Fulvestrant/Palbociclib Combo Yields Anti-Tumor Activity But Did Not Improve PFS In HR-positive, ERBB2-Negative Advanced Breast Cancer

Patients with hormone receptor–positive, ERBB2-negative advanced breast cancer experienced significant anti-tumor activity when treated with fulvestrant and palbociclib but did not see an improvement in progression-free survival compared with letrozole and palbociclib .

Fulvestrant and palbociclib (Ibrance), despite yielding significant antitumor activity, did not show an improvement in progression-free survival (PFS) compared with letrozole and palbociclib for patients with endocrine-sensitive hormone receptor–positive, ERBB2-negative advanced breast cancer, according to results from the PARSIFAL phase 2 trial (NCT02491983) published in JAMA Oncology.

Data from the trial indicated that the median PFS was 27.9 months (95% CI, 24.2-33.1) in the fulvestrant group compared with 32.8 months (95% CI, 25.8-35.9) in the letrozole group (HR, 1.13; 95% CI, 0.89-1.45; P = .32). The objective response rate for the fulvestrant group was 46.5% and 50.2% for the letrozole group. Patients had a 3-year overall survival rate of 79.4% in the fulvestrant group vs 77.1% in the letrozole group (HR, 1.00; 95% CI, 0.68-1.48; P = .99).

“These findings confirm nonsteroidal aromatase inhibitors as the preferred palbociclib partner for effective treatment with a tolerable safety profile in this patient population,” the study’s investigators wrote.

Patients who enrolled were randomly assigned to either the fulvestrant group (n = 243) or the letrozole group (n = 243). A total of 256 PFS events were reported, and 483 patients had received at least 1 dose of study treatment. Three patients did not start the study treatment because of either investigator decision, withdrawal of consent, or protocol violation.

In order to be eligible, patients needed to be 18 years or older and could have any menopausal status. The trial enrolled those who did not previously receive systemic therapy for advanced disease. An ECOG performance status of 0 to 2 was also required.

Patients in the experimental arm received 125 mg of daily palbociclib in cycles of 3 weeks on, 1 week off plus 500 mg of fulvestrant on days 1, 15, and 29 followed by once a month thereafter. The control group was given 2.5 mg of oral letrozole daily. Those who were perimenopausal also received a gonadotropin-releasing hormone agonist.

Visceral disease was present in 47.9% (n = 233) of patients, 40.7% (n = 198) presented with de novo advanced breast cancer, and 95.1% (n = 462) had an ECOG score of 0 to 1. Additionally, 46.1% (n = 224) of patients had previously received endocrine therapy.

Among patients who continued treatment, 29.6% (n = 72) were in the fulvestrant group and 36.2% (n = 88) were in the letrozole group. In each group, patients discontinued treatment primarily due to disease progression 50.2% (n = 122).

The median relative dose intensity for fulvestrant was 99.2% and 91.7% for palbociclib in the fulvestrant/palbociclib group, and for letrozole it was 98.8% and 90.0% for the palbociclib in the letrozole/palbociclib group. In the fulvestrant/palbociclib group, palbociclib was reduced in 35.3% (n = 85) od patients, and in the letrozole-palbociclib, it was reduced in 44.6% (n = 108) of patients.

A total of 51 deaths were reported across both groups. The overall survival data were immature at cutoff.

A total of 46.5% (n = 113) of patients had an objective response rate (ORR) in the fulvestrant group (95% CI, 40.1%-53.0%), and 50.2% (n = 122) responded in the letrozole group (95% CI, 43.7%-56.7%). Patients with measurable disease in the fulvestrant cohort had an ORR of 56.4% (n = 110; 95% CI, 49.1%-63.5%) and 65.7% (n = 119) had an objective response in the letrozole cohort (95% CI, 59.3%-72.9%).

Patients had a median duration of response of 34 months (95% CI, 23.3–not estimable [NE]) in the fulvestrant group, and 30.2 months (95% CI, 26.7 months-NE) in the letrozole group. The intent-to-treat population had a clinical benefit rate of 70.8% (n = 172) in the fulvestrant group (95% CI, 64.6%-76.4%) and 69.1% (n = 168; 95% CI, 62.9%-74.9%) in the letrozole group. Patients had a median time to response of 5.3 months (95% CI, 3.7-5.5) in the fulvestrant group and 5.2 months (95% CI, 2.9-5.5) in the letrozole group (HR, 0.9; 95% CI, 0.7-1.2).

The most common grade 3/4 adverse effect (AE) was neutropenia in both groups. A decrease in neutrophil count of grade 3 of higher occurred in 66.0% (n = 159) of patients in the fulvestrant group, and 68.2% (n = 165) in the letrozole group. In the fulvestrant group, 1.2% (n = 3) of patients reported febrile neutropenia, and 0.4% (n = 1) reported it in the letrozole group.

In total, 80.9% of patients in the fulvestrant group experienced grade 3 or 4 AEs and 29.9% serious AEs vs 78.5% and 21.1% of those in letrozole group, respectively. A total of 5.3% (n = 13) of patients in the fulvestrant group discontinued treatment due to AEs compared with 2.1% (n = 5) in the letrozole group. There were no treatment-related deaths reported by intestigators.

Pulmonary embolism, an AE of special interest, occurred in 5.0% (n = 12) of those in the fulvestrant group, and 2.5% (n = 6) in the letrozole group. In each group, 2.5% (n = 6) of patients had interstitial lung disease or pneumonitis of any grade. Grade 3 pneumonitis occurred in 0.8% (n = 2) of patients in the fulvestrant group, and 1.2% (n = 3) in the letrozole group.


Llombart-Cussac A, Pérez-García JM, Bellet M, et al. Fulvestrant-palbociclib vs letrozole-palbociclib as initial therapy for endocrine-sensitive, hormone receptor-positive, ERBB2-negative advanced breast cancer: a randomized clinical trial. JAMA Oncol. Published Online October 7, 2021. doi:10.1001/jamaoncol.2021.4301