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Pairing the CDK4/6 inhibitor palbociclib (Ibrance) with fulvestrant as first-line treatment for advanced, hormone receptor-positive/HER2-negative breast cancer did not improve survival compared with standard treatment, the phase II PARSIFAL trial found.

Over a median follow-up of 32 months, the primary endpoint of median investigator-assessed progression-free survival (PFS) was 27.9 months in the fulvestrant-palbociclib group versus 32.8 months for patients who received the standard treatment of palbociclib with the nonsteroidal aromatase inhibitor (NSAI) letrozole (HR 1.13, 95% CI 0.89-1.45, P=0.32), reported Antonio Llombart-Cussac, MD, of Hospital Arnau de Vilanova in Valencia, Spain, and colleagues.

No significant differences were observed in objective response rate (46.5% vs 50.2%; P=0.41) or 3-year overall survival rate (79.4% vs 77.1%; HR 1.00, 95% CI 0.68-1.48, P=0.99).

This study "demonstrated no improvement in PFS with fulvestrant-palbociclib over letrozole-palbociclib among patients receiving initial systemic treatment for endocrine-sensitive, hormone receptor-positive, ERBB2 [HER2]-negative advanced breast cancer," the authors wrote in . "These findings confirm NSAI as the preferred palbociclib partner for effective treatment with a tolerable safety profile in this patient population."

The combination of a CDK4/6 inhibitor and NSAI has become the standard initial therapy for these patients, Llombart-Cussac and team explained. However, previous studies have raised questions about the optimal endocrine partner for CDK4/6 inhibitors in this population.

The international, randomized, open-label PARSIFAL trial was designed to evaluate whether the fulvestrant-palbociclib combination was superior to the letrozole-palbociclib combination and was conducted from July 2015 to January 2018. It assessed 486 women (median age 63 years, 94.9% white) who were randomized 1:1 to palbociclib plus fulvestrant or letrozole. Investigator-assessed PFS was determined by Response Evaluation Criteria in Solid Tumors, version 1.1.

Overall survival data were immature at data cutoff, with 51 deaths (21%) in both treatment groups.

Median duration of response was 34 months in the fulvestrant-palbociclib group and 30.2 months in the letrozole-palbociclib group. In the intent-to-treat population, clinical benefit was achieved in 70.8% and 69.1% of patients, respectively (P=0.69).

Median time to progression was 28.9 months in the fulvestrant-palbociclib group and 32.8 months in the letrozole-palbociclib group (HR 1.09, 95% CI 0.85-1.40, P=0.49). Median time to response was 5.3 months and 5.2 months, respectively (HR 0.9, 95% CI 0.7-1.2).

As for safety, the most common adverse events of any grade in both groups were neutropenia, asthenia, arthralgia, anemia, and diarrhea, and the incidence of grade 3 or 4 toxicities was similar between groups.

Pulmonary embolism occurred in 5% of patients in the fulvestrant-palbociclib group compared with 2.5% of patients in the letrozole-palbociclib group, while 2.5% of patients in each group had interstitial lung disease or pneumonitis of any grade. No treatment-related deaths were reported.

Among the study limitations was the low number of Asian or Black participants, noted Llombart-Cussac and colleagues.

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