Palbociclib Fails to Improve PFS in HR+, AI-Resistant Metastatic Breast Cancer

January 12, 2021 - Palbociclib in combination with endocrine therapy failed to result in a statistically significant improvement in progression-free survival over capecitabine in patients with hormone receptor–positive metastatic breast cancer who were resistant to aromatase inhibitors.

Palbociclib (Ibrance) in combination with endocrine therapy failed to result in a statistically significant improvement in progression-free survival (PFS) over capecitabine in patients with hormone receptor–positive metastatic breast cancer who were resistant to aromatase inhibitors (AIs), according to data from the phase 3 PEARL trial (NCT02028507) published in Annals of Oncology.1

At median follow-up of 13.5 months, the median PFS reported in cohort 2 of the trial was 7.5 months (95% CI, 5.7-10.9) with palbociclib plus fulvestrant versus 10.0 months (95% CI, 6.3-12.9) with capecitabine (adjusted hazard ratio [HR], 1.13; 95% CI, 0.85-1.50; P = .398). At a median follow-up of 18.9 months, the median PFS in the wild-type ESR1 population was 8.0 months (95% CI, 6.5-10.9) in the investigational arm versus 10.6 months (95% CI, 7.4-13.0) in the control arm (adjusted HR, 1.11; 95% CI, 0.87-1.41; P = .404).

“The PEARL trial did not provide evidence of PFS superiority of palbociclib plus fulvestrant or of palbociclib plus endocrine therapy in patients without ESR1 mutations over capecitabine in AI-resistant metastatic breast cancer patients,” Miguel Martín, MD, PhD, Medical Oncology, of Instituto de Investigación Sanitaria Gregorio Marańón, and colleagues, wrote in the paper. “However, it is worth noticing that compared with capecitabine, palbociclib plus endocrine therapy was associated with a significant delay in quality-of-life [QoL] deterioration, less treatment discontinuations due to adverse effects [AEs], and a lower proportion of patients with related serious AEs.”

Although palbociclib in combination with endocrine therapy serves as the standard of care for patients with hormone receptor–positive, HER2-negative metastatic breast cancer; however, prior to this trial, the agent had yet to be compared with chemotherapy in a phase 3 trial.

In the multicenter, phase 3 PEARL trial, patients with metastatic breast cancer that was determined to be resistant to AIs were examined in 2 consecutive cohorts. Those who comprised cohort 1 (n = 296) were randomized 1:1 to receive either palbociclib at a daily dose of 125 mg for 3 weeks followed by 1 week off plus exemestane at a daily dose of 25 mg (n = 153) or capecitabine at a daily dose of 2500 mg/m2 for 2 weeks followed by 1 week off (n = 143).

After it had been discovered that ESR1 mutations could confer resistance to treatment with AIs, investigators amended the trial to include a second cohort. In cohort 2 (n = 305), patients were randomized 1:1 to receive palbociclib at the same schedule as cohort 1 plus fulvestrant via intramuscular injection at a dose of 500 mg on days 1 and 15 of cycle 1 and then on day 1 of subsequent 28-day cycles (n = 149) versus capecitabine, which was delivered at the same schedule as cohort 1 (n = 156).

In the trial, patients were stratified based on disease site (visceral vs non-visceral), previous sensitivity to endocrine treatment (relapse after 24 months of adjuvant endocrine therapy or response), previous chemotherapy received for metastatic disease (yes vs no), and their country of origin. Treatment continued until either progressive disease per RECIST v1.1 criteria, symptomatic deterioration was observed, intolerable toxicity was experienced, death occurred, or consent was withdrawn. Notably, dose reductions of palbociclib and capecitabine were permitted in the case of toxicity.

