A Comparative Study of AZD9833 Plus Palbociclib Versus Anastrozole Plus Palbociclib in Patients With ER-Positive HER2 Negative Breast Cancer Who Have Not Received Any Systemic Treatment for Advanced Disease

SERENA-4: A Randomised, Multicentre, Double-Blind, Phase III Study of AZD9833 (an Oral SERD) Plus Palbociclib Versus Anastrozole Plus Palbociclib for the Treatment of Patients With Estrogen Receptor-Positive, HER2-Negative Advanced Breast Cancer Who Have Not Received Any Systemic Treatment for Advanced Disease

The study is intended to show superiority of AZD9833 in combination with palbociclib (a CDK4/6 inhibitor) versus anastrozole (an aromatase inhibitor) and palbociclib as the initial treatment of patients with hormone receptor-positive (ER-positive), human epidermal growth factor 2-negative (HER2-negative) advanced/metastatic breast cancer.

INFORMATION FOR TRIAL PARTICIPANTS

In this trial, the researchers will look at how well camizestrant with palbociclib works, compared with anastrozole with palbociclib, in participants with breast cancer that has either spread into other parts of the body at the time of diagnosis, or has come back after at least 2 years of standard endocrine treatment.

Participants in this trial will have breast cancer that has ER proteins but does not have overexpression of HER2 protein.

A Randomised, Multicentre, Double-Blind, Phase III study will evaluate the safety and efficacy of AZD9833 (next generation oral SERD) in combination with palbociclib versus anastrozole in combination with palbociclib for the treatment of patients with ER-positive breast cancer. The goal of the study is to demonstrate superiority of AZD9833 over anastrozole in the context of combination with palbociclib in first line setting.

INFORMATION FOR TRIAL PARTICIPANTS

Researchers are looking for a better way to treat breast cancer.

In people with cancer, some cells have grown out of control to form tumours.

The trial drugs palbociclib, camizestrant, and anastrozole are designed to work by blocking the cancer's ability to grow. Camizestrant is also called AZD9833. Palbociclib and anastrozole are already available as treatments for people with certain type of breast cancer.

In this trial, the researchers want to find out how well taking camizestrant with palbociclib, or anastrozole with palbociclib, works in participants with breast cancer that has ER proteins but does not have overexpression of HER2 protein.

The researchers will look at which trial treatments help the participants live longer with cancer before it gets worse.

The trial will split participants into 2 groups:

• Participants in Group 1 will take camizestrant, palbociclib, and a placebo matched with anastrazole.
• Participants in Group 2 will take anastrozole, palbociclib, , and a placebo matched with camizestrant.

A placebo looks like a treatment but does not have any medicine in it.

A computer program will be used to randomly choose the treatments each participant gets. This helps make sure the groups are chosen fairly. Researchers do this so that comparing the results of each treatment will be as accurate as possible.

The participants will take their trial treatments in periods called "cycles". Each cycle will last 28 days. During each cycle, the participants will take:

• camizestrant or anastrozole once daily by mouth
• palbociclib once daily by mouth for 21 days. Then, they will not take any palbociclib for 7 days

Some participants will also get either goserelin or leuprorelin once every month. Participants could get goserelin or leuprorelin if:

• They are medically determined yet to reach menopause status
• They are male

They will get this treatment as an injection under the skin or into a muscle. Goserelin and leuprorelin work by decreasing the amount of sex hormones made by the body which will lead to reduction of ER production. This can help stop breast cancer from growing.

Participants will take trial treatment until the cancer gets worse or they leave the trial.

Participants will visit their trial site several times throughout the trial. At these visits, the trial doctors will check the health of the participants. They will also take blood samples and do scans of the participants' tumors.

INCLUSION CRITERIA

Full list of inclusion criteria

• Pre-/peri-menopausal women or men can be enrolled if amenable to be treated with concomitant, approved LHRH agonists for the duration of the study treatment.
• De novo Stage 4 disease, or recurrence from early stage disease after at least 24 months of standard adjuvant endocrine therapy. Note that at least 12 months must have elapsed since the patient's last dose of adjuvant AI therapy without disease progression on treatment. Note that a 2-week washout period is required after the last dose of tamoxifen prior to randomisation.
• Histologically or cytologically documented diagnosis of ER+, HER2-negative breast cancer based on local laboratory results.
• Previously untreated with any systemic anti-cancer therapy for their locoregionally recurrent or metastatic ER+ disease.
• Measurable disease as defined per RECIST v.1.1 OR at least one lytic or mixed (lytic + sclerotic) bone lesion with a soft tissue component that can be assessed by CT or MRI.
• Eastern Cooperative Oncology Group performance status of 0 or 1.
• Adequate organ and marrow function.
• Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

INFORMATION FOR TRIAL PARTICIPANTS

Participants can join the trial if they:

• Have breast cancer that cannot be treated with surgery or radiation
• Have breast cancer that has already spread into other parts of the body at the time of diagnosis, or has come back after at least 2 years of a standard endocrine treatment
• Have ER proteins but not overexpression of HER2 protein in their tumors
• Have never received any type of cancer therapy that affects the whole body for advanced breast cancer
• Are able to do their daily activities

EXCLUSION CRITERIA

Full list of exclusion criteria

• Previous neoadjuvant or adjuvant treatment with an AI treatment +/- CDK4/6 inhibitor with disease recurrence while on or within 12 months of completing treatment.
• Prior exposure to AZD9833, other investigational SERDs/endocrine agents or fulvestrant.
• Participation in another clinical study with a study treatment or investigational medicinal device administered in the last 4 weeks prior to randomization or concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.
• Advanced, symptomatic, visceral spread, that are at risk of life-threatening complications in the short term and/or impending visceral crisis
• Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease.
• Any clinically important and symptomatic heart disease .
• Currently pregnant (confirmed with positive pregnancy test) or breast-feeding.
• As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, renal transplant and active bleeding diseases) which, in the investigator's opinion, makes it undesirable for the participant to participate in the study or that would jeopardize compliance with the protocol.
• Any concurrent anti-cancer treatment.
• Active infection including tuberculosis, HBV and HCV.

INFORMATION FOR TRIAL PARTICIPANTS

Participants cannot join the trial if they:

• Have uncontrolled cancer that has spread to the brain or the spinal cord
• Have received certain treatments for cancer in the past but the cancer came back within 1 year
• Had certain types of tumors in the past, which the study doctors think could come back
• Are currently taking any treatment for cancer or are taking medications or supplements that affect certain proteins in the body
• Have any major health problem, infection, or surgery that could make it difficult or dangerous to participate in this trial, such as tuberculosis, HIV, heart problems, or a kidney transplant

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.