Advancing Breast Cancer Care: The Role of Palbociclib in HR+/HER2- Disease

Breast cancer remains the most frequent cancer found in women all over the world, with most cases being hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2–). Over the past few years, cyclin-dependent kinase (CDK)4/6 inhibitors—agents that slow the cancer's growth and improve patient outcomes—have emerged as a pivotal therapeutic class in managing advanced HR+/HER2– breast cancer. Palbociclib (Ibrance; Pfizer), the first CDK4/6 to receive FDA approval, is now a main part of the treatment and is often used alongside endocrine treatments such as letrozole (Femara; Novartis) or fulvestrant (Faslodex; AstraZeneca).

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Palbociclib works by inhibiting CDK4 and CDK6, key regulators needed for cells to progress from the G1 to S phase. Dysregulation of this pathway is a hallmark for breast cancer proliferation, making CDK4/6 inhibition a common therapeutic strategy. When used in addition to endocrine therapy, palbociclib has often shown much better results in progression-free survival (PFS) than endocrine therapy alone. Clinical trials have found that using palbociclib with either letrozole or fulvestrant nearly doubles median PFS, offering a valuable tool in extending disease control for patients with metastatic disease.¹

Real-life data have reinforced palbociclib's efficacy beyond clinical trials. A large analysis of first-time use of palbociclib with fulvestrant showed results consistent with pivotal trials, confirming its benefit in a broader patient population that includes individuals often excluded from clinical studies, such as those with comorbidities or poorer performance status.² These findings highlight why it is important to use both trial and real-world data when making choices on treatment.

Research continues to explore new ways to enhance palbociclib-based regimens. A recent study looked at the combination of hydroxychloroquine with palbociclib and letrozole in HR+/HER2- metastatic breast cancer. Hydroxychloroquine, an autophagy inhibitor, was demonstrated to increase palbociclib activity by interfering with the survival processes of cancer cells. This method showed positive results in how well and safe it was, showing that mixing planned drugs with ones that change how tumors act could work well.³

Similarly, investigation combinations with novel agents are advancing in clinical development. For instance, inavolisib, a PI3Kα inhibitor, is being tested in combination with palbociclib and fulvestrant. The phase 3 INAVO120 trial (NCT04191499) reported that this 3-drug regimen hit a secondary goal of PFS improvement compared with placebo plus palbociclib and fulvestrant. These findings show the chance to optimize results through rationally designed combinations that target multiple oncogenic pathways simultaneously.⁴

Palbociclib has changed how health care professionals treat HR+/HER2– breast cancer, offering patients improved outcomes when used in combination with endocrine therapies. Ongoing research continues to define its role, particularly in novel combinations aimed at overcoming resistance and deepening clinical benefit. With pharmacists at the forefront of patient care, the continued integration of palbociclib into clinical practice represents both a therapeutic success and an opportunity to further enhance the quality of life for individuals living with advanced breast cancer.

REFERENCES

1. Gerlach A. Study Shows Real-World Outcomes of First-Line Palbociclib Plus Fulvestrant in HR+, HER2– Metastatic Breast Cancer. Pharmacy Times. Published January 18, 2025. Accessed August 20, 2025. https://www.pharmacytimes.com/view/study-shows-real-world-outcomes-of-first-line-palbociclib-plus-fulvestrant-in-hr-her2-metastatic-breast-cancer

2. Butts A. FDA Sheds Light on New Drug Approvals in Breast Cancer. Pharmacy Times. January 24, 2025. Accessed August 20, 2025. https://www.pharmacytimes.com/view/fda-sheds-light-on-new-drug-approvals-in-breast-cancer

3. Gerlach A. Hydroxychloroquine Enhances the Efficacy of Palbociclib, Letrozole Therapy in Patients With HR+, HER2– Metastatic Breast Cancer. Pharmacy Times. January 28, 2025. Accessed August 20, 2025. https://www.pharmacytimes.com/view/hydroxychloroquine-enhances-the-efficacy-of-palbociclib-letrozole-therapy-in-patients-with-hr-her2-metastatic-breast-cancer

4. Gerlach A. Inavolisib in Combination With Palbociclib and Fulvestrant Meets Secondary End Point in the INAVO120 Trial. Pharmacy Times. January 30, 2025. Accessed August 20, 2025. https://www.pharmacytimes.com/view/inavolisib-in-combination-with-palbociclib-and-fulvestrant-meets-secondary-end-point-in-the-inavo120-trial