A study to learn how well patients with a specific type of early breast cancer (estrogen receptor-positive, HER2-negative) tolerate and stay on treatment with giredestrant and how they feel during treatment

1. Why is this study needed?

Early breast cancer is a cancer that forms in the cells of the breast but has not spread to other body parts. It comes in different types depending on the features of the cancer cells, such as whether they have receptors for the hormone estrogen (ER-positive) or lack a protein called human epidermal growth factor receptor 2 (HER2-negative). ER-positive cancer is influenced by estrogen hormones. In the cells of this type of cancer, there are proteins called estrogen receptors (ER) that interact with the hormone estrogen. When estrogen binds to these receptors, it can signal the cancer cells to grow. ER-positive breast cancer is often treated with hormone-blockers (also called endocrine therapy). Sometimes, people find it too hard to stay on their endocrine therapy due to unwanted effects, which is why new treatments are being studied.

This study is testing a medicine called giredestrant, which is designed to block estrogen from binding to the estrogen receptor, triggering its breakdown (known as degradation) and stopping or slowing down the growth of cancer cells. It is being developed to treat ER-positive, HER2-negative early breast cancer.

Giredestrant is an experimental medicine. This means health authorities (like the U.S. Food and Drug Administration and European Medicines Agency) have not approved giredestrant for the treatment of ER-positive, HER2-negative early breast cancer.

This study aims to test how well participants can stick to taking giredestrant daily, assess how safe it is, and understand how the treatment might affect the satisfaction and happiness one feels in their day-to-day life (quality of life).

2. Who can take part in the study?

People (males and females) who are 18 years or older with early-stage breast cancer can take part in the study if their cancer is ER-positive and HER2-negative. Participants must have already had surgery to completely remove their breast tumour and nearby lymph nodes.

People may not be able to take part in this study if their breast cancer has spread to other parts of the body. People with certain health conditions like liver or heart disease, a history of certain other cancers within the past 3 years, or who are not able to swallow pills will also be excluded. People who are pregnant, planning to become pregnant, or currently breastfeeding cannot take part in the study.

3. How does this study work?

People will be screened to check if they are able to participate in the study. The screening period will take place from 4 weeks before the start of treatment.

There are two groups in this study, depending on the participant's recent cancer care:

• Group A will include participants who are starting endocrine therapy for the first time.
• Group B will include participants who have already completed additional treatment (abemaciclib or ribociclib, along with endocrine therapy) and who are now changing their treatment to take only giredestrant.

Everyone who joins this study will be given giredestrant as a capsule (to be swallowed) every day for up to 5 years. This is an open-label study. This means everyone involved, including the participant and the study doctor, will know the study treatment the participant has been given. Female participants (who have not yet gone through menopause) and men will receive a type of medicine called a luteinizing hormone–releasing hormone (LHRH) agonist together with the study medicine.

During this study, the study doctor will see participants once a month for the first 3 months, then every 3 months for the rest of the first year, and every 6 months after that, until treatment ends. They will check the participants' overall health, and any unwanted effects they may have. Participants will have follow-up visits every 6 months after completing the study treatment, during which the study doctor will check on the participant’s well-being. Total time of participation in the study will be up to about 5 years. Participants have the right to stop study treatment and leave the study at any time, if they wish to do so.

4. What are the main results measured in this study?

The main results measured in the study are the percentage of participants who stop taking giredestrant for any reason, such as unwanted effects or the return of their disease.

Other key results measured in the study include:

• The number and severity of unwanted effects
• How well participants stick to their treatment plan over time
• Changes over time in specific symptoms, such as joint pain, hot flashes, vaginal dryness, sexual health, and general pain
• How much participants are bothered by any unwanted effects from the treatment
• The number of participants whose discomfort from unwanted effects improves over time
• How the treatment affects the participants’ physical and mental functioning, daily life, and overall quality of life at different times during the study

5. Are there any risks or benefits in taking part in this study?

Taking part in the study may or may not make participants feel better. But the information collected in the study can help other people with similar health conditions in the future.

It may not be fully known at the time of the study how safe and how well the study treatment works. The study involves some risks to the participant. But these risks are generally not greater than those related to routine medical care or the natural progression of the health condition. People interested in taking part will be informed about the risks and benefits, as well as any additional procedures or tests they may need to undergo. All details of the study will be described in an informed consent document. This includes information about possible effects and other options of treatment.

Risks associated with the study drug
Participants may have unwanted effects of the giredestrant used in this study. These unwanted effects can be mild to severe, even life-threatening, and vary from person to person. During this study, participants will have regular check-ups to see if there are any unwanted effects.

Giredestrant: Participants will be told about the known unwanted effects of giredestrant, and possible unwanted effects based on human and laboratory studies or knowledge of similar medicines. Known unwanted effects include a slow heartbeat (bradycardia), abnormal liver tests (possible liver damage), loose, watery, and more frequent stools, wanting to throw up, throwing up, muscle, bone or joint pain, feeling tired or weak, sudden feeling of warmth and sweating, the feeling of spinning, being unsteady, and losing balance, headache, and an infection in any part of the urinary tract.

Since giredestrant will be given as a capsule (to be swallowed), participants will be told about any known unwanted effects of swallowing capsules.

The study medicine may be harmful to an unborn baby. Women and men must take precautions to avoid exposing an unborn baby to the study treatment.