Palbociclib Plus Endocrine Therapy Is Less Toxic Than Standard Capecitabine for Treating AI-Resistant MBC

The combination of palbociclib and endocrine therapy demonstrated a more favorable safety profile and improved quality of life versus capecitabine among patients with metastatic breast cancer who were resistant to aromatase inhibitors, despite not improving progression-free survival.

With regard to progression-free survival (PFS) in patients with metastatic breast cancer (MBC) who were resistant to aromatase inhibitors (AIs), there was no statistical superiority of palbociclib (Ibrance) plus endocrine therapy (ET) over capecitabine, according to results from the phase 3 PEARL study (NCT02028507), published in Annals of Oncology.1

However, the combination of palbociclib and ET did demonstrate a more favorable safety profile and improved quality of life among this patient population.

“In addition, while the PEARL trial did not meet its coprimary objectives, it still provides evidence and suggestions for the management of hormone receptor–positive AI-resistant MBC,” wrote the study authors, who were led by Miguel Martin, MD, PhD.

The randomized, multicenter, international, open-label, controlled phase 3 PEARL study evaluated patients with AI-resistant MBC in 2 consecutive cohorts. In cohort 1, patients were randomized 1:1 to receive either palbociclib plus exemestane or capecitabine. Upon uncovering new evidence about ESR1 mutations and their ability to induce resistance to AIs in December 2015,2 the trial was amended to include cohort 2 in which patients were randomized 1:1 to receive either palbociclib plus fulvestrant or capecitabine.

From March 2014 to July 2018, 296 patients were enrolled in cohort 1 and 305 were enrolled in cohort 2. The dual primary end points of the study were PFS in cohort 2 and in patients with wild-type ESR1 across both cohorts. Key secondary end points included PFS with palbociclib plus ET versus capecitabine regardless of ESR1 mutational status, objective response rate (ORR), clinical benefit rate (defined as ORR plus stable disease rate of at least 24 weeks of duration), response duration, overall survival, safety, and patient-reported outcomes.

At the primary analysis cut-off date of January 14, 2019, 80 patients were still on the study treatment, including 10 (6.7%) on palbociclib plus exemestane, 37 (24.8%) on palbociclib plus fulvestrant, and 33 (11%) on capecitabine. The primary reason for permanent discontinuation of the treatment was disease progression. Among both cohorts, the proportion of patients who discontinued due to progressive disease was smaller in the capecitabine arm (65.7% in cohort 1, 58.6% in cohort 2) versus the palbociclib plus exemestane (81.3%) and palbociclib plus fulvestrant (68.5% in cohort 2) arms.

In terms of median PFS, palbociclib plus ET was not found to be superior to capecitabine in either cohort 2 (7.5 vs 10.0 months; adjusted HR [aHR], 1.13; 95% CI, 0.85-1.50) or in patients with wild-type ESR1 (8.0 vs 10.6 months; aHR, 1.11; 95% CI, 0.87-1.41). However, palbociclib plus ET offered better quality of life in terms of time to deterioration of global health status (aHR, 0.67; 95% CI, 0.53-0.85).

“This analysis showed that no chemotherapy regimen was significantly better than CDK4/6 inhibitors plus hormone therapies in the first- or second-line setting, supporting the treatment guideline recommendations for the use of ET plus targeted agents in earlier lines of treatment in women with hormone receptor–positive/HER2-negative MBC,” the authors explained.

Regarding safety, the most frequent grade 3 or 4 adverse events (AEs) with palbociclib plus exemestane, palbociclib plus fulvestrant, and capecitabine included neutropenia (57.4%, 55.7%, and 5.5%, respectively), hand-foot syndrome (0%, 0%, and 23.5%), and diarrhea (1.3%, 1.3%, and 7.6%) fatigue (1.3%, 0.7%, and 5.5%), and anemia (0.7%, 2.0%, and 3.5%). Moreover, serious AEs related to the study treatment were reported by 10.4% of those on capecitabine, 4.0% of those on palbociclib plus exemestane, and 3.4% of those on palbociclib plus fulvestrant.

Of a total of 17 deaths reported during the study treatment, 11 were due to progressive disease. Further, 2 serious AEs of pneumonitis and sepsis occurred while patients were on palbociclib plus ET; 4 occurred while the patients were on capecitabine (diarrhea, general health status worsening, colitis, and sudden death).

Importantly, though the PEARL trial did not meet its co-primary objectives, it still provides evidence and suggestions for the management of hormone receptor-positive AI-resistant MBC. Ultimately, the investigators suggested capecitabine, albeit having higher AEs, remains an appropriate alternative where health care costs are restricted.


1. Martin M, Zielinski C, Ruiz-Borrego M, et al. Palbociclib in combination with endocrine therapy versus capecitabine in hormonal receptor-positive, human epidermal growth factor 2-negative, aromatase inhibitor-resistant metastatic breast cancer: a phase III randomised controlled trial-PEARL. Annals of Oncology. Published online December 29, 2020. doi: 10.1016/j.annonc.2020.12.013

2. Schiavon G, Hrebien S, Garcia-Murillas I, et al. Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer. Sci Transl Med. 2015;7(313):313ra182. doi: 10.1126/scitranslmed.aac7551