Although patients with hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative, aromatase inhibitor resistant metastatic breast cancer maintained quality of life (QoL) for a longer time following treatment with palbociclib plus either exemestane or fulvestrant than capecitabine, those receiving chemotherapy demonstrated improved progression-free survival (PFS) and higher response rates compared with the palbociclib-treated patients.

Details from the phase III PEARL study were provided by lead author Miguel Martin of the Gregorio Marañón Institute in Madrid, Spain and co-investigators in an article published in the Annals of Oncology.

The authors noted that, although palbociclib plus endocrine therapy has become standard treatment for HR-positive, HER2-negative metastatic breast cancer, it had never been directly compared for efficacy with chemotherapy in a phase III trial.

Therefore, the investigators conducted the multicentre, phase III randomised PEARL study (NCT02028507) in patients with HR-positive, HER2-negative metastatic breast cancer who were resistant to aromatase inhibitors. The study comprised two consecutive cohorts, wherein 296 cohort 1 patients were randomised 1:1 to palbociclib plus exemestane or capecitabine. Upon emerging evidence that oestrogen receptor-1 (ESR1) mutations could induce resistance to aromatase inhibitors, the study was amended to include 305 cohort 2 patients who were randomised 1:1 to receive palbociclib plus fulvestrant or capecitabine. Patients in both cohorts were stratified according to disease site, prior sensitivity to endocrine therapy, receipt of prior chemotherapy for metastatic breast cancer, and country of origin. Circulating tumour DNA samples were obtained at baseline for analysis of ESR1 hotspot mutations.

The co-primary endpoints were PFS in cohort 2 patients and PFS in patients having wild-type ESR1 in both cohorts.

Palbociclib plus endocrine therapy was not superior to capecitabine

The median follow-up was 13.5 months (range, 0.0 to 30.7) in cohort 2 and the wild-type ESR1 population, and 18.9 months (range, 0.0 to 56.3) in cohort 1 and patients with mutated ESR1.

Regarding cohort 1 patients the median PFS was 7.5 months (95% confidence interval [CI] 5.7-10.9) with palbociclib/fulvestrant compared to 10.0 months (95% CI 6.3-12.9) with capecitabine (adjusted hazard ratio [aHR] 1.13; 95% CI 0.85-1.50; p = 0.398).

Patients with wild-type ESR1 demonstrated median PFS of 8.0 months (95% CI 6.5-10.9) with palbociclib plus endocrine therapy compared to 10.6 months (95% CI 7.4-13.0) with capecitabine (aHR 1.11; 95% CI 0.87-1.41; p = 0.404).

Evaluation of efficacy, the secondary endpoint of the study, showed that median PFS in cohort 1 and cohort 2 patients overall was 7.4 months (95% CI 5.9-9.3) with palbociclib plus endocrine therapy versus 9.4 months (95% CI 7.5-11.3) with capecitabine (aHR 1.11; 95% CI 0.92-1.34; p = 0.380).

The objective response rate (ORR) was also higher with capecitabine chemotherapy across treatment arms.

In cohort 2, the ORR was 26.7% for palbociclib plus fulvestrant versus 33.3% for capecitabine. Patients with ESR1 wild-type demonstrated an ORR of 27.8% with palbociclib plus endocrine therapy versus 36.9% ORR in patients receiving capecitabine.

Patient reported outcomes showed patients on palbociclib plus endocrine therapy maintained quality of life longer than patients receiving capecitabine

The completion rate of patient reported outcomes (PROs) was similar across the arms, surpassing 82% until cycle 13. The PROs showed the median time to deterioration in global health status was 8.6 months in patients treated with palbociclib plus endocrine therapy versus 6.2 months in those receiving capecitabine (aHR 0.67; 95% CI 0.53-0.85; p = 0.001).

Eighty patients remained on study treatment as of the 14th January 2019 cut-off date; of these 10 (6.7 %) were on palbociclib plus exemestane, 37 (24.8%) on palbociclib plus fulvestrant, and 33 (11%) patients remained on capecitabine.

The median time on study treatment differed between cohorts; cohort 1 patients remained on capecitabine for 7.9 months (range, 0.2 to 50.5) and on palbociclib plus exemestane for 6.3 months (range, 0.5 to 52.3) whereas in cohort 2 patients showed median time on study of 6.3 months for capecitabine (range, 0.2 to 26.4) and 7.8 months for palbociclib plus fulvestrant (range, 0.8- 31.1).

Permanent discontinuation of treatment was primarily due to progressive disease (PD). Fewer patients, 65.7% in cohort 1 and 58.6% in cohort 2 receiving capecitabine discontinued due to PD, whereas 81.3% of those treated with palbociclib plus exemestane and 68.5% of patients on palbociclib plus fulvestrant arms discontinued treatment due to PD.

Adverse events were reported in 147 (98.0%) patients receiving palbociclib/exemestane, 148 (99.3%) with palbociclib/fulvestrant, and 286 (99.0%) patients receiving capecitabine; of these 133 (88.7%), 128 (85.9%), and 275 (95.2%), respectively, were considered treatment-related.

Serious adverse events occurred in 24 (16.0%) patients on palbociclib plus exemestane and 19 (12.8%) of those on palbociclib/fulvestrant versus 63 (21.8%) of patients receiving capecitabine.


The investigators indicated that no statistical superiority of palbociclib plus endocrine therapy over capecitabine was observed with respect to PFS in patients with HR-positive, HER2-negative metastatic breast cancer that was resistant to aromatase inhibitors.

They wrote that findings from PEARL indirectly suggest that palbociclib combinations are less effective in pretreated patients with metastatic breast cancer and should be used earlier in the treatment timeline, with capecitabine being reserved for later lines.

While the PEARL study did not meet its co-primary objectives, it still provides evidence and suggestions for the management of HR-positive, HER2-negative aromatase inhibitor resistant metastatic breast cancer, the authors stated. Although PFS with palbociclib plus endocrine therapy and capecitabine were similar, toxicity with capecitabine was higher, and patients showed earlier QoL deterioration with capecitabine chemotherapy. Therefore, they underlined that the palbociclib endocrine combination could be the best choice for these patients.

This study was sponsored by the GEICAM Spanish Breast Cancer Group. In addition, Pfizer provided palbociclib and exemestane and AstraZeneca provided fulvestrant.


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 29 December 2020. DOI: