CAMBRIA-2: A Phase III, Open-Label, Randomised Study to Assess the Efficacy and Safety of Camizestrant (AZD9833, a Next Generation, Oral Selective Estrogen Receptor Degrader) vs Standard Endocrine Therapy (Aromatase Inhibitor or Tamoxifen) as Adjuvant Treatment for Patients With ER+/HER2- Early Breast Cancer and an Intermediate-High or High Risk of Recurrence Who Have Completed Definitive Locoregional Treatment and Have No Evidence of Disease

The primary objective is to demonstrate the superiority of camizestrant with or without abemaciclib compared to standard endocrine therapy with or without abemaciclib in preventing breast cancer recurrence in patients with ER-positive/HER2-negative early breast cancer. This comparison is clinically relevant for establishing whether camizestrant, a next-generation oral selective estrogen receptor degrader, offers improved disease-free outcomes in the adjuvant setting for patients at intermediate-high or high risk of recurrence who have completed definitive locoregional treatment.

The secondary objectives include:

• Evaluation of the efficacy of camizestrant ± abemaciclib compared to standard endocrine therapy ± abemaciclib in terms of overall survival and other efficacy measures

• Assessment of the safety profile of camizestrant ± abemaciclib compared to standard endocrine therapy ± abemaciclib

• Characterization of camizestrant pharmacokinetics

• Assessment of patient-reported treatment-associated symptoms and quality of life in patients treated with camizestrant ± abemaciclib compared to standard endocrine therapy ± abemaciclib

This clinical trial enrolled a total of **3,628 participants**, including both **women and men** aged **18 years or older** at the time of screening. The study population consisted of individuals with histologically confirmed **ER+/HER2- early-stage resected invasive breast cancer**, with no evidence of **metastatic disease**. Participants had completed adequate locoregional therapy, including surgery with or without radiotherapy, and could have received neoadjuvant or adjuvant chemotherapy. Randomization occurred within 12 months of definitive breast surgery, and patients may have received up to 12 weeks of **endocrine therapy** prior to enrollment. Eligible participants demonstrated an **Eastern Cooperative Oncology Group (ECOG) performance status** of 1 or less and had adequate organ and marrow function. The trial population was selected based on specific clinical and pathological characteristics to evaluate the efficacy of camizestrant with or without abemaciclib compared to standard endocrine therapy in preventing breast cancer recurrence.

This is a Phase III, open-label, randomised clinical trial evaluating the efficacy and safety of **camizestrant** (AZD9833), an oral selective estrogen receptor degrader, compared to standard endocrine therapy (aromatase inhibitor or **tamoxifen**) as adjuvant treatment in patients with **ER+/HER2- early breast cancer** who have an intermediate-high or high risk of recurrence. The study employs an open-label design, meaning that both participants and investigators are aware of the treatment allocation. Participants are randomised to receive either camizestrant with or without **abemaciclib**, or standard endocrine therapy with or without abemaciclib. Standard endocrine therapy options include **anastrozole**, **letrozole**, **exemestane**, or tamoxifen, administered orally. For premenopausal or perimenopausal patients, ovarian function suppression may be achieved using **goserelin** (subcutaneous), **triptorelin** (intramuscular), or **leuprorelin acetate** (intramuscular). The maximum treatment period is 84 months (7 years) for most investigational medicinal products, with ovarian suppression agents administered for up to 36 or 60 months depending on the specific agent.

The primary objective is to demonstrate the superiority of camizestrant with or without abemaciclib compared to standard endocrine therapy with or without abemaciclib in preventing breast cancer recurrence. The primary efficacy endpoint is invasive breast cancer free-survival (IBCFS) as defined by STEEP 2.0 criteria. Secondary efficacy endpoints include invasive disease-free survival (IDFS), distant relapse-free survival (DRFS), and overall survival (OS), all defined according to STEEP 2.0 criteria. Safety endpoints encompass treatment-emergent adverse events, serious adverse events, clinical laboratory tests, and vital signs. Clinical outcome assessments include the proportion of time on study treatment with high side-effect burden as measured by the PGI-TT, as well as changes from baseline and time to deterioration of health-related quality of life assessed using the EORTC QLQ-C30 global quality of life items. Pharmacokinetic assessments include plasma concentrations of camizestrant at pre-dose (trough concentration).

Eligible participants include women and men aged 18 years or older at screening, with histologically confirmed ER+/HER2- early-stage resected invasive breast cancer and no evidence of metastatic disease. Participants must have completed adequate definitive locoregional therapy (surgery with or without radiotherapy) for the primary breast tumour, with or without neoadjuvant or adjuvant chemotherapy. Randomisation must occur within 12 months of definitive breast surgery. Patients may have received up to 12 weeks of endocrine therapy in either the adjuvant or neoadjuvant setting prior to randomisation. Additional inclusion criteria require an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and adequate organ and marrow function.

