Palbociclib Plus Fulvestrant Maintains Long‐Term Overall Survival Benefit in HR+/HER2– Advanced Breast Cancer

Short abstract

With more than 6 years of follow‐up in the phase III PALOMA‐3 trial, the addition of palbociclib to fulvestrant maintained a significant survival benefit compared with fulvestrant alone in patients with HR‐positive, HER2‐negative advanced breast cancer that progressed on prior endocrine therapy.

The phase III PALOMA‐3 trial established the role of palbociclib, a cyclin dependent kinase (CDK) 4/6 inhibitor, plus fulvestrant in patients with hormone receptor (HR)‐positive, human epidermal growth factor receptor 2 (HER2)‐negative that progressed on prior endocrine therapy [1, 2, 3].

First presented at the 2015 American Society of Clinical Oncology Annual Meeting, results from PALOMA‐3 showed that palbociclib significantly improved progression‐free survival (PFS) compared with fulvestrant alone [1, 2]. In 2018, with a median follow‐up of 44.8 months, another report from PALOMA‐3 showed a nonsignificant trend toward improved overall survival (OS) with palbociclib added to fulvestrant relative to endocrine therapy alone [3].

In the current analysis, Massimo Cristofanilli, M.D., of Northwestern University, presented updated OS data from the PALOMA‐3 trial with a median follow‐up of 73.3 months [4].

Study Design

The international, multicenter, phase III PALOMA‐3 trial enrolled 521 patients with HR‐positive, HER2‐negative advanced breast cancer that had progressed on or after prior endocrine therapy. Eligible patients received up to one prior chemotherapy regimen for advanced cancer. In total, 34% of patients received any prior chemotherapy, and 35% of patients received ≥2 prior regimens for advanced breast cancer. At study entry, patients were stratified by menopausal status, presence of visceral metastases, and documented sensitivity to prior hormonal therapy.

Patients were randomly assigned 2:1 to palbociclib plus fulvestrant (n = 374) or placebo plus fulvestrant (n = 174). The primary endpoint was investigator‐assessed PFS.

Key Findings

Results demonstrate a significant OS benefit with palbociclib added to fulvestrant compared with fulvestrant alone. The median OS was 34.8 months in the palbociclib arm and 28.0 months in the placebo arm (p < .0221). This represents a statistically significant 19% reduction in the relative risk of mortality with the addition of palbociclib to fulvestrant (HR, 0.81; 95% CI, 0.65–0.99).

The 5‐year OS rates were 23.3% and 16.8% in the palbociclib and placebo groups, respectively. The OS analysis favored palbociclib across patient subgroups defined by menopausal status, performance status, and site of metastatic disease at study entry, as well as sensitivity to hormonal therapy.

In a subgroup analysis defined by prior chemotherapy exposure, the survival benefit of palbociclib appeared to be limited to those patients who had not undergone prior chemotherapy (Table 1). Among those without prior exposure to chemotherapy (n = 344), palbociclib was associated with a statistically significant 28% reduction in the relative risk of death compared with fulvestrant alone (HR, 0.72; 95% CI, 0.55–0.94; p = .008). By comparison, among patients who had previously been treated with chemotherapy (n = 177), there was no difference between palbociclib and placebo in OS (HR, 0.97; 95% CI, 0.69–1.36).

Table 1.

Overall survival with palbociclib or placebo by prior exposure to chemotherapy

	Palbociclib plus fulvestrant	Placebo plus fulvestrant	HR (95% CI)	p value
No Prior Chemotherapy	(n = 234)	(n = 110)
Median OS	39.3 months	29.7 months	0.71 (0.55–0.94)	.008
Prior Chemotherapy	(n = 113)	(n = 64)
Median OS	24.6 months	24.3 months	0.97 (0.69–1.36)	.432

Abbreviations: CI, confidence interval; HR, hazard ratio; OS, overall survival.

Investigators also evaluated OS by tumor mutation status, showing a consistent survival benefit with palbociclib irrespective of molecular signature (Table 2). In total, 330 patients consented to a biomarker subgroup analysis consisting of plasma collection and circulating tumor DNA (ctDNA) analysis for ESR1, PIK3CA, and TP53 gene mutation status. Relative to wild type, each of these mutations is associated with worse prognosis in patients with HR‐positive, HER2‐negative advanced breast cancer.

Table 2.

Overall survival with palbociclib or placebo by tumor mutation status

	Palbociclib plus fulvestrant	Placebo plus fulvestrant	HR (95% CI)
No ESR1 Mutation	(n = 154)	(n = 80)
Median OS	32.8 months	28.0 months	0.81 (0.59–1.11)
ESR1 Mutation	(n = 69)	(n = 28)
Median OS	27.7 months	20.2 months	0.59 (0.37–0.94)
No PIK3CA Mutation	(n = 173)	(n = 87)
Median OS	32.8 months	26.6 months	0.78 (0.58–1.04)
PIK3CA Mutation	(n = 50)	(n = 21)
Median OS	27.7 months	18.3 months	0.73 (0.42–1.25)
No TP53 Mutation	(n = 186)	(n = 88)
Median OS	36.1 months	28.0 months	0.78 (0.57–1.00)
TP53 Mutation	(n = 37)	(n = 20)
Median OS	23.0 months	16.4 months	0.83 (0.46–1.52)

Abbreviations: CI, confidence interval; HR, hazard ratio; OS, overall survival.

In summary, final results from the PALOMA‐3 trial support the sustained and clinically meaningful survival benefits of palbociclib added to fulvestrant across a range of patients with HR‐positive, HER2‐negative advanced breast cancer that progressed on prior endocrine therapy.