Phase III Randomized Study of Camizestrant and CDK4/6 Inhibitor Versus Aromatase Inhibitor and CDK4/6 Inhibitor in HR+/HER2- Advanced Breast Cancer with ESR1 Mutation

The primary objective of this study is to demonstrate the superiority of **AZD9833** plus a **CDK4/6 inhibitor** compared to an aromatase inhibitor (AI) plus a CDK4/6 inhibitor by assessing progression-free survival (PFS) in the full analysis set (FAS). This is clinically relevant as it aims to improve treatment outcomes for patients with estrogen receptor-positive, HER2-negative advanced breast cancer, potentially offering a more effective therapeutic option.

Secondary objectives include:

• Demonstrating the superiority of AZD9833 plus CDK4/6 inhibitor relative to AI plus CDK4/6 inhibitor by assessing second progression-free survival (PFS2) and overall survival (OS) in the FAS.
• Assessing breast and arm symptoms, pain, and physical functioning in participants treated with AZD9833 plus CDK4/6 inhibitor relative to AI plus CDK4/6 inhibitor.
• Evaluating the steady-state pharmacokinetics (PK) of AZD9833 in combination with Palbociclib, Abemaciclib, or Ribociclib in all participants who receive at least one dose of AZD9833.
• Assessing the safety and tolerability of AZD9833 plus CDK4/6 inhibitor relative to AI plus CDK4/6 inhibitor in participants with advanced HR+/HER2-negative breast cancer.
• Estimating the effectiveness of AZD9833 plus CDK4/6 inhibitor relative to AI plus CDK4/6 inhibitor by assessing chemotherapy-free survival in the FAS.
• Estimating the effectiveness of AZD9833 plus CDK4/6 inhibitor relative to AI plus CDK4/6 inhibitor by assessing the objective response rate (ORR) in patients with measurable disease in the FAS.
• Estimating the effectiveness of AZD9833 plus CDK4/6 inhibitor relative to AI plus CDK4/6 inhibitor by assessing the clinical benefit rate at 24 weeks (CBR24), and time to first and second subsequent treatment in the FAS.

The clinical trial involves a total of **172 participants** diagnosed with **Estrogen Receptor-Positive, HER-2 negative Advanced Breast Cancer**. The study population includes both male and female subjects, with an age range that spans from adults to the elderly. Participants were selected based on specific criteria, including a proven diagnosis of adenocarcinoma of the breast with evidence of locoregionally recurrent or metastatic disease. The trial population is characterized by individuals who are currently on an aromatase inhibitor (letrozole or anastrozole) combined with a CDK4/6 inhibitor, with or without LHRH, as the initial endocrine-based treatment for advanced disease. Participants are required to have an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate organ and marrow function. The study also includes a vulnerable population, and participants must demonstrate willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of AZD9833, a next-generation oral selective estrogen receptor degrader (SERD), in combination with a CDK4/6 inhibitor, compared to the continuation of an aromatase inhibitor (letrozole or anastrozole) with a CDK4/6 inhibitor in patients with **estrogen receptor-positive, HER-2 negative advanced breast cancer**. The trial aims to demonstrate the superiority of the AZD9833 combination by assessing progression-free survival (PFS) as the primary endpoint. Secondary endpoints include overall survival, progression-free survival 2, objective response rate, and other clinical outcomes. The trial is expected to last until November 2027, with recruitment starting in July 2024.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a confirmed diagnosis of breast cancer, current treatment with an aromatase inhibitor and CDK4/6 inhibitor, and detection of ESR1 mutation. Follow-up visits will be scheduled to monitor treatment response, adverse events, and compliance with the study protocol. The end-of-study visit will conclude the participant's involvement, assessing final outcomes and any long-term effects of the treatment. The expected duration of participant involvement is up to 77 weeks, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent.

The trial will involve the administration of investigational products, including AZD9833 and various CDK4/6 inhibitors such as **abemaciclib**, **palbociclib**, and **ribociclib**, all administered orally. The study will also utilize placebos to maintain blinding. Participants will be monitored for plasma concentrations of AZD9833 and changes in quality of life measures. The trial's design ensures rigorous assessment of the investigational treatment's efficacy and safety, contributing valuable data to the management of advanced breast cancer.

**Abemaciclib** is administered in the form of a **film-coated tablet**. The active substance, abemaciclib, is of chemical origin. The maximum daily dose is 150 mg, administered orally. The treatment period is up to 77 days. The product is relabelled for use in clinical trials.

**Camizestrant** is provided as a **film-coated tablet**. The active substance, camizestrant, is chemically derived. The maximum daily dose is 75 mg, administered orally, with a treatment period of up to 77 days. The product is identified by the sponsor product code AZD9833.

**IBRANCE** (palbociclib) is available in **film-coated tablets** of 125 mg, 100 mg, and 75 mg. The active substance, palbociclib, is of chemical origin. The maximum daily dose is 125 mg, administered orally, with a treatment period of up to 77 days. The product is relabelled for clinical trial use.

**Letrozole** is administered as a **tablet**. The active substance, letrozole, is chemically derived. The maximum daily dose is 2.5 mg, administered orally, with a treatment period of up to 77 days. For blinding purposes in clinical trials, the tablets are over-encapsulated.

**Goserelin Acetate** is provided as an **implant in a pre-filled syringe**. The active substance, goserelin acetate, is of chemical origin. The maximum daily dose is 0.13 mg, administered subcutaneously, with a treatment period of up to 77 days.

**Ribociclib** is available as a **film-coated tablet**. The active substance, ribociclib, is chemically derived. The maximum daily dose is 600 mg, administered orally, with a treatment period of up to 77 days. The product is relabelled for clinical trial use.

**Leuprorelin Acetate** is administered as a **powder and solvent for prolonged-release suspension for injection**. The active substance, leuprorelin acetate, is of chemical origin. The maximum daily dose is 0.13 mg, administered intramuscularly, with a treatment period of up to 77 days.

**Anastrozole** is provided as **film-coated tablets** under the brand name Arimidex®. The active substance, anastrozole, is chemically derived. The maximum daily dose is 1 mg, administered orally, with a treatment period of up to 77 days. For blinding purposes, a 'clinical tablet' presentation is available, which is identical to the commercial formulation except for tablet intagliation, clinical trials packaging, and labelling.

**Placebos** are used to match anastrozole, letrozole, and camizestrant. These placebos are provided in forms that match the active treatments but contain no active substance. They are used to maintain blinding in the clinical trial.

Efficacy in this clinical trial will be assessed primarily through the measurement of **Progression-Free Survival (PFS)**. PFS is defined as the time from randomization until disease progression, as determined by the investigator using RECIST 1.1 criteria, or death from any cause. This endpoint will be evaluated to demonstrate the superiority of AZD9833 plus a CDK4/6 inhibitor compared to an aromatase inhibitor (AI) plus a CDK4/6 inhibitor in patients with HR+/HER2- metastatic breast cancer (MBC) who have a detectable ESR1 mutation.

Secondary efficacy endpoints include Overall Survival (OS), Progression-Free Survival 2 (PFS2), Objective Response Rate (ORR) as assessed by the investigator using RECIST version 1.1, Chemotherapy-Free Survival, Clinical Benefit Rate at 24 weeks (CBR24), Time to First Subsequent Anti-Cancer Therapy (TFST), Time to Second Subsequent Therapy (TSST), Time to Deterioration (TTD), and plasma concentration of AZD9833 at specified timepoints. Additionally, changes from baseline in the EORTC QLQ-C30 and EORTC QLQ-BR23 scales will be measured to assess patient-reported outcomes.