To be eligible for enrollment, patients had to be postmenopausal with hormone receptor–positive and HER2-negative metastatic breast cancer that was resistant to AIs. They had to have measurable disease per RECIST v1.1 criteria or at least 1 lytic or mixed bone lesion present. Patients were able to have received 1 line of chemotherapy for metastatic disease. Additionally, patients needed to have an ECOG performance status of 0-1, a life expectancy of 12 weeks or longer, and acceptable organ function.

If patients had previously undergone CDK4/6 inhibition, or treatment with mTOR or PI3K inhibitors, they could not participate. Those who had received prior capecitabine or who had visceral crisis were also excluded from the analysis.

The co-primary end points of the trial included PFS in cohort 2 and in the subgroup of patients with wild-type ESR1-mutated disease. Key secondary end points comprised PFS with palbociclib/endocrine treatment regardless of ESR1 mutational status, objective response rate (ORR), clinical benefit rate (CBR), duration of response (DOR), overall survival (OS), safety, and patient-reported outcomes (PROs).

ESR1 mutations were evaluated in 92.7% of patients (n = 557) on the trial; 91% of these patients were in the capecitabine arms and 94% were in the palbociclib/endocrine therapy arms. Twenty-nine percent of patients (n = 164) were found to have these mutations present. Baseline demographics and disease characteristics were found to be well balanced between the arms.

At the time of data cutoff for the primary analysis, which was January 14, 2019, a total of 80 patients remained on treatment; 6.7% (n = 10) were on the palbociclib/exemestane arm, 24.8% (n = 37) were on the palbociclib/fulvestrant arm, and 11% (n = 33) were on the capecitabine arm.

Additional data revealed that the median PFS in all patients in cohorts 1 and 2 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 (adjusted HR, 1.11; 95% CI, 0.92-1.34; P = .380). In the ESR1-mutant population, the adjusted HR was 1.12 (95% CI, 0.78-1.60; P = .540).

Moreover, in cohort 2, palbociclib/fulvestrant elicited an ORR of 26.7% versus 33.3% with capecitabine. In the subgroup of patients with ESR1 wild-type disease, palbociclib/endocrine therapy induced an ORR of 27.8% versus 36.9% with capecitabine. The CBR proved to be comparable between the investigative and control arms in cohort 2 and in those with ESR1 wild-type disease. In cohort 2, the median DOR was 9.4 months with palbociclib/fulvestrant versus 12.9 months with capecitabine (HR, 0.69; 95% CI, 0.33-1.46; P = .335). Moreover, in the ESR1 wild-type subgroup, the median DOR was 9.7 months with palbociclib/endocrine therapy versus 11.2 months with capecitabine (HR, 0.75; 95% CI, 0.44-1.25; P = .269).

Regarding PROs, the median time to deterioration in global health status with palbociclib plus endocrine therapy was 8.6 months versus 6.2 months with capecitabine (adjusted HR, 0.67; 95% CI, 0.53-0.85; P = .001).

The most common toxicities to be reported with palbociclib/exemestane, palbociclib/fulvestrant, or capecitabine included neutropenia (57.4% vs 55.7% vs 5.5%, respectively), febrile neutropenia (1.3% vs 0.7% vs 1.4%), hand/foot syndrome (0% vs 0% vs 23.5%), diarrhea (1.3% vs 1.3% vs 7.6%), fatigue (1.3% vs 0.7% vs 5.5%), and anemia (0.7% vs 2.0% vs 3.5%).

Approximately 16% of patients who received capecitabine discontinued treatment because of toxicities compared with 6% of those given palbociclib/exemestane and 6.7% of those given palbociclib/fulvestrant.

A total of 17 deaths were reported on the study; 11 were because of disease progression. Two serious toxicities, pneumonitis and sepsis, were reported in patients who received palbociclib plus endocrine therapy; 4 were reported in those given capecitabine and included diarrhea, worsening of general health status, colitis, and sudden death.


Martín M, Zielinski C, Borrego-Ruiz 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. Ann Oncol. Published online December 29, 2020. doi:10.1016/j.annonc.2020.12.013