Palbociclib Plus First-Line Endocrine Maintenance Improves PFS in HR+, HER2+ Advanced Breast Cancer

The addition of the CDK4/6 inhibitor palbociclib (Ibrance) to first-line maintenance HER2-directed and endocrine therapy significantly improved progression-free survival (PFS) compared with standard therapy alone in patients with hormone receptor–positive, HER2-positive advanced breast cancer, according to findings from the phase 3 PATINA trial (NCT02947685) published in The New England Journal of Medicine.¹

At a median follow-up of 53.5 months, patients in the palbociclib arm (n = 261) achieved a median PFS of 44.3 months (95% CI, 32.4-56.8) compared with 29.1 months (95% CI, 23.3-38.6) among those who received HER2-targeted and endocrine therapies without palbociclib (n = 257). This translated to a 25% reduction in the risk of disease progression or death (HR, 0.75; 95% CI, 0.59-0.96; 2-sided P = .02).

“The achievement of PFS beyond 44 months with a regimen represents a meaningful clinical advance,” lead study author Otto Metzger, MD, and coauthors wrote in a discussion of the data. “Palbociclib in combination with anti-HER2 and endocrine therapy was an effective first-line strategy for patients with hormone receptor–positive, HER2-positive advanced breast cancer.”

Metzger is associate medical director of International Strategic Initiatives and a physician at Dana-Farber Cancer Institute, as well as an assistant professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

What was the rationale for investigating palbociclib in hormone receptor–positive, HER2-positive breast cancer?

Although dual anti-HER2 therapy plus chemotherapy followed by maintenance HER2-targeted and endocrine therapies is the standard frontline treatment for patients with hormone receptor–positive, HER2-positive metastatic breast cancer, crosstalk between the HER2 and estrogen receptor (ER) pathways can promote resistance. Preclinical data indicated that the Cyclin D1 and CDK4/6 axis drives tumor proliferation and resistance in HER2-positive disease.

Furthermore, early-phase clinical trials have demonstrated the safety, feasibility, and potential added efficacy of combining CDK4/6 inhibitors with HER2-targeted and endocrine therapies in patients with advanced hormone receptor–positive, HER2-positive breast cancer. For instance, primary results from the phase 2 TOUCH trial (NCT03644186) showed that the addition of palbociclib and letrozole to trastuzumab (Herceptin) and pertuzumab (Perjeta) elicited a pathologic complete response (CR) rate of 38.5% (95% CI, 20.2%-59.4%) vs 31.2% (95% CI, 16.1%-50.0%) with weekly paclitaxel plus trastuzumab and pertuzumab in patients with hormone receptor–positive, HER2-positive early breast cancer and RBsig-high expression (OR, 1.4; 95% CI, 0.5-4.1).²

The PATINA investigators hypothesized that adding palbociclib to the maintenance phase of treatment would provide longer disease control by simultaneously inhibiting HER2, the ER, and the cell cycle.¹

What was the design of the PATINA trial?

This international, open-label, randomized trial enrolled patients with hormone receptor–positive, HER2-positive advanced breast cancer who had completed 4 to 8 cycles of induction chemotherapy plus HER2-targeted therapy without evidence of disease progression. Induction therapy typically included trastuzumab and pertuzumab plus a taxane.

Eligible patients were randomly assigned 1:1 to receive maintenance treatment consisting of:

• HER2-directed therapy (trastuzumab with or without pertuzumab) plus endocrine therapy (an aromatase inhibitor or fulvestrant [Faslodex]) and palbociclib (at 125 mg daily for 21 days on and 7 days off), or
• Standard HER2-directed and endocrine therapies alone

Investigator-assessed PFS served as the primary end point. Secondary end points included overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), and safety.

What were the baseline characteristics of the patients enrolled in PATINA?

The trial enrolled 518 patients between June 2017 and July 2021. Patients had a median age of 53.4 years (range, 44.2-61.4), and 99.4% of patients were female. At the time of random assignment, 70.1% of patients had achieved a CR or partial response to induction therapy, and 29.3% of patients had stable disease. Dual HER2-directed therapy was used in 94.0% of patients, and 90.7% of patients received an aromatase inhibitor as their endocrine backbone.

What additional efficacy findings were seen in the PATINA trial?

The confirmed ORR (excluding patients who achieved a CR to induction) was 32.9% (95% CI, 26.9-39.4) in the palbociclib arm compared with 24.8% (95% CI, 19.3-30.0) in the standard-of-care (SOC) arm. The median duration of confirmed response was 44.9 months (95% CI, 27.1-51.6) with palbociclib vs 30.8 months (95% CI, 26.0-not evaluable) with SOC.

Additionally, the percentage of patients achieving clinical benefit was 88.9% (95% CI, 84.4%-92.4%) in the palbociclib arm vs 80.9% (95% CI, 75.6%-85.6%) in the control arm. OS data remain immature, with 123 deaths reported at the data cutoff (HR, 0.86; 95% CI, 0.61-1.23). The 6-month OS rate exceeded 99% in both groups.

What was the safety profile of the palbociclib-containing regimen in the PATINA trial?

The investigators noted that the safety profile of palbociclib plus HER2-directed therapy and endocrine therapy was consistent with the known toxicities of the individual agents. Grade 3 adverse effects (AEs) were reported more frequently in the palbociclib arm (79.7%) than in the SOC arm (30.6%). Grade 4 AEs occurred in 10.0% and 3.6% of patients, respectively.

The most common grade 3/4 AEs in the palbociclib arm included:

• Neutropenia (60.5%)
• Leukopenia (16.1%)
• Diarrhea (9.6%)
• Fatigue (5.0%)

Notably, febrile neutropenia was rare, occurring in only 2 patients in the palbociclib arm, despite the absence of growth factor support. Dose reductions of palbociclib were required in 57.7% of patients in the investigational arm, primarily due to neutropenia, and 18.0% of patients in this arm discontinued palbociclib due to AEs. No treatment-related deaths were reported in either group.

“Limitations of this trial include its open-label design and the limited racial diversity of the trial population,” the authors concluded. “We are compiling additional data regarding patient-reported outcomes, biomarker data, and outcomes related to the incidence of metastases in the central nervous system.”

References

1. Metzger O, Mandrekar S, Goel S, et al. Palbociclib for hormone-receptor-positive, HER2-positive advanced breast cancer. N Engl J Med. 2026;394(5):451-462. doi:10.1056/NEJMoa2511218
2. Malorni L, Tyekucheva S, Zamagni C, et al. Palbociclib plus letrozole versus weekly paclitaxel, both in combination w/ trastuzumab plus pertuzumab, as neoadjuvant treatment for patients w/ HR+/HER2+ early breast cancer: primary results from the randomized phase II TOUCH trial (IBCSG 55-17). Clin Cancer Res. 2025;31(suppl_12):RF1-02. doi:10.1158/1557-3265.SABCS24-RF1-02