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Palbociclib Improves Survival in Women with Hormone Receptor-Positive Metastatic Breast Cancer


Interim results from a randomized phase III clinical trial show that women with estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer that progressed during prior hormone therapy lived longer without their disease progressing if they received palbociclib (Ibrance®) plus fulvestrant (Faslodex®) than if they received a placebo plus fulvestrant.


New England Journal of Medicine, June 1, 2015 (See the journal abstract.)


A mainstay of treatment for ER-positive, HER2-negative early breast cancer is hormone therapy. Although this treatment reduces relapse rates, some women do relapse and subsequently their cancers are difficult to treat. One promising treatment may be to use drugs that target cyclin-dependent kinases (CDK4 and CDK6), which appear to promote tumor cell proliferation in hormone-receptor positive breast cancer.

Palbociclib is an oral agent that inhibits CDK4 and CDK6. This drug received accelerated approval from the Food and Drug Administration (FDA) to be used together with the hormone therapy letrozole (Femara®) as a first-line (initial) treatment for postmenopausal women with ER-positive, HER2-negative metastatic breast cancer, based on the improvement in progression-free survival seen in a trial called PALOMA1.

Fulvestrant, like letrozole, is a hormone therapy. However, the two work in different ways. Letrozole is an aromatase inhibitor, which stops production of estrogen in the ovaries and other tissues, whereas fulvestrant is an antiestrogen that binds to the estrogen receptor and leads to its destruction.

The PALOMA3 phase III trial was designed to test whether adding palbociclib to fulvestrant results in longer progression-free survival than fulvestrant alone in women with advanced ER-positive, HER2-negative breast cancer that had progressed during prior hormone therapy.  

The Study

More than 520 women with ER-positive, HER2-negative breast cancer that had relapsed or progressed during prior hormone therapy were enrolled in the PALOMA3 trial. These patients were recruited into the study from more than 140 sites in 17 countries. They were randomly assigned, in a two-to-one ratio, to receive palbociclib and fulvestrant (347 patients) or a placebo and fulvestrant (174 patients).  

The patients were permitted to have had one line of chemotherapy for metastatic disease before trial enrollment. Twenty percent of those enrolled in each arm of the trial were premenopausal or perimenopausal and received the drug goserelin to suppress ovarian function.

The trial’s primary endpoint was progression-free survival. The secondary endpoints included overall survival, objective response, rate of clinical benefit, patient-reported outcomes, and safety.

Nicolas Turner, M.D., Ph.D., of the Royal Marsden Hospital and Institute of Cancer Research in London, led the study, which was sponsored by Pfizer, the maker of palbociclib.


This paper reported a prespecified interim analysis. At the time of the analysis, the median progression-free survival for women in the palbociclib-plus-fulvestrant group was 9.2 months, compared with 3.8 months for women who received a placebo plus fulvestrant. An analysis by menopausal status showed that the addition of palbociclib to fulvestrant improved progression-free survival in both premenopausal/perimenopausal and postmenopausal women.

Rates of overall objective (measurable) response were 10.4 percent in the palbociclib group and 6.3 percent in the placebo group. The rate of clinical benefit (the response of prolonged stable disease) at the interim analysis was 34 percent in the palbociclib group and 19 percent in the placebo group.

Serious adverse events (any cause) occurred in 9.6 percent of the patients in the palbociclib group and 14.0 percent of the patients in the placebo group. Hematologic side effects were more frequent in the palbociclib group.

Treatment was discontinued due to adverse events in 2.6 percent of patients in the palbociclib group and 1.7 percent in the placebo group. The adverse events included disorders of the blood such as neutropenia, leukopenia, anemia, and thrombocytopenia, most of which were treatable. The adverse events reported in the PALOMA3 study were consistent with those identified in the PALOMA1 study.

Women who received palbociclib plus fulvestrant maintained their global quality of life, whereas quality of life declined in women who received a placebo plus fulvestrant.

At the time of this analysis, overall survival data were still immature.


“The data are based on a prespecified interim analysis that showed the study had met the primary endpoint of improved progression-free survival,” said Stan Lipkowitz, M.D., Ph.D., of NCI’s Center for Cancer Research. “However, the median follow up was short—5.6 months—and the overall survival data were not mature.

“An issue not addressed is the use of palbociclib with fulvestrant after it has already been given as a first-line treatment in combination with letrozole. Based on the PALOMA1 data, and the accelerated FDA approval, many patients will likely receive palbociclib and letrozole in the first-line setting. Such patients who received palbociclib and letrozole would not have met the entry criteria for the PALOMA3 study,” Dr. Lipkowitz added. “It will increasingly be the case that patients will have received palbociclib with letrozole as first-line therapy. Thus, this study does not provide guidance for whether patients who have had palbociclib and letrozole in the first-line will still benefit by adding palbociclib to fulvestrant in second-line treatment.”


“At present palbociclib is not approved as a second-line treatment with fulvestrant,” said Dr. Lipkowitz. “Fulvestrant is approved for second-line use alone. However, these data showing a two- to three-fold increase in progression-free survival are likely to lead many oncologists to use palbociclib plus fulvestrant as a second-line treatment of ER-positive, HER2-negative metastatic breast cancer in postmenopausal women. This will include patients who have gone through menopause or who have menopause induced by ovarian ablation.”

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