A Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Giredestrant Plus Palbociclib Compared With Anastrozole Plus Palbociclib for Postmenopausal Women With Estrogen Receptor-Positive and HER2-Negative Untreated Early Breast Cancer (coopERA Breast Cancer)

A Randomized, Multicenter, Open-Label, Two-Arm, Phase II, Neoadjuvant Study Evaluating the Efficacy, Safety, and Pharmacokinetics of GDC-9545 Plus Palbociclib Compared With Anastrozole Plus Palbociclib for Postmenopausal Women With Estrogen Receptor-Positive and HER2-Negative Untreated Early Breast Cancer

This is a randomized, multicenter, open-label, two-arm, Phase II study to evaluate the efficacy, safety, and pharmacokinetics of giredestrant versus anastrozole (in the window-of-opportunity phase) and giredestrant plus palbociclib compared with anastrozole plus palbociclib (in the neoadjuvant phase) in postmenopausal women with untreated, estrogen receptor (ER)-positive, human epidermal growth factor receptor-2 (HER2)-negative, early breast cancer.

The study consists of a screening period of up to 28 days, a window-of-opportunity phase for 14 days, followed by a neoadjuvant treatment phase for 16 weeks (four 28-day cycles), surgery, and an end of study visit (28 days after the final dose of study treatment).

Inclusion Criteria:

• Postmenopausal women age ≥18 years
• Histologically confirmed operable or inoperable invasive breast carcinoma
• Candidate for neoadjuvant treatment and considered appropriate for endocrine therapy
• Willingness to undergo breast surgery after neoadjuvant treatment and to provide three mandatory tumor samples
• Documented estrogen receptor (ER)-positive tumor in accordance to American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines (Allison et al.2020), assessed locally and defined as ≥1% of tumor cells stained positive on the basis of the most recent tumor biopsy
• Documented progesterone receptor status (positive or negative) as per local assessment
• Documented human epidermal growth factor receptor-2 (HER2)-negative tumor in accordance to 2018 ASCO/CAP guidelines (Wolff et al. 2018), assessed locally on the most recent tumor biopsy
• Ki67 score ≥5% analyzed centrally or locally
• Eastern Cooperative Oncology Group Performance Status 0-1
• Adequate organ function

Exclusion Criteria:

• Stage IV (metastatic) breast cancer
• Inflammatory breast cancer (cT4d)
• Bilateral invasive breast cancer
• History of invasive breast cancer, ductal carcinoma in situ or lobular carcinoma in situ and other malignancy within 5 years prior to screening
• Previous systemic or local treatment for the primary breast cancer currently under investigation
• History of any prior treatment with aromatase inhibitors (AIs), tamoxifen, selective estrogen receptor down regulator, or cyclin-dependent kinase 4 and 6 inhibitors
• Major surgery within 4 weeks prior to randomization
• Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, including hepatitis
• Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study
• History of allergy to anastrozole, or palbociclib or any of its excipients
• Known issues with swallowing oral medication
• History of documented hemorrhagic diathesis, coagulopathy, or thromboembolism
• Active cardiac disease or history of cardiac dysfunction
• Current treatment with medications that are well known to prolong the QT interval
• Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or major upper gastrointestinal surgery including gastric resection
• Treatment with strong CYP3A4 inhibitors or inducers within 14 days or 5 drug elimination half-lives prior to randomization
• Known HIV infection
• Serious infection requiring oral or IV antibiotics, or other clinically significant infection within 14 days prior to screening
• Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study