In the phase II PARSIFAL trial reported in JAMA Oncology, Antonio Llombart-Cussac, MD, and colleagues found that the combination of fulvestrant plus palbociclib did not improve progression-free survival vs letrozole plus palbociclib in women with advanced endocrine-sensitive, hormone receptor (HR)-positive, HER2-negative breast cancer.

Antonio Llombart-Cussac, MD

Study Details

In the open-label trial, 486 women from sites in seven countries were randomly assigned between July 2015 and January 2018 to receive fulvestrant/palbociclib (n = 243) or letrozole/palbociclib (n = 243). Treatment consisted of palbociclib at 125 mg per day in cycles of 3 weeks on treatment followed by 1 week off in combination with fulvestrant at 500 mg on days 1, 15, 29, and once monthly thereafter or letrozole at 2.5 mg per day continuously, with treatment continued until disease progression or unacceptable toxicity. Premenopausal or perimenopausal women received a gonadotropin-releasing hormone agonist. The primary endpoint was investigator-assessed progression-free survival.

Progression-Free Survival

Median follow-up was 32 months (interquartile range = 24.2–39.7 months). Median progression-free survival was 27.9 months (95% confidence interval [CI] = 24.2–33.1 months) in the fulvestrant/palbociclib group vs 32.8 months (95% CI = 25.8–35.9 months) in the letrozole/palbociclib group (hazard ratio [HR] = 1.13, 95% CI = 0.89-1.45, P = .32). No significant differences were observed according to the stratification factors of de novo metastatic vs recurrent disease and presence vs absence of visceral involvement.

Objective response was observed in 46.5% (95% CI = 40.1%­–53.0%) vs 50.2% (95% CI = 43.7%–56.7%) of patients (P = .41), with median response durations of 34 months (95% CI = 23.3 months–not estimable) vs 30.2 months (95% CI = 26.7 months–not estimable). Overall survival data were not mature at time of analysis. Estimated overall survival at 3 years was 79.4% (95% CI = 73.1%–84.4%) in the fulvestrant/palbociclib group vs 77.1% (95% CI = 70.2%–82.5%) in the letrozole/palbociclib group (HR = 1.00, 95% CI = 0.68­–1.48, P = .99). 

Adverse Events

Grade 3 or 4 adverse events occurred in 80.9% of patients in the fulvestrant/palbociclib group vs 78.5% of the letrozole/palbociclib group, with neutropenia being the most common in both groups (66.0% vs 68.2%). Febrile neutropenia was observed in 1.2% vs 0.4% of patients. Serious adverse events occurred in 29.9% vs 21.1% of patients. Adverse events led to treatment discontinuation in 5.3% vs 2.1%. Among adverse events of special interest, pulmonary embolism occurred in 5.0% vs 2.5%, any-grade interstitial lung disease or pneumonitis occurred in 2.5% vs 2.5%, and grade 3 pneumonitis occurred in 0.8% vs 1.2%. No treatment-related deaths were reported.

The investigators stated, “To our knowledge, PARSIFAL is the only randomized clinical trial to directly compare the therapeutic efficacy of fulvestrant or letrozole in combination with the CDK4/6 inhibitor palbociclib [in this setting].” 

They concluded, “Although fulvestrant/palbociclib demonstrated significant antitumor activity, this randomized clinical trial failed to identify an improvement in progression-free survival with this regimen over letrozole/palbociclib in patients with endocrine-sensitive, HR-positive, HER2-negative advanced breast cancer.”

Dr. Llombart-Cussac, of Hospital Arnau de Vilanova, Valencia, Spain, is the corresponding author for the JAMA Oncology article.

Disclosure: The study was supported by Pfizer Inc. For full disclosures of the study authors, visit jamanetwork.com.