CAMBRIA-1: A Phase III, Open-Label, Randomised Study to Assess the Efficacy and Safety of Extended Therapy With Camizestrant (AZD9833, a Next Generation, Oral Selective Estrogen Receptor Degrader) versus Standard Endocrine Therapy (Aromatase Inhibitor or Tamoxifen) in Patients with ER+/HER2- Early Breast Cancer and an Intermediate or High Risk of Recurrence Who Have Completed Definitive Locoregional Therapy and at Least 2 Years of Standard Adjuvant Endocrine-Based Therapy Without Disease Recurrence

The primary objective of this study is to demonstrate the superiority of extended therapy with **camizestrant** over standard endocrine therapy in preventing breast cancer recurrence in patients with ER+/HER2- early breast cancer. This is clinically relevant as it aims to improve long-term outcomes and reduce the risk of recurrence in patients who have completed definitive locoregional therapy and at least two years of standard adjuvant endocrine-based therapy without disease recurrence.

Secondary objectives include:

• Evaluating the efficacy of extended therapy with camizestrant compared to standard endocrine therapy in terms of overall survival and other measures.
• Assessing the safety of extended therapy with camizestrant compared to standard endocrine therapy.
• Characterizing the pharmacokinetics of camizestrant.
• Assessing patient-reported treatment-associated symptoms and quality of life between camizestrant and standard endocrine therapy.

The clinical trial involves a total of **3148 participants** diagnosed with **ER+/HER2- Early Breast Cancer**. The study population includes both women and men aged 18 years and older, as per national guidelines. Participants have histologically confirmed early-stage resected invasive breast cancer with a high or intermediate risk of recurrence, based on clinical-pathological risk features. All participants have completed adequate locoregional therapy, which may include surgery with or without radiotherapy, and have undergone at least 2 years but no more than 5 years of adjuvant endocrine therapy, with or without a CDK4/6 inhibitor. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants are required to have adequate organ and marrow function. The selection process ensures a diverse representation of both genders, and the trial includes vulnerable populations. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the efficacy and safety of **camizestrant**, a next-generation oral selective estrogen receptor degrader, compared to standard endocrine therapy in patients with ER+/HER2- early breast cancer. This is a Phase III, open-label, randomized study. The trial aims to demonstrate the superiority of extended therapy with camizestrant over standard endocrine therapy in preventing breast cancer recurrence. The study will involve participants who have completed definitive locoregional therapy and at least two years of standard adjuvant endocrine-based therapy without disease recurrence. The trial is expected to run from July 2023 to March 2036, with a maximum treatment period of 60 months for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, histologically confirmed ER+/HER2- early-stage resected invasive breast cancer, and adequate organ and marrow function. Follow-up visits will be scheduled to monitor the participants' health status, adherence to the treatment regimen, and any adverse events. The primary endpoint is invasive breast cancer-free survival, while secondary endpoints include invasive disease-free survival, distant relapse-free survival, overall survival, and various safety and clinical outcome assessments. The end-of-study visit will conclude the participant's involvement, assessing the overall treatment efficacy and safety.

Participant involvement is expected to last up to 60 months, with conditions for early termination including significant adverse events, disease progression, or withdrawal of consent. The trial will employ a randomized design to ensure unbiased comparison between the treatment groups. The study will not be low-intervention, given its Phase III classification and the investigational nature of the treatment. The trial will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the results.

The clinical trial involves the administration of several **experimental medications** and comparator treatments. **Goserelin** is provided as an implant in a pre-filled syringe, with a maximum daily dose of 0.13 mg and a total dose of 10.8 mg over a treatment period of 60 days. It is administered subcutaneously. Goserelin is a synthetic analogue of naturally occurring LHRH and is classified as a protein of other origin.

**Leuprorelin** is administered as a prolonged-release suspension for injection, with a maximum daily dose of 0.13 mg and a total dose of 11.25 mg over 60 days. The route of administration is intramuscular. Leuprorelin is also a protein of other origin.

**Triptorelin** is another prolonged-release suspension for injection, with a maximum daily dose of 0.13 mg and a total dose of 3.75 mg over the same treatment period. It is administered intramuscularly and is classified similarly as a protein of other origin.

**Anastrozole**, marketed as Arimidex® 1 mg film-coated tablets, is administered orally with a maximum daily dose of 1 mg. The total dose is 1 mg per day over 60 days. This medication is a chemical substance and has been repackaged and relabeled for clinical trial use.

**Tamoxifen citrate**, marketed as Nolvadex® 20 mg film-coated tablets, is administered orally with a maximum daily dose of 20 mg. The total dose is 20 mg per day over the treatment period. It is a chemical substance and has undergone packaging and relabeling for the trial.

**Exemestane** is provided in tablet form, administered orally with a maximum daily dose of 25 mg. The total dose is 25 mg per day over 60 days. It is classified as a chemical substance and has been repackaged and relabeled for the trial.

**Letrozole** is also administered in tablet form, with a maximum daily dose of 2.5 mg and a total dose of 2.5 mg per day over the treatment period. It is a nonsteroidal aromatase inhibitor and has been repackaged and relabeled for clinical trial use.

**Camizestrant**, a next-generation oral selective estrogen receptor degrader, is provided as a film-coated tablet. The dosing information is not specified, but it is administered orally over a 60-day period. It is a chemical substance and is part of the investigational treatment in the trial.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen. The trial aims to assess the efficacy and safety of these treatments in patients with ER+/HER2- early breast cancer at an intermediate or high risk of recurrence.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary efficacy endpoint is **IBCFS** (invasive breast cancer-free survival), defined by the STEEP 2.0 criteria. Secondary efficacy endpoints include **IDFS** (invasive disease-free survival), **DRFS** (distant relapse-free survival), and **OS** (overall survival), all defined by the STEEP 2.0 criteria. Additionally, secondary endpoints will evaluate safety, clinical outcome assessments, and pharmacokinetics. Safety endpoints will include treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), clinical laboratory tests, and vital signs. Clinical outcome assessments will focus on patient-reported tolerability, changes from baseline in symptoms such as arthralgia, hot flush, and vaginal dryness, and the proportion of patients experiencing each level of symptomatic adverse events as measured by the EORTC-IL-194. Changes from baseline and time to deterioration (TTD) of health-related quality of life (QoL) will be measured using the two global QoL items from the EORTC-QLQ-C30. Pharmacokinetic assessments will involve measuring plasma concentrations of camizestrant pre-dose (Ctrough).