Abstract OT-01-02: Adaptlate -a randomized, controlled, open-label, phase-iii trial on adjuvant dynamic marker - adjusted personalized therapy comparing abemaciclib combined with standard adjuvant endocrine therapy versus standard adjuvant endocrine therapy in (clinical or genomic) high risk, hr+/her2- early breast cancer

Goals: The WSG ADAPT trial program is one of the first new generation trials addressing the issue of individualization of (neo)-adjuvant decision-making in early breast cancer (EBC) in a subtype-specific manner. The first WSG ADAPT umbrella trial (NCT01779206) aimed to establish early predictive molecular surrogate markers for response after a short 3-week induction treatment and to omit chemotherapy in a large cohort of early high risk HR+/HER2- patients. The aim of the ADAPTlate phase-III-trial is to improve adjuvant therapy for patients at high risk for late disease recurrence, who have completed definite locoregional therapy (with or without neoadjuvant or adjuvant chemotherapy) and are under adjuvant endocrine treatment. This high-risk population does not derive optimal benefit from standard ET, often develops secondary resistance against ET and consequently late recurrences. With ADAPTlate, it is planned to evaluate whether patients with high-risk EBC derive additional benefit from adding abemaciclib to ET even 2-6 year after their initial diagnosis. Abemaciclib has been shown to improve outcome in metastatic breast cancer and recently, even in early breast cancer when given as part of primary therapy. Methods: WSG-ADAPTcycle is a prospective, multi-center, interventional, two-arm, non-blinded, randomized, controlled adjuvant phase III trial (NCT not yet assigned). It investigates whether patients with HR+/HER2- EBC identified as high-risk during screening (based on clinical or genomic risk) derive additional benefit from 2 years of the CDK4/6 inhibitor abemaciclib combined with ET compared to ET alone. Starting Q3 2020 (enrollment 36 months, 50 sites), 1250 patients will be screened and 903 randomized in a ratio 3:2 (602 to abemaciclib + ET; 301 to standard ET). Pre-/postmenopausal patients with histologically confirmed invasive HR+/HER2- EBC and 2-6 years after primary diagnosis, with either known high clinical risk (c/pN 2-3 OR high CTS score in pN 0-1 OR non-pCR after neoadjuvant chemotherapy in cN 1 or G3 tumors OR G3 and Ki-67 ≥ 40% in pN 0-1) or known high genomic risk (Oncotype Dx® / RS >25 in c/pN 0, RS >18 in c/pN 1 OR high risk Prosigna®, EPclin® or Mammaprint® in pN 0-1) or intermediate clinical, but unknown genomic risk (luminal B-like (G3 or Ki-67 ≥20%) in c/pN 0-1 AND Oncotype DX® in screening either RS >25 in c/pN 0 or RS >18 in c/p N1) will be eligible. Treatment duration is 2 years for the interventional abemaciclib + ET (premenopausal: AI+GnRH) arm, followed by at least 3-6 years ET alone. Patients in control arm will receive 5-8-years ET at investigator´s choice. ePROs are collected using CANKADO. Primary objective is to demonstrate superiority of invasive disease-free survival (iDFS) of abemaciclib + ET vs. standard ET. Secondary objectives include overall survival (OS), distant disease-free survival (dDFS), occurrence of CNS metastases, quality of life (EORTC QLQ-C30, QLQ-BR23, EQ-5D-5L) and translational research. Translational analyses: Exploratory tissue biomarker research will be conducted to assess alterations in molecular markers (e.g., ESR1, PIK3CA, CCND1, CDKN2A, RB1). In addition, ctDNA/ctRNA from optional blood samples will be assessed for mutations and gene expression relevant for HR+/HER2- EBC using the most appropriate technology at the time of testing. Conclusions: ADAPTlate seeks to evaluate whether enhancing ET with a CDK 4/6 inhibitor is superior to ET alone in patients with clinical or genomic high risk EBC even 2-6 years after their initial diagnosis. Translational research aims at assessing potential mechanisms of resistance to endocrine and/or CDK4/6 targeted therapy. Citation Format: Oleg Gluz, Tom Degenhardt, Norbert Marschner, Matthias Christgen, Hans Heinrich Kreipe, Ulrike Nitz, Ronald Kates, Timo Schinkoethe, Monika Graeser, Rachel Würstlein, Sherko Kuemmel, Nadia Harbeck, West German Study Group. Adaptlate -a randomized, controlled, open-label, phase-iii trial on adjuvant dynamic marker - adjusted personalized therapy comparing abemaciclib combined with standard adjuvant endocrine therapy versus standard adjuvant endocrine therapy in (clinical or genomic) high risk, hr+/her2- early breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-01-02.