A randomized phase II study of palbociclib plus exemestane with GNRH agonist versus capecitabine in premenopausal women with hormone receptor-positive metastatic breast cancer (KCSG-BR 15-10, NCT02592746).

Background: Endocrine treatment is preferred recommendation by clinical guidelines in premenopausal as well as postmenopausal women with hormone receptor(HR)-positive, HER2-negative metastatic breast cancer(MBC). In real-world clinical practice, however, substantial numbers of patients are treated with chemotherapy in earlier lines based on endocrine resistance and/or on physician's concern of worse prognosis associated with aggressive tumor behavior and younger age. In terms of the chemotherapy regimens, capecitabine seems one of the most popular options. The purpose of this phase II study is to assess the safety and the clinical anti-tumor activity of exemestane plus GNRH agonist in combination with palbociclib versus capecitabine in premenopausal HR-positive MBC patients.Methods: This is a prospective, two-arm, randomized, multi-center open-label phase II study of the Korean Cancer Study Group. Patients were allowed with previous 1 line of chemotherapy for MBC. De Novo metastatic patients should have been treated with tamoxifen before enrollment. Patients were randomized to chemotherapy (capecitabine 1250 mg/rrftwice a day from day 1 to 14 every 3 weeks) or endocrine therapy combination (exemestane 25 mg for 28 days and palbociclib 125 mg for 21 days every 4 weeks with GNRH agoinst). Primary endpoint was Progression-Free Survival (PFS). Results: Among 189 patients enrolled between 2016 and 2018 from 14 centers, 184 patients were randomly assigned to chemotherapy (n = 92) or endocrine therapy with palbociclib (n = 92). Median age was 44 (range 28-58). De Novo MBC was found equally in both arm (30%). During median 14 months of follow-up, median PFS was superior in endocrine with palbociclib than in capecitabine arm [19.0 vs. 11.3 months, p = 0.0493 by log-rank test; Hazard Ratio (HR) 0.643 (0.415-0.999), p = 0.0493]. Approximately half of the patients (51%) were treatment naive in the advanced setting (49% for palbociclib vs. 5 1% for capecitabine). Grade III or more hematologic toxicities were more common in palbociclib than in capecitabine with statistical significance (60.9% vs. 19.2%, p < 0.0001). Diarrhea (11% vs. 38%) and Hand-Foot syndromes (1%vs. 76%) were more common in capecitabine arm. Conclusions:Exemestane plus palbociclib with ovarian suppression showed clinical benefit in terms of PFS compared with capecitabine in patients with premenopausal ER-positive MBC.