Extended Follow-up of PALOMA-3 Supports Survival Benefit of Palbociclib Plus Fulvestrant in Advanced Breast Cancer

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An updated analysis of the PALOMA-3 randomized, placebo-controlled trial demonstrated continued superiority for the combination of palbociclib (CDK4/6 inhibitor) plus fulvestrant over fulvestrant plus placebo in women with hormone receptor–positive, HER2-negative advanced breast cancer whose disease progressed on prior endocrine therapy.1

At a median follow-up of 73.3 months, updated median overall survival for the palbociclib/fulvestrant combination was 34.8 months vs 28 months for the fulvestrant/placebo arm (P = .0221), representing a 19% improvement with the combination. An earlier analysis of overall survival, published after a median follow-up of 44.8 months, showed a median overall survival of 34.9 months with the combination therapy vs 28 months with fulvestrant plus placebo (P = .0429), a 19% difference favoring the combination.2

“Overall, the study clearly demonstrated that the combination of palbociclib/fulvestrant in patients for whom previous endocrine therapy failed is superior to single-agent fulvestrant and is associated with improved progression-free and overall survival irrespective of mutations or previous therapy at the time of study entry. Palbociclib/fulvestrant is a new standard of care associated with continued benefit. This remains the most important treatment we have for hormone receptor–sensitive metastatic breast cancer,” said lead investigator Massimo Cristofanilli, MD, Associate Director for Translational Research at the Lurie Cancer Center and Professor of Medicine in the Division of Hematology/Oncology at Northwestern University Feinberg School of Medicine, Chicago.

Massimo Cristofanilli, MD

Massimo Cristofanilli, MD


“An improvement in overall survival with palbociclib plus fulvestrant continues to be observed with more than 6 years of median follow-up in patients with hormone receptor–positive, HER2-negative advanced breast cancer whose disease progressed on prior endocrine therapy,” Dr. Cristofanilli said. “This prolonged overall survival benefit is particularly evident in patients with endocrine-sensitive disease and those without prior exposure to chemotherapy in the advanced setting. Remarkable in this metastatic setting is that the 5-year overall survival rate is 23.3% in the palbociclib arm compared with 16.8% in the placebo arm.”

In patients who had not received prior chemotherapy for advanced disease (66% of the study population), the median overall survival was 39.3 months with the combination therapy vs 29.7 months with fulvestrant plus placebo (P = .008), representing a 10-month difference and “a remarkable 28% improvement” for the palbociclib combination, commented Dr. Cristofanilli. By contrast, no survival benefit was observed with the combination in the 34% of patients who did receive chemotherapy previously (24.6 vs 24.3 months, respectively).

“It is important to notice that 34% of the study population received prior chemotherapy for advanced breast cancer and 35% received more than two prior regimens for advanced breast cancer. These types of heavily pretreated patients were excluded from other phase III trials of CDK4/6 inhibitors and fulvestrant,” Dr. Cristofanilli stated.

At the beginning of the trial, 331 patients consented to having circulating tumor DNA analysis of mutations in plasma samples, and mutational status was available for 195 patients at the end of treatment. ESR1 was the most commonly identified mutation, found in about 30% of patients. PIK3CA was present in about 21% and TP53, in 19%.

“Overall survival was generally favorable with palbociclib/fulvestrant vs fulvestrant/placebo across subgroups, regardless of ESR1, PIK3CA, or TP53 mutational status,” Dr. Cristofanilli said. The presence of any of those three mutations confers shorter survival, but the association with the PIK3CA mutation is not as strong as it is with TP53 or ESR1.

As previously reported, the most common treatment-emergent adverse events associated with palbociclib/fulvestrant were neutropenia, leukopenia, and infections. No new safety signals emerged with extended follow-up.

Study Details

The PALOMA-3 trial enrolled 521 patients with metastatic breast cancer whose disease progressed on or following endocrine treatment and randomly assigned them 2:1 to fulvestrant plus palbociclib (n = 347) or fulvestrant plus placebo (n = 174). The median patient age was about 56 years in both arms. About three-quarters of the study population (73.7% of the combination arm and 76.7% of the placebo arm) were sensitive to prior hormonal therapy. About 66% were not exposed to prior chemotherapy. Stratification factors were menopausal status, sensitivity to prior hormonal therapy, and visceral metastases.

The combination of palbociclib/fulvestrant is approved by the U.S. Food and Drug Administration for the treatment of previously treated hormone receptor–positive, HER2-negative metastatic breast cancer. 

DISCLOSURE: Dr. Cristofanilli has received honoraria from Foundation Medicine and Pfizer; has served as a consultant or advisor to CytoDyn, Foundation Medicine, Lilly, Menarini, and Novartis; and has received research funding from Angle, Lilly, and Merck.


1. Cristofanilli M, Rugo HS, Im SA, et al: Overall survival with palbociclib + fulvestrant in women with hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer: Updated analyses from PALOMA-3. 2021 ASCO Annual Meeting. Abstract 1000. Presented June 4, 2021.

2. 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.


The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.