What is the role of Palbociclib (Ibrance), Ribociclib (Kisqali), and Abemaciclib (Verzenio) in the treatment of Breast Cancer (BCBM)?

From the Guidelines

CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, are the standard-of-care for ER-positive, HER2-negative metastatic breast cancer (MBC) when combined with endocrine therapy (ET), due to their improved progression-free survival (PFS) and overall survival (OS) as well as a favorable toxicity profile, as seen in several trials 1. The use of CDK4/6 inhibitors in combination with ET has been shown to be effective in de novo or recurrent MBC, in cases of primary or secondary endocrine resistance, in postmenopausal or premenopausal women, and in men 1. Key points to consider when using CDK4/6 inhibitors include:

• The combination of a CDK4/6 inhibitor with an aromatase inhibitor (AI) is advised for patients who did not relapse on an AI, or within 12 months of stopping adjuvant AI 1.
• For patients who relapsed on adjuvant AI therapy, or within 12 months of stopping adjuvant AI, a CDK4/6 inhibitor in combination with fulvestrant is recommended 1.
• Although there have been no head-to-head comparisons of the three approved CDK4/6 inhibitors, the efficacy of the three drugs in the metastatic setting appears similar, with abemaciclib demonstrating limited single-agent efficacy 1.
• The toxicity profiles of these three drugs are slightly different, and patients who develop severe toxicity characteristic of one CDK4/6 inhibitor may switch to a different CDK4/6 inhibitor 1. Other studies have also demonstrated the efficacy of CDK4/6 inhibitors in combination with ET, including a phase III study of palbociclib in combination with letrozole, which showed an improvement in PFS and objective response rate compared to letrozole alone 1. Similarly, a phase III study of ribociclib in combination with letrozole also showed an improvement in PFS and objective response rate compared to letrozole alone 1. The NCCN guidelines also recommend the use of CDK4/6 inhibitors in combination with ET as a first-line option for postmenopausal women and premenopausal women with ovarian ablation/suppression with HR-positive, HER2-negative recurrent/stage IV breast cancer 1.

From the FDA Drug Label

1.1 Early Breast Cancer VERZENIO® (abemaciclib) is indicated: in combination with endocrine therapy (tamoxifen or an aromatase inhibitor) for the adjuvant treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive, early breast cancer at high risk of recurrence

1. 2 Advanced or Metastatic Breast Cancer VERZENIO (abemaciclib) is indicated: in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer

What is IBRANCE IBRANCE is a prescription medicine used in adults to treat hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer that has spread to other parts of the body (metastatic) in combination with:

• an aromatase inhibitor as the first hormonal based therapy, or

• fulvestrant in people with disease progression following hormonal therapy

The role of Palbociclib (Ibrance), Ribociclib (Kisqali), and Abemaciclib (Verzenio) in the treatment of Breast Cancer is to:

• Treat hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor or fulvestrant.
• Treat early breast cancer in combination with endocrine therapy (tamoxifen or an aromatase inhibitor) for the adjuvant treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive, early breast cancer at high risk of recurrence. Key points:
• Abemaciclib (Verzenio) is used in combination with endocrine therapy for the adjuvant treatment of early breast cancer and in combination with an aromatase inhibitor or fulvestrant for the treatment of advanced or metastatic breast cancer.
• Palbociclib (Ibrance) is used in combination with an aromatase inhibitor or fulvestrant for the treatment of advanced or metastatic breast cancer.
• Ribociclib (Kisqali) is not mentioned in the provided drug labels, but it is also a CDK4/6 inhibitor used in the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer. 2, 2, 3

From the Research

Role of Palbociclib, Ribociclib, and Abemaciclib in Breast Cancer Treatment

• Palbociclib, ribociclib, and abemaciclib are CDK4/6 inhibitors used in combination with endocrine therapy for the treatment of hormone receptor-positive (HR+), HER2-negative advanced breast cancer 4.
• These agents have been shown to increase response rates and prolong disease control, with a 40-45% improvement in progression-free survival seen when added to non-steroidal aromatase inhibitors in first-line therapy for post-menopausal women 4.
• The primary outcome of overall survival (OS) was similar for palbociclib + fulvestrant versus ribociclib + fulvestrant and abemaciclib + fulvestrant, suggesting similar efficacy between treatments 5.

Indications and Efficacy

• Palbociclib is indicated for the treatment of women with HR+, HER2-negative advanced or metastatic breast cancer, in combination with an aromatase inhibitor as initial endocrine-based therapy, and in combination with fulvestrant in those previously treated with endocrine therapy 6.
• Ribociclib is FDA-approved in combination with letrozole for the treatment of postmenopausal women with HR+, HER2-negative recurrent or metastatic breast cancer, and in combination with fulvestrant for initial- and subsequent-line endocrine therapy for postmenopausal women with metastatic HR+, HER2-negative breast cancer 7.
• Abemaciclib is also indicated as monotherapy in women with disease progression after endocrine therapy and prior chemotherapy 8.

Safety and Toxicity

• Neutropenia is a dose-limiting adverse effect of palbociclib and ribociclib, while fatigue is more common with use of palbociclib and abemaciclib, and gastrointestinal effects are more common with abemaciclib use 8.
• Ribociclib has a higher incidence of liver function test abnormalities than other CDK4/6 inhibitors and can cause QTc prolongation, and therefore may be prudently avoided in patients with cardiac morbidities or other risk factors for QTc prolongation 7.