Palbociclib Prolongs Progression-Free Survival in Patients with Advanced Breast Cancer
Endocrine therapies are the basis of treatment for patients with hormone-receptor (HR)-positive breast cancers, but many women experience disease relapse during or after completing adjuvant therapy. The selective estrogen receptor degrader fulvestrant (Faslodex) has moderate activity in these patients, and a phase 2 clinical trial has shown that single-agent palbociclib (Ibrance), an inhibitor of cyclin-dependent 4 kinase (CDK4) and CDK6, induces responses in patients with HR-positive breast cancer.
A new double-blind, phase 3, randomized clinical trial investigated the efficacy of fulvestrant plus palbociclib in patients with HR-positive, HER2-negative advanced breast cancer that had relapsed or progressed during endocrine therapy (Turner NC, et al. N Engl J Med. 2015;373:209-219).
The study included 521 patients from 144 centers in 17 countries who were randomly assigned to receive palbociclib (125 mg daily orally for 3 weeks, followed by 1 week off) and fulvestrant (500 mg intramuscularly per standard of care every 14 days for the first 3 injections and then every 28 days) or placebo and fulvestrant.
The primary end point was investigator-assigned progression-free survival (PFS), and the secondary end points were overall survival, objective response rate, patient-reported outcomes, and safety.
The median PFS was 9.2 months (95% confidence interval [CI], 7.5 to not estimable) with the combination of palbociclib plus fulvestrant compared with 3.8 months (95% CI, 3.5-5.5) with fulvestrant plus placebo, a significant difference (hazard ratio for disease progression or death, 0.42; 95% CI, 0.32-0.56; P <.001).
The most common grade 3 or 4 adverse events in the combination therapy were neutropenia, leukopenia, anemia, thrombocytopenia, and fatigue. The rate of discontinuation because of adverse events was 2.6% with palbociclib and 1.7% in the fulvestrant-alone group.
Among patients with HR-positive metastatic breast cancer who had progression of disease during endocrine therapy, the addition of palbociclib to fulvestrant resulted in significantly longer PFS than fulvestrant alone, regardless of menopausal status. Quality of life was generally maintained with the addition of palbociclib but declined significantly in the fulvestrant-alone group.
Patients receiving palbociclib also had a significant improvement in emotional functioning compared with patients receiving fulvestrant alone.
These results suggest that “targeting CDK4 and CDK6 may represent a therapeutic strategy across diverse mechanisms of acquired resistance to endocrine therapy, including activation of receptor tyrosine kinase signaling,” upregulation of mTOR signaling, and mutation of ESR1, the investigators concluded.