Neoadjuvant Palbociclib Plus Endocrine Therapy Does Not Improve PEPI Scores in Resectable HR+ Breast Cancer

The addition of palbociclib (Ibrance) to neoadjuvant endocrine therapy did not lead to a statistically significant improvement in preoperative endocrine prognostic index (PEPI) scores compared with endocrine therapy plus placebo in patients with operable, hormone receptor (HR)–positive, HER2-negative breast cancer, according to data from a phase 3 trial (NCT03969121).1

Findings published in Endocrine-Related Cancer showed that in the palbociclib arm (n = 66), 15.2% of patients had low PEPI scores, 50.0% had moderate scores, and 34.8% had scores. Conversely, the respective rates of patients with low, moderate, or high PEPI scores in the placebo arm were 13.3%, 55.0%, and 31.7%, respectively (1-sided P = .563).

Since the difference in PEPI scores was not statistically significant, investigators did not perform a statistical analysis for EndoPredict risk scores. In the palbociclib arm, the rates of patients with low and high EndoPredict scores were 37.9% and 62.1%, respectively. These respective rates were 31.7% and 68.3% in the placebo arm.

“In addition, the combination of palbociclib with neoadjuvant endocrine treatment did not show additional significant therapeutic effects to placebo with endocrine therapy in secondary end points including clinical response rate, reduction in Ki-67 level, pCR, and breast-conserving rate,” lead study author Takayuki Ueno, MD, PhD, of the department of Breast Surgical Oncology at the Breast Oncology Center of Cancer Institute Hospital at the Japanese Foundation for Cancer Research in Tokyo, and colleagues wrote in a publication of the data.

What Was the Rationale for Exploring Neoadjuvant Palbociclib?

Palbociclib is currently approved by the FDA for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine-based therapy; or in combination with fulvestrant (Faslodex) in patients with who experienced disease progression following endocrine therapy.2 The CDK4/6 inhibitor is also approved in combination with inavolisib and fulvestrant for the treatment of adult patients with endocrine-resistant, PIK3CA-mutated, HR-positive, HER2-negative, locally advanced or metastatic breast cancer, as detected by an FDA-approved test, following recurrence on or after completing adjuvant endocrine therapy.

In the phase 3, multicenter, international, randomized, double-blind study, investigators enrolled pre-, peri-, or postmenopausal patients with operable HR-positive, HER2-negative breast cancer who had a tumor size of at least 15 mm, T1c-3 N0-1 disease, a Ki-67 labeling index of at least 14% per central assessment, and no previous radiotherapy or systemic therapy administered for breast cancer.1

Patients were randomly assigned 1:1 to receive endocrine therapy plus palbociclib at 125 mg per day in a 3-weeks-on/1-week-off schedule; or endocrine therapy plus placebo for 16 weeks. Postmenopausal patients in both arms received letrozole at 2.5 mg per day as endocrine therapy, and pre- and peri-menopausal patients were given tamoxifen at 20 mg per day plus ovarian function suppression with either leuprorelin or goserelin.

PEPI score based on relapse-free survival and EndoPredict score served as the trial’s primary end points. Secondary end points included clinical response rate, the proportion of patients with a reduction in Ki-67 levels of no more than 2.7%, pathological complete response (pCR) rate, breast-conserving rate, safety, and biomarkers.

A total of 141 patients were randomly assigned between the palbociclib arm (n = 72) and placebo arm (n = 69); 93.1% and 91.3% of patients completed treatment, respectively.

In the modified intention-to-treat population, the median age was 57 years (range, 38-84) in the palbociclib arm vs 54 years (range, 29-84) in the placebo arm. Most patients were postmenopausal (palbociclib arm, 56.1%; placebo arm, 58.3%), had T2 disease (86.4%; 93.3%), had N0 disease (77.3%; 75.0%), had stage IIA disease (63.6%; 68.3%), had histological grade 2 disease (74.2%; 60.0%), and had a KI-67 labeling index of at least 20% (83.3%; 83.3%).

Clinical Outcomes and Safety

Findings also showed that the clinical response rate was 55.6% in the palbociclib arm vs 44.9% in the placebo arm. Additionally, the breast-conserving rate was 57.4% in the palbociclib arm vs 67.2% in the placebo arm.

Regarding safety, adverse effects (AEs) led to treatment discontinuation in 9.7% of patients in the palbociclib arm vs no patients in the placebo arm.

The rates of any-grade treatment-emergent AEs (TEAEs) were 98.6% in the palbociclib arm (n = 72) and 95.7% in the placebo arm (n = 69). The most common TEAEs of any grade included neutropenia (palbociclib arm, 87.5%; placebo arm, 4.3%), leukopenia (69.4%; 1.4%), procedural pain (38.9%; 47.8%), stomatitis (33.3%; 8.7%), anemia (22.2%; 1.4%), and nausea (13.9%; 20.3%).

References

1. Ueno T, Chow LWC, Han W, et al. Neoadjuvant palbociclib in women with operable, hormone receptor-positive breast cancer. Endocr Relat Cancer. 2025;32(9):e240353. doi:10.1530/ERC-24-0353
2. Ibrance. Prescribing information. Pfizer. Updated April 2025. Accessed September 16, 2025. https://labeling.pfizer.com/ShowLabeling.aspx?id=2191