ESMO 2018: PALOMA-3: Palbociclib in Hormone Receptor–Positive, HER2-Negative Advanced Breast Cancer


Key Points

  • Results showed that median overall survival improved by 6.9 months with palbociclib plus fulvestrant (median overall survival = 34.9 months) compared to placebo plus fulvestrant (median overall survival = 28.0 months).
  • The improvement was even greater in patients with sensitivity to prior endocrine therapy, with an absolute improvement in median overall survival of 10.0 months.
  • No new safety signals were observed with longer follow-up.

Treatment with the cyclin-dependent kinase (CDK) 4/6 inhibitor palbociclib (Ibrance) achieved a clinically meaningful improvement in overall survival in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer that has relapsed or progressed on hormonal therapy, according to the final analysis of overall survival results from the PALOMA-3 study reported by Cristofanilli et al at the European Society for Medical Oncology 2018 Congress (Abstract LBA2_PR).

Most patients with HR-positive breast cancer become resistant to hormonal therapies over time, and inhibiting CDK4/6 has been identified as a target for overcoming or delaying resistance to hormonal therapy in advanced HR-positive, HER2-negative breast cancer. The prospective, randomized phase III PALOMA-3 trial, first reported by Cristofanilli et at in The Lancet Oncology, showed that the first-in-class CDK4/6 inhibitor palbociclib in combination with fulvestrant (Faslodex) significantly improved progression-free survival in 521 women with HR-positive, HER2-negative metastatic breast cancer that had progressed on previous hormonal therapy.

Overall Survival Analysis

The new analysis assessed overall survival, a key secondary endpoint of PALOMA-3, after a median follow-up of 44.8 months in 521 patients with HR-positive, HER2-negative advanced breast cancer. The patients had relapsed or shown disease progression on prior endocrine therapy before being randomly assigned to receive palbociclib (125 mg/d orally, schedule 3/1) plus fulvestrant (500 mg per standard of care) or placebo plus fulvestrant. Researchers carried out the overall survival analysis when approximately 60% (~130) of the 521 patients in the study had died.

Results showed that median overall survival improved by 6.9 months with palbociclib plus fulvestrant (median overall survival = 34.9 months, 95% confidence interval [CI] = 28.8–40.0) compared to placebo plus fulvestrant (median overall survival = 28.0 months, 95% CI = 23.6–34.6, P = .043).

The improvement was even greater in patients with sensitivity to prior endocrine therapy, with an absolute improvement in median overall survival of 10.0 months. Median overall survival improved significantly by 11.5 months in patients without visceral disease. No new safety signals were observed with longer follow-up.

“Here, we present the first-ever overall survival results from a phase III study for a CDK4/6 inhibitor in a preplanned analysis of the PALOMA-3 trial. Importantly, this is the first report demonstrating that the absolute gain in survival is similar to the absolute gain in progression-free survival in the whole population. Moreover, this prolongation of life is of a large magnitude in patients with prior sensitivity to endocrine therapy,” said lead author Massimo Cristofanilli, MD, Professor of Medicine, Robert H. Lurie Comprehensive Cancer Center of Northwestern University Feinberg School of Medicine, Chicago.

“This is very important for patients, as it shows that the improvement in progression-free survival observed in previous studies may have a positive impact on overall survival, an ultimate goal of treatment, therefore improving the chance for a long-term life in spite of advanced disease,” said Dr. Cristofanilli. He added, “The demonstration of a positive impact on overall survival also provides additional confidence to clinicians and patients as to the benefits of this combination as an appropriate and effective treatment approach.”


Commenting on the findings, Carmen Criscitiello, MD, PhD, of the European Institute of Oncology, Milan, Italy, said in a statement, “These data were much awaited, as the clinical benefit obtained with CDK4/6 inhibitors was incontestable, but there was the hot question whether the progression-free survival benefit translates into overall survival benefit. This randomized phase III trial shows for the first time an improvement in overall survival with a CDK4/6 inhibitor in the metastatic setting for HR-positive, HER2-negative breast cancer.” She added, “The study was unpowered for overall survival, so the data should be cautiously interpreted. Although the results strongly suggest that the progression-free survival benefit may translate into an overall survival benefit, the other trials conducted with CDK4/6 inhibitors will contribute to confirm the estimate of the overall survival benefit observed in this study.”

In the same statement, Matteo Lambertini, MD, ESMO fellow at the Institut Jules Bordet, Brussels, agreed, “Collecting mature overall survival data at longer follow-up from randomized trials that investigated the combination of endocrine therapy and CDK4/6 inhibitors is crucial to have a clearer understanding on the benefit of these expensive agents. The limited overall survival data that we had so far from these trials are now supported by the PALOMA-3 updated results, which strongly suggest that this treatment should become widely available for women with advanced HR-positive, HER2-negative disease.” He said, “Further research is needed to better understand how to optimize the sequencing of the available treatment options in this setting, as well as to identify patients who may benefit from endocrine therapy alone.”

Dr. Cristofanilli concluded, “The significant impact of CDK4/6 inhibitors on disease-free and overall survival in metastatic disease lead us to be excited about the potential of this class of agents in early-stage breast cancer, where our goal is to improve the cure rate. On that front, two large randomized adjuvant trials of palbociclib in early-stage breast cancer—PENELOPE-B and PALLAS—are ongoing.”

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®.