Evaluation of CDK4/6 Inhibitor Discontinuation in Metastatic HR+ HER2- Breast Cancer with Exemestane, Fulvestrant, Anastrozole, Letrozole, and Endocrine Therapy

The primary objective of this study is to evaluate the **long-term disease stabilization** following the discontinuation of CDK4/6 inhibitors in patients with metastatic HR positive, HER2 negative breast cancer who have achieved at least stable disease after a minimum of 12 months of combination treatment with continued endocrine therapy. This is clinically relevant as it aims to determine the potential for maintaining disease control without the continuous use of CDK4/6 inhibitors, which could reduce treatment burden and associated side effects for patients.

The clinical trial focuses on **metastatic HR positive, HER2 negative breast cancer** and involves a study population exclusively comprising female participants. The trial does not provide specific data on the total number of participants, as this information was not disclosed by the sponsor. Participants are required to be postmenopausal women aged 18 years or older, with a confirmed diagnosis of metastatic adenocarcinoma of the breast that is estrogen receptor positive and HER2 negative. The trial population was selected based on their prior treatment history, specifically those who have undergone at least 12 months of combination treatment with CDK4/6 inhibitors and endocrine therapy, achieving disease control as assessed by their treating physician. Participants must have a preserved performance status, with an ECOG score of 2 or less, and demonstrate adequate bone marrow, renal, and hepatic function. The study excludes male subjects and does not involve a vulnerable population. Lifestyle considerations such as diet and physical activity are not specified in the trial data provided.

The clinical trial is designed to evaluate the long-term disease stabilization following the discontinuation of **CDK4/6 inhibitors** in patients with metastatic HR positive, HER2 negative breast cancer who have achieved durable disease control. This is a randomized, low-intervention, phase II trial, which is open-label and non-comparative. The trial will involve the use of market-approved investigational medicinal products, including **palbociclib**, **ribociclib**, and **abemaciclib**, in combination with continued endocrine therapy such as **exemestane**, **fulvestrant**, **anastrozole**, and **letrozole**. The trial is expected to last until May 2028, with recruitment starting in November 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, menopausal status, and previous treatment history. The primary inclusion criteria require participants to have been treated with a **CDK4/6 inhibitor** plus endocrine therapy for at least 12 months with disease control. Follow-up visits will be scheduled to monitor progression-free survival, which is the primary endpoint, defined as the proportion of patients alive and without progression 12 months after randomization. The end-of-study visit will conclude the participant's involvement, assessing the overall outcomes and any adverse events.

The expected length of participant involvement is up to 12 months, with conditions for early termination including disease progression or withdrawal of consent. The trial's design ensures minimal risk to participants, as no additional diagnostic or monitoring procedures beyond normal clinical practice are performed. The trial's methodology emphasizes safety and efficacy, with a focus on maintaining disease stabilization after the discontinuation of **CDK4/6 inhibitors**.

The clinical trial involves the administration of several **experimental medications** and **non-experimental treatments** to evaluate their efficacy in patients with metastatic HR-positive, HER2-negative breast cancer. The primary experimental medication is **PALBOCICLIB**, a CDK4/6 inhibitor, provided in the form of a hard capsule. The maximum daily dose is 125 mg, with a total maximum dose of 31,500 mg over a 12-month period. The medication is administered orally, and participant compliance is monitored throughout the trial.

Another experimental medication used in the trial is **RIBOCICLIB**, also a CDK4/6 inhibitor, available as a film-coated tablet. The maximum daily dose is 600 mg, with a total maximum dose of 151,200 mg over the course of 12 months. This medication is administered orally, and adherence to the dosing schedule is closely monitored.

**ABEMACICLIB** is included as an additional CDK4/6 inhibitor in the study, provided in the form of a film-coated tablet. The maximum daily dose is 300 mg, with a total maximum dose of 109,500 mg over a 12-month period. The administration route is oral, and participant compliance is ensured through regular monitoring.

In addition to the CDK4/6 inhibitors, the trial includes **EXEMESTANE**, an endocrine therapy, administered as a film-coated tablet. The maximum daily dose is 25 mg, with a total maximum dose of 9,125 mg over 12 months. This medication is taken orally, and adherence is tracked throughout the study.

**FULVESTRANT** is another endocrine therapy used in the trial, provided as a solution for infusion in a pre-filled syringe. The maximum daily dose is 500 mg, with a total maximum dose of 6,500 mg over 12 months. The administration route is intramuscular, and compliance is monitored to ensure accurate dosing.

**ANASTROZOLE** is included as an endocrine therapy, available in the form of film-coated tablets. The maximum daily dose is 1 mg, with a total maximum dose of 365 mg over a 12-month period. This medication is administered orally, and participant adherence is regularly assessed.

Lastly, **LETROZOLE** is used as an endocrine therapy, provided in tablet form. The maximum daily dose is 2.5 mg, with a total maximum dose of 912.5 mg over 12 months. The administration route is oral, and compliance is monitored to ensure proper dosing throughout the trial.

Efficacy in this clinical trial will be assessed primarily through the measurement of **progression-free survival** (PFS) at 12 months post-randomization. This endpoint is defined as the proportion of patients who are alive and without disease progression, as determined by radiologic imaging assessments. The trial focuses on patients with metastatic hormone receptor-positive, HER2-negative breast cancer who have achieved at least stable disease after a minimum of 12 months of combination treatment with CDK4/6 inhibitors and endocrine therapy.

The trial is designed as a low-intervention, phase II study, where the investigational medicinal products are market-approved and used according to their marketing authorization. No additional diagnostic or monitoring procedures are implemented beyond standard clinical practice, ensuring minimal risk to participants. The trial aims to evaluate the long-term disease stabilization following the discontinuation of CDK4/6 inhibitors while continuing endocrine therapy. The efficacy assessments will be conducted in a randomized, open-label, multicenter setting, ensuring a comprehensive evaluation of the treatment strategy's impact on disease progression.