Treatment with the CDK4/6 inhibitor palbociclib, in combination with endocrine therapy, did not significantly improve progression-free survival (PFS) when compared with capecitabine in patients with metastatic breast cancer whose disease progressed on aromatase inhibitor therapy, according to phase 3 study results presented at the 2019 San Antonio Breast Cancer Symposium.

The investigative combination also failed to provoke statistically superior results in a subgroup of patients with luminal tumors.

Photo by © MedMeetingImages/Todd Buchanan 2018

The US Food and Drug Administration approved palbociclib for the treatment of patients with hormone receptor-positive, HER2-negative breast cancer, in combination with endocrine therapy. 

Although the combination is approved as both a first-line and subsequent therapy, there is little evidence of its efficacy in comparison to chemotherapy among previously treated women.

The controlled, open label, phase 3 PEARL compared the safety and efficacy of palbociclib plus endocrine therapy with capecitabine in women with hormone receptor-positive, HER2-negative breast cancer that progressed after treatment with aromatase inhibitors.

An initial cohort of patients were randomly assigned to treatment (exemestane plus palbociclib vs. capecitabine) in a 1:1 ratio. After research suggesting that ESR1 mutations may provoke resistance to aromatase inhibitors but not to fulvestrant, a second cohort (fulvestrant plus palbociclib vs. capecitabine) was added.

The study’s coprimary endpoints were the PFS superiority of fulvestrant plus palbociclib, and the PFS superiority of either endocrine therapy in patients with ESR1 wild type tumors.

The entire study population included data from 601 women (Cohort 1, n = 296; Cohort 2, n = 305). The median age of Cohort 2 was 61 years; 28.2% harbored ESR1 mutations; 65.2% had visceral disease; 26.9% had received one previous chemotherapy for metastatic breast cancer; and 26.6% received no previous therapy for metastatic breast cancer.

After a median follow-up of 13.5 months (range, 0-30.7), the researchers observed no PFS benefit for the investigational combination. Patients in Cohort 2 assigned fulvestrant plus palbociclib achieved a median PFS of 7.5 months, compared with 10 months for capecitabine (adjusted hazard ratio [HR], 1.09; 95% CI, 0.83-1.44). The objective response rate (ORR) also favored capecitabine (26.7% vs. 33.3%).

Subtype data were available for 74.4% of patients. The combination arm included 89.1% of patients with luminal tumors, as did 91.5% of the capecitabine arm. PFS favored capecitabine among patients with luminal tumors (median, 7.5 months vs. 10 months; HR, 1.07; 95% CI, 0.77-1.5) and non-luminal tumors (4.4 months vs. 14.8 months; HR, 2.39; 95% CI, 0.81-7.08).

With a median follow-up of 19 months (range, 0-56.3), results showed that patients with ESR1 wild type tumors did not experience a significantly improved PFS with palbociclib and endocrine therapy (median, 8 months vs. 10.6 months; adjusted HR, 1.08; 95% CI, 0.85-1.36). ORR also favored capecitabine (27.8% vs. 39.6%).

In this cohort, 89.2% of patients assigned to combination therapy and 91.8% of patients assigned to capecitabine had luminal tumors. PFS outcomes favored capecitabine for patients with luminal tumors (9.3 months vs. 11 months; HR, 1.02; 95% CI, 0.77-1.34) and non-luminal tumors (2.7 months vs. 13.7 months; HR, 3.19; 95% CI, 1.28-7.95).

In general, combination therapy was well tolerated. The most common grade 3 or grade 4 adverse events were neutropenia (exemestane, 57.4%; fulvestrant, 55.7%; capecitabine, 5.5%), febrile neutropenia (1.3% vs. 0.7% vs. 1.4%), hand/foot syndrome (0 vs. 0 vs. 23.5%) and diarrhea (1.3% vs. 1.3% vs. 7.6%).