with an inclusion (screening) visit where eligibility criteria are assessed. Participants must provide signed informed consent and meet specific criteria, such as having measurable disease and being post-menopausal. Follow-up visits will occur at regular intervals to monitor the participants' health, assess the efficacy of the treatment, and record any adverse events. The end-of-study visit will conclude the trial for each participant, where final assessments will be conducted.

Participant involvement is expected to last until the study's estimated end date, unless early termination is warranted. Conditions for early termination include significant adverse events, withdrawal of consent, or any other medical reasons deemed necessary by the investigator. The trial's design ensures that data collected will contribute to understanding the clinical efficacy of camizestrant compared to fulvestrant in the specified patient population.

The clinical trial involves the administration of **camizestrant**, a selective estrogen receptor degrader (SERD), as the experimental medication. Camizestrant is provided in the form of a **film-coated tablet** and is administered orally. The maximum daily dose of camizestrant is 300 mg, and the treatment period is set to a maximum duration of 9999999 days, indicating long-term administration. The active substance, camizestrant, is of chemical origin and is also known by the sponsor product code AZD9833. The pharmaceutical formulation is designed for adult use, and the medication is not a pediatric formulation. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.

In addition to camizestrant, the trial includes the administration of **fulvestrant** as a comparator treatment. Fulvestrant is also a selective estrogen receptor degrader (SERD) and is provided in the form of a **solution for injection**. The route of administration for fulvestrant is intramuscular, with a maximum daily dose of 500 mg. Similar to camizestrant, the treatment period for fulvestrant is set to a maximum of 9999999 days. Fulvestrant is of chemical origin and is utilized in the study to compare its efficacy and safety against camizestrant in women with advanced ER-positive HER2-negative breast cancer. Monitoring of participant compliance with the dosing schedule is conducted to ensure accurate assessment of treatment outcomes.

The efficacy of the clinical trial titled "SERENA-2: A Randomised, Open-Label, Parallel-Group, Multicentre Phase 2 Study Comparing the Efficacy and Safety of Oral AZD9833 versus Fulvestrant in Women with Advanced ER-Positive HER2-Negative Breast Cancer" will be assessed primarily through **progression-free survival (PFS)**. This primary endpoint will evaluate the duration during which patients remain free from disease progression. Secondary endpoints include objective response rate, duration of response, percentage change in tumor size at 16 weeks, overall survival, and clinical benefit rate at 24 weeks. Additionally, plasma concentrations of AZD9833 and its metabolites, if applicable, will be measured. Changes in estrogen receptor (ER) and progesterone receptor (PgR) expression, assessed by the manual H-score method, and changes in the Ki67 labeling index will also be evaluated. Patient-reported outcomes will be assessed through changes from baseline in total and subscale scores of health-related quality of life (HrQoL) questionnaires.