PALOMA-3 Exploratory Analysis: Who Benefits Most From Palbociclib?

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The phase III PALOMA-3 trial significantly reduced the risk of disease progression by 50% in patients with hormone receptor–positive/HER2-negative advanced breast cancer, but the improvement in overall survival did not reach statistical significance.1 An exploratory subgroup analysis has now shown the survival benefit to be particularly encouraging in patients with no prior chemotherapy for advanced disease, especially those with endocrine-sensitive disease, Hope S. Rugo, MD, FASCO, reported at the European Organisation for Research and Treatment of Cancer (EORTC) 12th European Breast Cancer Conference, which was held virtually this year.2

“These analyses are exploratory, and the data must be interpreted with caution; however, our findings suggest that patients may derive greater clinical benefit from palbociclib plus fulvestrant if they are treated before chemotherapy for advanced breast cancer,” said Dr. Rugo, Professor of Medicine and Director of Breast Oncology and Clinical Trials Education at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center.

Hope S. Rugo, MD, FASCO

Hope S. Rugo, MD, FASCO

PALOMA-3 Background: Key Findings

PALOMA-3 randomly assigned 521 patients with hormone receptor–positive HER2-negative advanced breast cancer after disease progression 1:2 to endocrine treatment with fulvestrant at 500 mg plus placebo or fulvestrant plus 125 mg/d of the cyclin-­dependent kinase 4/6 (CDK4/6) inhibitor palbociclib every 3 weeks. The median follow-up was 44.8 months, with a 60% data maturity for overall survival.

The combination resulted in a statistically significant 6.6-month median improvement in progression-free survival, the primary endpoint, compared with placebo plus fulvestrant (11.2 vs 4.6 months; hazard ratio [HR] = 0.50: P < .000001). Overall survival, a secondary endpoint, improved by an absolute 6.9 months with the combination, but the difference did not reach the prespecified threshold for statistical significance. Median survival for the combination was 34.9 months vs 28.0 months (stratified HR = 0.81; one-sided P = .0429).

The bulk of the benefit was seen in the endocrine-sensitive subset, who experienced a 10-month improvement in survival with the addition of palbociclib (HR = 0.72; one-sided P = .0081). Patients with endocrine-insensitive disease had no benefit at all from the addition of palbociclib (HR = 1.14; P = .2969). Of importance to Dr. Rugo’s presentation, median overall survival was not improved at all with the addition of palbociclib among patients previously treated with chemotherapy for advanced disease (median, approximately 26 months in each) and among patients who were pre- or perimenopausal (median, 38 months).

“Subgroup analyses suggested the use of prior chemotherapy in advanced disease and pre/perimenopausal status may have impacted the survival benefit of palbociclib combined with fulvestrant,” Dr. Rugo said. “This post hoc analysis examined the efficacy and baseline characteristics of patients with and without prior chemotherapy for advanced disease and by menopausal status in the overall and endocrine-sensitive populations in PALOMA-3.”

Exploratory Analysis

In both the overall and endocrine-sensitive populations, palbociclib plus fulvestrant prolonged progression-free survival in all subgroups, regardless of whether they had received prior chemotherapy or not for advanced disease. However, regardless of the treatment arm, patients without prior chemotherapy remained progression-free longer than those who had received chemotherapy. Patients with endocrine-sensitive disease had slightly longer remission than the overall population, Dr. Rugo reported.

Receipt of prior chemotherapy, and also menopausal status, emerged as important in the exploratory analysis of overall survival. The proportion of patients having received prior chemotherapy for advanced disease was 34%; the previously untreated proportion was 66%.

Median overall survival was prolonged in previously untreated patients by 10.2 months, based on 39.7 months with the combination vs 29.5 months with fulvestrant alone (HR = 0.75; 95% confidence interval = 0.56–1.01). In contrast, patients who had prior chemotherapy for advanced disease had a detriment in overall survival of –0.6 months with the combination (HR = 0.91). Findings were similar in the endocrine-sensitive subset (Table 1).

The analysis also examined the impact of visceral disease and found an improvement in overall survival with palbociclib plus fulvestrant in all subsets: patients with visceral disease (HR = 0.85); those with nonvisceral disease without prior chemotherapy and up to two prior (nonchemotherapy) regimens (HR = 0.74); those with nonvisceral disease (HR = 0.69); and those with nonvisceral disease who had no prior chemotherapy and received no more than two prior (nonchemotherapy) regimens, reported Dr. Rugo. 

DISCLOSURE: PALOMA-3 was sponsored by Pfizer. Dr. Rugo has served as a consultant or advisor to Celtrion, Puma, and Samsung; has received institutional research funding from Daiichi Sankyo, Eisai, Genentech, Immunomedics, Lilly, ­MacroGenics, Merck, Novartis, OBI Pharma, Odonate Therapeutics, Pfizer, and Seattle Genetics; and has been reimbursed for travel, accommodations, or other expenses by AstraZeneca Spain, Daiichi Sankyo, MacroGenics, Mylan, Novartis, and Pfizer.


1. Turner NC, Slamon DJ, Ro J, et al: Overall survival with palbociclib and fulvestrant in advanced breast cancer. N Engl J Med 379:1926-1936, 2018.

2. Rugo H, Cristofanilli M, Loibl S, et al: Predictors of efficacy in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: Subgroup analyses of PALOMA-3. 2020 European Breast Cancer Conference. Abstract 9. Presented October 3, 2020.


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