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Palbociclib not statistically superior to capecitabine in PFS

Conference
SABCS 2019
Trial
Phase 3, PEARL

The PEARL study did not demonstrate a statistical superiority in progression-free survival (PFS) for palbociclib + exemestane versus capecitabine in metastatic breast cancer patients who progress to aromatase inhibitors, neither did it demonstrate superiority of palbociclib + exemestane in the luminal subgroup. Treatment with palbociclib + exemestane was generally better tolerated than capecitabine.

Palbociclib is approved for use in combination with endocrine therapy in hormone receptor (HR)-positive, human epidermal growth factor 2 (HER2)-negative metastatic breast cancer patients in first and later lines. However, the relative value of palbociclib plus endocrine therapy versus chemotherapy in pre-treated patients has not been established yet. PEARL is a multinational, open-label, controlled, randomised phase 3 trial comparing the efficacy and safety of palbociclib in combination with endocrine therapy (exemestane or fulvestrant) versus capecitabine in postmenopausal women with HR-positive, HER2-negative metastatic breast cancer whose disease progressed on aromatase inhibitors [1]. The study had 2 successive cohorts. In cohort 1, patients were randomised 1:1 to exemestane 25 mg daily + palbociclib 125 mg 3 weeks on/1 week off, every 28 days versus capecitabine 1,250 mg/m2 twice daily 2 weeks on/1 week off, every 21 days. Patients aged >70 years received capecitabine 1,000 mg/m2. In 2016, after data showing that ESR1 mutations may induce resistance to aromatase inhibitors but not to fulvestrant, cohort 2 was added to the trial, with fulvestrant 500 mg (days 1 and 15 of cycle 1 and then every 28 days) plus palbociclib 125 mg 3 weeks on/1 week off, every 28 days versus capecitabine 1,250 mg/m2 (with the same dose reduction in patients aged >70 years as in cohort 1). It needs to be noted that retrospective data suggested that patients with ESR1 mutations derived little or no benefit from aromatase inhibitor therapy. In contrast, fulvestrant may exhibit non-cross resistance to tamoxifen or aromatase inhibitors and seems to be active in ESR1 mutant tumours [2]. Stratification criteria were disease site (visceral vs non-visceral), prior sensitivity to endocrine therapy (yes vs no), prior chemotherapy for metastatic breast cancer (yes vs no), and country. Co-primary objectives were PFS of palbociclib + fulvestrant versus capecitabine regardless of the ESR1 mutational status and PFS of palbociclib + endocrine therapy (exemestane or fulvestrant) versus capecitabine with ESR1 wildtype tumours. An exploratory analysis of intrinsic breast cancer subtypes determined by an algorithm derived from the HTG EdgeSeq Oncology Biomarker Panel was performed as well. Between March 2014 and July 2018, a total of 601 patients were recruited in 4 countries (cohort 1: n=296; cohort 2: n=305). Baseline characteristics are outlined in the Table.

Table. Demographics and disease characteristics [1]

Median follow-up was 13.5 months (range 0.0-30.7); median PFS was 7.5 months for patients who received palbociclib + fulvestrant versus 10 months for patients who were treated with capecitabine (adjusted HR [HRa] 1.09; 95% CI 0.83-1.44; P=0.537). The objective response rate (ORR) was 26.7% for palbociclib + fulvestrant versus 33.3% for capecitabine. The analysis of breast cancer subtypes was performed for 74.4% of patients; it was shown that 89.1% (palbociclib + endocrine therapy) and 91.5% (capecitabine) had luminal tumours. For luminal patients, median PFS was 7.5 months for patients on palbociclib + fulvestrant versus 10 months for those on capecitabine (HR 1.07; 95% CI 0.77-1.50; P=0.684); for non-luminal patients, it was 4.4 months with palbociclib + fulvestrant versus 14.8 months with capecitabine (HR 2.39; 95% CI 0.81-7.08; P=0.116).

ESR1 wildtype results (both cohorts) showed that with a median follow-up of 19.0 months (range 0.0-56.3), median PFS was 8.0 months for patients on palbociclib + endocrine therapy versus 10.6 months in capecitabine (HRa 1.08; 95% CI 0.85-1.36; P=0.526). The ORR was 27.8% for palbociclib + endocrine therapy versus 36.9% for capecitabine. The analysis of breast cancer subtypes was performed for 79.6% of patients: 89.2% (palbociclib + endocrine therapy) and 91.8% (capecitabine) had luminal tumours. For luminal patients, median PFS was 9.3 months with palbociclib + endocrine therapy versus 11.0 months with capecitabine (HR 1.02; 95% CI 0.77-1.34; P=0.913); for non-luminal patients, it was 2.7 months with palbociclib + endocrine therapy versus 13.7 months for those on capecitabine (HR 3.19; 95% CI 1.28-7.95; P=0.013).

Most frequent grade 3-4 toxicities with exemestane + palbociclib, palbociclib + fulvestrant, and capecitabine, respectively, were neutropenia (57.4%, 55.7%, and 5.5%), febrile neutropenia (1.3%, 0.7%, and 1.4%), hand/foot syndrome (0%, 0%, and 23.5%), and diarrhoea (1.3%, 1.3%, and 7.6%).

1. Turner NC, et al. J Clin Oncol. 2016;34:512-512.
2. Martín M, et al. GS2-07. SABCS 2019.



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