A study to compare the effects of giredestrant with the standard of care endocrine therapy given as follow-up treatment after surgery in people with estrogen receptor-positive, HER2- negative early breast cancer.

1. Why is this study needed?

Early breast cancer is a type of cancer that forms in the cells of the breast but has not spread to other parts of the body. Estrogen receptor (ER)-positive, HER2-negative breast cancer is a type of cancer that is influenced by estrogen hormones. It is the most common type of breast cancer. The cells of this cancer do not have high levels of the HER2 protein, which is responsible for cell growth. However, these cancer cells have proteins called "estrogen receptors" that bind to estrogen hormones. When estrogens bind to these receptors, they can signal the cancer cells to grow. ER-positive breast cancer is often treated with hormone-blockers. Sometimes, when treatments stop working, the cancer can come back, or they cause symptoms that make taking certain treatments difficult. There is still a need for safe, effective treatment options after surgery, to help prevent the cancer from returning.
This study is testing a drug called giredestrant. Giredestrant is being developed to treat ER-positive HER2- negative early breast cancer. Giredestrant is an experimental drug. This means health authorities (like the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) have not approved giredestrant for the treatment of ER-positive, HER2-negative early breast cancer. This study compares how well giredestrant works and how safe it is versus the standard of care endocrine therapy (accepted standard treatment, that blocks cancer cells from using the body's natural hormones to grow), given after surgery (adjuvant treatment), in people with ER-positive, HER2-negative early breast cancer.

2. Who can take part in the study?

People (females and males) of 18 years of age and older, with early ER-positive breast cancer, can take part in the study if their breast cancer is also “HER2-negative” (which means it does not have extra proteins called “HER2-receptors”).
People may not be able to take part in this study, if their cancer has spread to other parts of the body. They will also be excluded, if they have certain health conditions like liver or heart disease, a history of other cancers in the past 3 years, or if they are not able to swallow pills. People who are pregnant, planning to become pregnant, or currently breastfeeding also cannot take part in the study.

3. How does this study work?

People will be screened to see if they are able to participate in the study. The screening period will take place within 28 days before participants are placed into a treatment group.
Everyone who joins this study will be randomly assigned to one of 2 groups (like flipping a coin):

• Giredestrant, given as a pill every day, for 5 years OR
• Standard of care endocrine therapy (i.e., tamoxifen, anastrozole, letrozole, or exemestane), given every day for 5 years

Participants will have an equal chance of being placed in either treatment group. After completing 5 years of study treatment in either treatment group, the study doctor may continue standard of care endocrine therapy if they think it is necessary.
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. Female participants who have not yet gone through menopause and men taking tamoxifen as their standard of care endocrine therapy will receive an LHRH agonist if the study doctor thinks it is necessary. This is an open-label study, which means the participant and the study doctor will know the study treatment the participant has been given. 
During this study, the study doctor will see participants every month for the first 3 months, and then every 3 months after that during the first 5 years. After that, the study doctor will see the participants every 6 months. They will see how well the treatment is working and any new things you might notice or feel. Participants will have a follow-up visit about 1 month after completing the study treatment. After that, they will continue to have follow-up visits or receive follow-up telephone calls from the study doctor every 6 months, during which the study doctor will check the participants’ well-being and see if the disease comes back. The total time of participation in the study will be about 10 years. Participants have the right to stop the study treatment and leave the study at any time.

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

The main results measured in the study are to assess if the drug has worked from the time when a participant is assigned to a study treatment to when the cancer returns or spreads to another part of the body. Other results measured in the study include:

• How long participants live
• The time between when a participant is assigned to a study treatment and when the cancer first comes back in the same area where it started or close by
• The time between when a participant is assigned to a study treatment and when the cancer first comes back in a different part of the body (far from where it started)
• Changes in the participant’s physical and mental health (self-reported) over time
• The number, intensity, and seriousness of unwanted effects

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. However, the information collected in the study may 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. These risks are not considered greater than those related to the standard of care or the natural progression of the disease. People interested in taking part will be informed about the risks and the benefits, as well as any additional procedures or tests they may need to have done. All details of the study will be described in an informed consent document, including any known information about possible effects and other options for treatment.

Risks associated with the study drug
Participants may have unwanted effects of the drug 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.
Participants will be told about the known unwanted effects of giredestrant, tamoxifen, anastrozole, letrozole, and exemestane and possible unwanted effects based on human and laboratory studies or knowledge of similar medicines.
Known unwanted effects of giredestrant include muscle or bone pain, pain in joints, tiredness, wanting to throw up, sudden feeling of heat or warmth, pain or discomfort in the head, slow heartbeat, throwing up, loose, watery [and more frequent] stools, abnormal liver test results indicating possible liver damage, an infection in any part of the urinary tract, and the feeling of spinning, being unsteady, and losing balance. Known unwanted effects of tamoxifen include vaginal dryness and bleeding, tiredness, rash, sudden feeling of warmth in the upper body, wanting to throw up, changes in liver test results, indicating possible liver injury. Known unwanted effects of anastrozole include headache, sudden feeling of heat or warmth, wanting to throw up, rash, pain in joints, bone pain, and a persistent feeling of sadness. Known unwanted effects of letrozole include high blood cholesterol levels, sudden feeling of heat or warmth, increased sweating, pain in joints, and feeling tired. Known unwanted effects of exemestane include low levels of white blood cells that may increase the risk of infection, headache, dizziness, sudden feeling of heat or warmth, belly pain, and wanting to throw up.
The study drugs may be harmful to an unborn baby. Both women and men must take precautions to avoid exposing an unborn baby to the study treatment.