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Palbociclib Misses OS Endpoint in PALOMA-3 Breast Cancer Study

Silas Inman @silasinman
Published: Monday, Jun 25, 2018

Nicholas Turner, MD, PhD
Nicholas Turner, MD, PhD
The combination of palbociclib (Ibrance) and fulvestrant (Faslodex) failed to improve overall survival (OS) compared with fulvestrant and placebo in the phase III PALOMA-3 trial for patients with HR-positive, HER2-negative metastatic breast cancer who received prior endocrine therapy, according to Pfizer, the developer of the CDK4/6 inhibitor.

OS was a secondary endpoint for the PALOMA-3 trial. The primary endpoint of progression-free survival (PFS) was previously reported and led to FDA approval for palbociclib plus fulvestrant for pretreated women with HR+/HER2- metastatic breast cancer. In findings published in The Lancet Oncology,1 the median PFS was 9.5 months with palbociclib/fulvestrant compared with 4.6 months for fulvestrant alone (HR, 0.46; 95% CI, 0.36-0.59; P <.0001).

Pfizer did not release OS data but noted that a "trend" toward improvement in survival was experienced by patients treated with palbociclib. The company said that, as a secondary endpoint, the study was not "optimized" to detect a statistically significant difference in OS.

“While the difference in overall survival narrowly missed the threshold for statistical significance—a high bar for any trial in this patient population—it is similar, in absolute terms, to the improvement in median progression-free survival previously demonstrated in this trial," Mace Rothenberg, MD, chief development officer, Oncology, Pfizer Global Product Development, said in a statement. "We are encouraged by these results, which build on the compelling clinical benefit delivered by Ibrance.”

The double-blind PALOMA-3 study randomized 521 patients with metastatic breast cancer whose disease progressed on or following endocrine treatment in a 2:1 ratio to fulvestrant plus either palbociclib (n = 347) or placebo (n = 174). At the first initial interim analysis, which was published in the New England Journal of Medicine in 2015,2 19 patients had died in the palbociclib arm (5.5%) compared with 9 (5.2%) in the placebo group. OS data were not reported in The Lancet Oncology publication.

“The duration of the survival in hormone receptor-positive metastatic breast cancer patients, and the potential for subsequent therapies to confound overall survival outcomes, make demonstrating statistically significant improvement in overall survival extremely difficult,” principal investigator Nicholas Turner, MD, PhD, professor of molecular oncology at The Institute of Cancer Research, London, and consultant medical oncologist at The Royal Marsden NHS Foundation Trust, said in a statement.

Baseline patient characteristics were similar between the arms. The median age was 57 and 56 years in the palbociclib and placebo arms, respectively. Patients were stratified by menopausal status, sensitivity to prior hormonal therapy, and visceral metastases. In both treatment arms, 79% of patients were sensitive to previous endocrine treatment, 60% had visceral disease, and 79% were postmenopausal. In addition to prior endocrine therapy, 1 previous line of chemotherapy for advanced disease was permitted, of which 33% of patients in the overall population had received.

The overall response rate was 24.6% for the palbociclib arm compared with 10.9% for the placebo plus fulvestrant arm. The duration of response was 9.3 months versus 7.6 months, respectively.

Improvements in PFS were seen regardless of menopause status and remained consistent across all prespecified subgroups. In premenopausal perimenopausal patients, who also received goserelin with study treatments, the median PFS was 9.5 months with palbociclib compared with 5.6 months with placebo (HR, 0.50; 95% CI, 0.29-0.87). In postmenopausal patients, the median PFS was 9.9 vs 3.9 months, respectively (HR, 0.45; 95% CI, 0.34-0.59).

The most common all-grade adverse events (AEs) for the palbociclib versus the control arm, respectively, included neutropenia (81% vs 4%), leukopenia (50% vs 5%), infections (42% vs 30%), fatigue (39% vs 28%), nausea (32% vs 28%), anemia (28% vs 11%), headache (24% vs 19%), diarrhea (21% vs 19%), thrombocytopenia (22% vs 0%), constipation (19% vs 16%), and vomiting (17% vs 15%).

Neutropenia (65%) and leukopenia (28%) were the most common grade 3/4 AEs. Serious AEs were reported for 13% of patients in the palbociclib arm compared with 17% in the placebo group. Dose reduction related to AEs occurred in 34% of patients versus 2% with placebo. Discontinuations due to AEs were required for 4% and 2% of patients, respectively.

“The results from this overall survival analysis support the strong progression-free survival results from PALOMA-3 and, while not statistically significant, are encouraging for physicians and patients,” said Turner. “We look forward to presenting the detailed data at an upcoming medical meeting.”

The FDA initially granted palbociclib an accelerated approval in February 2015 as a frontline treatment for postmenopausal women with ER-positive, HER2-negative metastatic breast cancer. Pfizer has not yet release a scheduled date for presentation of the PALOMA-3 findings.


  1. Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016;17(4):425-439.
  2. Turner NC, Ro J, André F, Loi S, et al. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med. 2015;373(3):209-219.

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