The estimated recruitment start date is 10 March 2024, and the estimated end date of the trial is 17 April 2037. Participant involvement in the study extends for the duration of the treatment period, up to a maximum of 84 months, followed by long-term follow-up for survival and recurrence outcomes. Early termination from the study may occur due to withdrawal of consent, disease progression, unacceptable toxicity, non-compliance with study procedures, or at the discretion of the investigator if continuation is deemed not in the participant's best interest. The trial involves multiple study visits, including a screening visit to assess eligibility and baseline characteristics, regular follow-up visits during the treatment phase to monitor efficacy and safety, and an end-of-study visit to document final outcomes and assess long-term effects.

The experimental medication **camizestrant** (also designated as AZD9833) is administered as a **film-coated tablet** via the **oral route**. Camizestrant is a next-generation **selective estrogen receptor degrader** that represents the primary investigational product in this clinical trial. The maximum treatment period for camizestrant is 84 months. This product is supplied in a formulation specifically designated for clinical trial use.

**Abemaciclib** serves as an additional experimental treatment in this study and is administered as a **film-coated tablet** via the **oral route**. The maximum daily dose is **150 mg** with a maximum total dose of **393.5 grams** over a treatment period of up to 84 months. The product undergoes secondary repacking and labelling specifically for clinical trial use. Abemaciclib functions as a test product that may be combined with camizestrant or standard endocrine therapy according to the study protocol.

**Anastrozole** (marketed as Arimidex 1 mg film-coated tablets) is employed as a comparator treatment and belongs to the class of **non-steroidal aromatase inhibitors**. The product is administered orally as a film-coated tablet with a maximum daily dose of **1 mg**. The maximum total dose is **2.55 grams** over a maximum treatment period of 84 months. The clinical trial formulation is identical to the commercial formulation except for tablet intagliation, clinical trials packaging and labelling, and shelf life.

**Letrozole** is utilized as a comparator treatment and is classified as a **nonsteroidal aromatase inhibitor**. This medication is administered as a **tablet** via the **oral route** with a maximum daily dose of **2.5 mg**. The maximum total dose is **6.39 grams** over a treatment period of up to 84 months. The product undergoes secondary repackaging and relabelling for use in clinical trials.

**Exemestane** serves as a comparator treatment and belongs to the class of **aromatase inhibitors**. The medication is administered as a tablet via the oral route with a maximum daily dose of **25 mg**. The maximum total dose is **63.9 grams** over a maximum treatment period of 84 months. The product undergoes secondary repackaging and relabelling for use in clinical trials.

**Tamoxifen citrate** (marketed as Nolvadex 20 mg film-coated tablets) functions as a comparator treatment and is classified as an **antiestrogen**. The product is administered orally as a film-coated tablet with a maximum daily dose of **20 mg**. The maximum total dose is **51.1 grams** over a maximum treatment period of 84 months. The bulk authorized product is primary packed and labelled for clinical trial use.

**Goserelin** is employed as an auxiliary medication and is described as a **synthetic analogue of naturally occurring LHRH**. The product is supplied as an **implant in pre-filled syringe** and is administered via the **subcutaneous route**. The maximum daily dose is **0.12 mg** with a maximum total dose of **10.8 mg** over a treatment period of up to 36 months.

**Triptorelin** serves as an auxiliary treatment and is supplied as a **powder and solvent for prolonged-release suspension for injection**. The medication is administered via the **intramuscular route** with a maximum daily dose of **0.12 mg**. The maximum total dose is **11.5 mg** over a maximum treatment period of 60 months.

**Leuprorelin acetate** functions as an auxiliary medication and is supplied as a powder and solvent for prolonged-release suspension for injection. The product is administered via the intramuscular route with a maximum daily dose of **0.25 mg**. The maximum total dose is **22.5 mg** over a treatment period of up to 36 months.

The primary efficacy endpoint is **invasive breast cancer free-survival** (IBCFS) as defined by STEEP 2.0 criteria. Secondary efficacy endpoints include **invasive disease-free survival** (IDFS) as defined by STEEP 2.0 criteria, **distant relapse-free survival** (DRFS) as defined by STEEP 2.0 criteria, and **overall survival** (OS). Additional secondary endpoints encompass safety assessments, including **treatment-emergent adverse events** (TEAEs), **serious adverse events** (SAEs), clinical laboratory tests, and vital signs. Clinical outcome assessments will evaluate the proportion of time on study treatment with high side-effect burden as measured by the PGI-TT, as well as change from baseline and **time to deterioration** (TTD) of health-related **quality of life** (QoL) as measured by the 2 global QoL items from the EORTC QLQ-C30. Pharmacokinetic assessments will include plasma concentrations of camizestrant pre-dose (**trough concentration**, Ctrough).