A Study to Investigate the Efficacy and Safety of Letrozole SIE Compared With Femara® (Both Combined With the CDK4/6 Inhibitor Ribociclib) in Postmenopausal Women With HR-Positive, HER2-Negative, Inoperable Locally Advanced or Metastatic Breast Cancer

A Multicenter, Randomized, Double-Blind, Double-Dummy, Phase III Study to Evaluate the Efficacy and Safety of Letrozole SIE Compared to Femara® (Both in Combination With the CDK4/6 Inhibitor Ribociclib) in Postmenopausal Women With HR-Positive, HER2-Negative, Inoperable Locally Advanced or Metastatic Breast Cancer (SIE-3)

The purpose of this study is to evaluate the efficacy and safety of Letrozole SIE (injectable) compared to Femara® (oral tablet), both given together with ribociclib, for the first-line treatment of postmenopausal women with HR-positive, HER2-negative, inoperable locally advanced or metastatic breast cancer.

This is a multicenter, randomized, double-blind, double-dummy, active-controlled Phase III study comparing Letrozole SIE with Femara® (both in combination with the CDK4/6 inhibitor ribociclib) in postmenopausal women with HR-positive, HER2-negative, inoperable locally advanced or metastatic breast cancer. The study employs double-blinding with matching placebos (double-dummy technique) to minimize bias on the part of participants, investigators, and analysts. Participants will be randomized in a 1:1 ratio to receive either Letrozole SIE (experimental use) or Femara® (active comparator), both in combination with the CDK4/6 inhibitor ribociclib. Randomization occurs after Screening and confirmation of eligibility and will be stratified by visceral metastasis (Yes/No) and prior adjuvant endocrine therapy (Yes/No).

The Treatment Period will last from Cycle 1 Day 1 (C1D1) until study intervention discontinuation due to disease progression, symptomatic deterioration, unacceptable toxicity, withdrawal of consent, loss to follow-up, participant's death, or end of study, whichever occurs first. After study intervention discontinuation, a post-discontinuation visit will be performed. Then, participants will be followed until withdrawal of consent, loss to follow-up, the participant's death, or end of study, whichever occurs first.

Inclusion Criteria:

• Female participants with inoperable locally advanced or metastatic breast cancer.
• Confirmed diagnosis of HR-positive/HER2-negative breast cancer.
• Postmenopausal woman.
• Previously untreated with any systemic anticancer therapy for their locoregionally recurrent or metastatic HR-positive disease. Participants may have received cytotoxic chemotherapy within (neo) adjuvant previous treatment of breast cancer but must show progressive disease prior to enrollment.
• Have either measurable disease or non-measurable bone-only disease.
• ECOG performance status 0-2.
• Adequate organ and marrow function.
• Resolution of all acute toxic effects of prior anticancer therapy or surgical procedures to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 6.0 Grade ≤ 1 (except alopecia or other toxicities not considered a safety risk for the participant at the investigator's discretion).
• BMI ≥ 19 and ≤ 39 kg/m2.

Exclusion Criteria:

• Participants with advanced, symptomatic, visceral spread who are at risk of life-threatening complications in the short term.

• Participants with inflammatory breast cancer.

• Known uncontrolled or symptomatic central nervous system (CNS) metastases.

• Concurrent malignancy or malignancy within 3 years of randomization, with the exception of adequately treated basal or squamous cell carcinoma, non-melanomatous skin cancer, or curatively resected cervical cancer.

• Active cardiac disease or documented history of cardiac dysfunction.

• Uncontrolled hypertension.

• History of symptomatic vertebral fragility fracture or any fragility fracture of the hip, pelvis, wrist, or other location (defined as any fracture without a history of trauma or because of a fall from standing height or less, excluding fingers, toes, face and skull).

• Presence of medical conditions associated with low bone mass.

• History of ILD/pneumonitis.

• Other severe acute or chronic medical or psychiatric condition, including recent or active suicidal ideation/behavior, or laboratory or ECG abnormalities that may increase the risk associated with study participation or study intervention 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.

• Presence of detectable viral infection, including HBV, HCV, and HIV. Screening is not required for enrollment. Note: Participants who have been effectively treated and have a sustained virologic response are eligible for enrollment.

• Major surgery, chemotherapy, radiotherapy, any investigational agents, or other anticancer therapy within 14 days (2 weeks) before randomization. Participants who received prior radiotherapy to > 25% of bone marrow are not eligible independent of when it was received.

• Bisphosphonates or receptor activator of nuclear factor kappa-β ligand (RANKL) inhibitors initiated or have their dose changed within 14 days prior to randomization, i.e., participants should be on stable dose treatment for at least 14 days prior to randomization.

• Hormonal medications or medications or products known to affect serum LH, FSH (except spironolactone which is allowed if medically indicated), or estrogen/E2 levels within 3 months prior to randomization. This includes, but is not limited to, estrogen or progesterone hormone replacement therapy, oral contraceptives, androgens, LHRH analogs, prolactin inhibitors, or antiandrogens and other medications, herbal remedies, and/or supplements for the treatment of vasomotor hot flush symptoms administered via any route, including topical or intravaginal administration.

• Use of the following medications within the 3 previous days or a period of 5 half-lives, (whichever is longer) prior to randomization:

  1. Any medications or products including St. John's wort, known to be strong inducers of CYP3A.
  2. Any medications or products known to be strong inhibitors of CYP3A (e.g., grapefruit or grapefruit juice).
  3. Any medications known to be inducers of CYP2A6.
  4. Any medications known to be inhibitors of CYP2A6.

• Concurrently use of other anticancer therapy.