medwireNews: Palbociclib plus endocrine therapy does not improve progression-free survival (PFS) compared with capecitabine in women with aromatase inhibitor (AI)-resistant metastatic breast cancer (MBC), results of the phase 3 PEARL study show.
Nonetheless, Miguel Martín (CIBERONC-ISCIII GEICAM Spanish Breast Cancer Group, Madrid) and co-investigators found that palbociclib in combination with either exemestane or fulvestrant was better tolerated than capecitabine and was associated with slower declines in global health status.
The multicenter PEARL study included 601 postmenopausal women with hormone receptor-positive, HER2-negative, AI-resistant MBC across two consecutive cohorts.
The first cohort included 296 women who were randomly assigned to receive palbociclib 125 mg/day (3 weeks on, 1 week off) plus the AI exemestane 25 mg/day or to capecitabine 2000 mg/m2 or 2500 mg/m2 per day (2 weeks on, 1 week off) with the dose dependent on age.
During the course of the study, prior to data analysis, evidence emerged that patients pretreated with AIs can develop ESR1 mutations that lead to AI resistance. The researchers therefore added a second cohort in which 305 patients were randomly assigned to receive palbociclib plus intramuscular fulvestrant 500 mg (days 1 and 15 of cycle 1; then day 1 of subsequent 28-day cycles) or capecitabine.
In all, 29% of study participants had ESR1 mutations.
As reported in the Annals of Oncology, there was no significant difference in median PFS between the palbociclib plus fulvestrant and capecitabine groups, regardless of mutation status, at 7.5 and 10.0 months, respectively.
There was also no difference between palbociclib plus endocrine therapy (exemestane or fulvestrant) and capecitabine in people with wild-type ESR1 from both cohorts, at a median of 8.0 and 10.6 months, respectively.
However, fewer patients receiving palbociclib plus exemestane or fulvestrant discontinued treatment due to adverse events (AEs) compared with those receiving capecitabine (6.0 and 6.7 vs 15.9%) and fewer experienced serious treatment-related AEs (4.0 and 3.4 vs 10.4%).
The most common grade 3 or 4 AEs with palbociclib plus exemestane, palbociclib plus fulvestrant, and capecitabine were neutropenia (57.4, 55.7, and 5.5%, respectively), hand–foot syndrome (0.0, 0.0, and 23.5%), and diarrhea (1.3, 1.3, and 7.6%).
The researchers also found that the median time to deterioration in global health status was significantly longer with palbociclib plus endocrine therapy than with capecitabine, at 8.6 versus 6.2 months.
Martín and co-authors say that although “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.”
They add that, when taken together with the results of other trials in this patient population, such as PAOLMA-3, and initial evidence of an overall survival benefit for endocrine therapy and CDK4/6 inhibitors in AI-sensitive MBC, the data from PEARL “indirectly suggest that palbociclib combinations are less effective in pre-treated MBC patients and should be used earlier in the treatment timeline, while capecitabine can be left for later lines.”
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