PENELOPE-B Trial Shows Mixed Palbociclib Results in Breast Cancer Subtypes

Palbociclib with endocrine therapy improved invasive DFS in patients with lobular breast cancer in the phase 3 PENELOPE-B trial.

Palbociclib (Ibrance) did not show statistically significant survival improvements in patients with hormone receptor–positive, HER2-negative breast cancer with residual disease and high relapse risk after taxane-based neoadjuvant chemotherapy, according to data from the phase 3 PENELOPE-B trial (NCT01864746) published in Annals of Oncology.¹ The trial results also found, in exploratory analyses, a trend toward improved invasive disease-free survival (DFS) with palbociclib in patients with lobular breast cancer.

At a median follow-up of 77.8 months, the 6-year overall survival (OS) rate was 82.4% (95% CI, 78.8%-85.4%) with palbociclib vs 80.3% (95% CI, 76.6%-83.5%) with placebo (HR, 0.87; 95% CI, 0.67-1.14; P = .31). Deaths occurred in 17.1% (n = 108) of the palbociclib arm and 18.9% (n = 117) of the placebo arm.

The estimated 6-year invasive DFS rate was 65.1% (95% CI, 61.0%-69.0%) with palbociclib and 64.5% (95% CI, 60.3%-68.3%) with placebo (HR, 0.94; 95% CI, 0.78-1.142; P = .55); invasive DFS events occurred in 34.1% (n = 215) of the palbociclib arm and 35.1% (n = 217) of the placebo arm. The 6-year invasive breast cancer-free survival (BCFS) rate was 66.0% with palbociclib and 65.2% with placebo (HR, 0.94; 95% CI, 0.78-1.14; P = .58), and the 6-year distant DFS (DDFS) rate was 67.4% and 66.9%, respectively (HR, 0.93; 95% CI, 0.76-1.13; P = .48).

In patients with lobular breast cancer, those who received palbociclib experienced an estimated 6-year DFS rate of 73.5% compared with 51.1% in the placebo group (HR, 0.52; 95% CI, 0.28-0.97; P = .035); the estimated 6-year OS rates were 88.8% and 73.2%, respectively (HR, 0.45; 95% CI, 0.19-1.07; P = .062). The authors noted that low E-cadherin (CDH1) expression correlated with visible differences in effect between those who received palbociclib and those who received placebo with regard to OS (HR, 0.30; 95% CI, 0.07-1.25; P = .08) and invasive DFS (HR, 0.33; 95% CI, 0.09-1.17; P = .07).

“No notable survival improvement was observed with palbociclib over placebo in the overall population in the PENELOPE-B trial,” Sibylle Loibl, MD, PhD, chair of the German Breast Group, CEO of the German Breast Group Forschungs GmbH, an associate professor of obstetrics and gynecology at the University of Frankfurt, and lead study author, stated.¹ “However, patients with [lobular breast cancer], particularly those with reduced E-cadherin expression, may derive benefit from addition of 1-year palbociclib to standard care or [endocrine therapy] treatment.”

PENELOPE-B was a randomized, double-blind, placebo-controlled trial that enrolled a total of 1250 patients who were randomly assigned, in a 1:1 ratio, to receive either 125 mg of palbociclib or matching placebo from days 1 to 21 every 4 weeks for 13 cycles with endocrine therapy at the discretion of the investigator given for at least 5 years.

Eligible patients were 18 years or older and had histologically confirmed unilateral or bilateral primary invasive carcinoma of the breast, residual invasive disease post neoadjuvant therapy in the breast or as residual nodal invasion, and prior neoadjuvant chemotherapy for at least 16 weeks with at least 6 weeks on taxane-based chemotherapy.² Additional criteria included an ECOG performance status of 0 or 1 and a life expectancy of at least 5 years. Those with concurrent treatment with other experimental drugs, major surgery within 2 weeks of random assignment, and evidence of infection were excluded from participation.

The median age of patients was 49.0 years, 85.1% had an ECOG performance status of 0, 88.2% had ductal or ductal-lobular invasive histological tumor type, 44.9% had a clinical and pathologic stage/estrogen receptor and histologic grade score of 3, 89.4% started endocrine therapy prior to palbociclib or placebo, and 50.2% received an aromatase inhibitor with or without ovarian suppression.

The trial’s primary end point was invasive DFS. Previously, in October 2020, it was reported that the trial failed to meet that end point.³ Secondary end points included OS, invasive BCFS, DDFS, and loco-regional relapse-free interval.

References

1. Loibl S, Martin M, Bonnefoi H, et al. Final survival results from the Penelope-B trial investigating palbociclib vs placebo for patients with high-risk HR+/HER2- breast cancer and residual disease after neoadjuvant chemotherapy - PENELOPE-B. Ann Oncol. Published online March 24, 2025. doi:10.1016/j.annonc.2025.03.010
2. A study of palbociclib in addition to standard endocrine treatment in hormone receptor positive HER2 normal patients with residual disease after neoadjuvant chemotherapy and surgery (PENELOPE-B). ClinicalTrials.gov. Updated December 12, 2023. Accessed April 8, 2025. https://tinyurl.com/3ha9wabt
3. PENELOPE-B trial of IBRANCE (palbociclib) in early breast cancer did not meet primary endpoint. News release. Pfizer. October 9, 2020. Accessed April 8, 2025. https://tinyurl.com/5bf8a368