Although patients with hormone receptor (HR)-positive, HER2-negative, aromatase inhibitor–resistant metastatic breast cancer maintained quality of life for a longer time following treatment with palbociclib plus either exemestane or fulvestrant than capecitabine, those receiving chemotherapy demonstrated improved progression-free survival and higher response rates compared with the palbociclib-treated patients. Details from the phase III PEARL study were published by Miguel Martín, MD, PhD, in 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.
Miguel Martín, MD, PhD
PEARL Methods
Therefore, the investigators conducted the multicenter, phase III randomized PEARL study in patients with HR-positive, HER2-negative metastatic breast cancer who were resistant to aromatase inhibitors. The study comprised two consecutive cohorts.
In cohort 1, 296 patients were randomly assigned 1:1 to palbociclib plus exemestane or capecitabine. Upon emerging evidence that estrogen receptor-1 (ESR1) mutations could induce resistance to aromatase inhibitors, the study was amended to include 305 patients in cohort 2 who were randomly assigned 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 tumor DNA samples were obtained at baseline for analysis of ESR1 hotspot mutations.
The co-primary endpoints were progression-free survival in cohort 2 patients and progression-free survival in patients having wild-type ESR1 in both cohorts.
Progression-Free Survival
The median follow-up was 13.5 months (range = 0.0–30.7) in cohort 2 and the wild-type ESR1 population, and 18.9 months (range = 0.0–56.3) in cohort 1 and patients with mutated ESR1.
Regarding cohort 1 patients, the median progression-free survival 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 = .398).
Patients with wild-type ESR1 demonstrated a median progression-free survival 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 = .404).
Evaluation of efficacy, the secondary endpoint of the study, showed that median progression-free survival in cohort 1 and cohort 2 patients overall was 7.4 months (95% CI = 5.9–9.3) with palbociclib plus endocrine therapy vs 9.4 months (95% CI = 7.5–11.3) with capecitabine (aHR = 1.11, 95% CI = 0.92–1.34, P = .380).
The objective response rate was also higher with capecitabine chemotherapy across treatment arms. In cohort 2, the objective response rate was 26.7% for palbociclib plus fulvestrant vs 33.3% for capecitabine. Patients with wild-type ESR1 demonstrated an objective response rate of 27.8% with palbociclib plus endocrine therapy vs 36.9% in patients receiving capecitabine.
The completion rate of patient-reported outcomes was similar across the arms, surpassing 82% until cycle 13. The patient-reported outcomes showed the median time to deterioration in global health status was 8.6 months in patients treated with palbociclib plus endocrine therapy vs 6.2 months in those receiving capecitabine (aHR = 0.67, 95% CI = 0.53–0.85, P = .001).
Eighty patients remained on study treatment as of the January 2019 cut-off date; of these, 10 (6.7%) were being treated with palbociclib plus exemestane, 37 (24.8%) were being treated with 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 = 0.2–50.5) and on palbociclib plus exemestane for 6.3 months (range = 0.5–52.3), whereas in cohort 2, patients showed median time on study of 6.3 months for capecitabine (range = 0.2–26.4) and 7.8 months for palbociclib plus fulvestrant (range = 0.8–31.1).
Permanent discontinuation of treatment was primarily due to progressive disease. Fewer patients— 65.7% in cohort 1 and 58.6% in cohort 2—receiving capecitabine discontinued due to progressive disease, whereas 81.3% of those treated with palbociclib plus exemestane and 68.5% of patients on palbociclib plus fulvestrant arms discontinued treatment due to progressive disease.
Adverse events were reported in 147 (98.0%) patients receiving palbociclib/exemestane, 148 (99.3%) receiving 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 vs 63 (21.8%) of patients receiving capecitabine.
Conclusions
The investigators indicated that no statistical superiority of palbociclib plus endocrine therapy over capecitabine was observed with respect to progression-free survival 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 progression-free survival with palbociclib plus endocrine therapy and capecitabine were similar, toxicity with capecitabine was higher, and patients showed earlier quality-of-life deterioration with capecitabine chemotherapy. Therefore, they underlined that the palbociclib endocrine combination could be the best choice for these patients.
Disclosure: This study was sponsored by the GEICAM Spanish Breast Cancer Group. For full disclosures of the study authors, visit annalsofoncology.org.
