Abstract OT2-01-06: Phase III study of <u>p</u>albociclib (PD-0332991) in combination with <u>e</u>ndocrine therapy (exemestane or fulvestrant) versus chemotherapy (capecitabine) in hormonal receptor (HR) positive/HER2 negative metastatic breast cancer (MBC) patients with <u>r</u>esistance to <u>a</u>romatase inhibitors. <i>“The PEARL study”</i> (GEICAM/2013-02)
Authors: M Martín, Z Kahan, E Carrasco, CH Bartlett, M Casas, M Gil-Gil, M Muñoz, EM Ciruelos, M Ruiz-Borrego, M Margelí, A Antón, B Bermejo, S Morales, E Gal-Yam, M Koehler, JA García-Sáenz, J de la Haba, I Chacón, C Zielinski
Journal: Cancer Research (2017)

Abstract Background: Endocrine therapy (ET) is the cornerstone treatment for HR–positive, HER2-negative breast cancer patients. However, endocrine resistance is a major clinical challenge.Treatment options at recurrence/progression to AIs include sequential endocrine-based therapiesin monotherapy or in combination with a targeted agent or chemotherapy. Preclinical data suggest that ER+/HER2- BC is dependent on cyclin-dependent kinases 4/6 (CDK4/6) function; the inhibition of this target may be effective in overcome endocrine resistance. Palbociclib (P) is an oral novel CDK4/6 inhibitor that is synergistic with ET in preclinical and clinical studies. Initially this study was designed to demonstrate the clinical benefit of P plus exemestane (E) vs capecitabine (C) (cohort1). Recent studies revealed that the acquisition of ESR1 mutations is a major mechanism of resistance to the treatment of AIs in the metastatic setting. Retrospective analyses show that patients with ESR1 mutation derived no benefit from sequential AI monotherapy. In contrast, preclinical and clinical data indicated that SERD, fulvestrant (F), is active in ESR1 mutant tumors. Hence the choice of endocrine partner with P is particularly important to create optimal synergy in endocrine resistance setting. The current design added cohort 2 of P plus F vs C. The overall study goal is to prospectively answer the question of optimal endocrine partner with P and its efficacy/safety over chemotherapy in endocrine resistant setting. Trial Design:This is an international (5 countries) randomized phase III study with 2 cohorts, patients will be randomized 1:1 to ET (cohort 1: E 25 mg daily, cohort 2: F 500mg days 1 and 15 cycle 1 and then day 1 every 4 weeks) plus P (125 mg daily x3 weeks every 4 weeks) vs. C (1,250 mg/m2 twice daily x2 weeks every 3 weeks). Postmenopausal patients with HR+/HER2- MBC are eligible if resistant to previous AI (letrozole or anastrozole in cohort 1 or any AI in cohort 2) defined as:recurrence while on or within 12 months after the end of adjuvant treatment orprogression while on or within 1 month after the end of treatment for MBC. Previous chemotherapy is permitted either in the (neo)adjuvant setting and/or as first line for MBC. Patients must have measurable disease according to RECIST 1.1 or bone lesions, lytic or mixed, in the absence of measurable disease. The primary objectives are to demonstrate that P plus F is superior to C and that P plus ET is superior to C inwomen whose tumor had estrogen receptor ESR1 wild type in terms of Progression-Free Survival (PFS); secondary objectives are PFS regardless the ESR1 mutational status, overall survival, response rate, clinical benefit rate, response duration, safety, quality of life and biomarkers. The study will recruit approximately 302 patients in cohort 1 and 300 patients in cohort 2. The study started recruitment in March 2014; 290 patients have been included so far (289 cohort1 + 1 cohort 2). Analysis of primary endpoint is planned in Sep2019 (ClinTrials.gov reference NCT02028507. Citation Format: Martín M, Kahan Z, Carrasco E, Bartlett CH, Casas M, Gil-Gil M, Muñoz M, Ciruelos EM, Ruiz-Borrego M, Margelí M, Antón A, Bermejo B, Morales S, Gal-Yam E, Koehler M, García-Sáenz JA, de la Haba J, Chacón I, Zielinski C. Phase III study of palbociclib (PD-0332991) in combination with endocrine therapy (exemestane or fulvestrant) versus chemotherapy (capecitabine) in hormonal receptor (HR) positive/HER2 negative metastatic breast cancer (MBC) patients with resistance to aromatase inhibitors. “The PEARL study” (GEICAM/2013-02) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-01-06.