Abstract GS3-01: Investigating denosumab as an add-on treatment to neoadjuvant chemotherapy and two different nab-paclitaxel schedules in a 2x2 design in primary breast cancer - First results of the GeparX study
Authors: Blohmer Jens-Uwe , Link Theresa , Kümmel Sherko , Untch Michael , Just Marianne , Fasching Peter A , Schneeweiss Andreas , Wimberger Pauline , Stötzer Oliver , Huober Jens , Thill Marc , Jackisch Christian , Rhiem Kerstin , Hanusch Claus , Denkert Carsten , Engels Knut , Nekljudova Valentina , Loibl Sibylle 
Published: March 2020

Abstract
Background Pharmacologic inhibition of the receptor RANK with denosumab can prevent or delay bone metastasis in patients with breast cancer (BC) and may improve disease-free survival in postmenopausal woman with hormone receptor (HR) positive BC. The GeparSepto study demonstrated an increased pCR rate after weekly nab-paclitaxel compared to weekly standard solvent-based paclitaxel, whereas the ETNA did not. It remains still unclear which administration regimen should be preferred for nab-paclitaxel. GeparX investigates whether the addition of denosumab to anthracycline/taxan-containing neoadjuvant chemotherapy (NACT) increases the pCR rate and which nab-paclitaxel schedule should be preferred for primary BC. Methods GeparX, a phase II study, was planned to randomize 778 patients to NACT+/-denosumab (120mg s.c. q4w for 6 cycles), stratified by lymphocyte predominant BC (≤50% vs &gt;50% stromal tumor infiltrating lymphocytes [sTILs]), subtype (HER2-/HR+ vs triple negative (TNBC) vs HER2+), and epirubicin/cyclophosphamide (EC, q2w vs q3w). Secondarily, patients are randomized to different taxane backbones: nab-paclitaxel 125mg/m² weekly+EC or nab-paclitaxel 125mg/m² day 1,8 q22 (2/3)+EC. Carboplatin was given in TNBC and ABP 980 + pertuzumab (biosimilar substudy) in HER2+ BC. Patients with primary cT1c-cT4a-d BC and centrally assessed HR, HER2, Ki-67, and sTILs on core biopsy could be enrolled. Co-primary objectives compare the pCR (ypT0 ypN0) rates of NACT+/-denosumab and the pCR rates between the two backbone nab-paclitaxel treatments. Secondary objectives are interaction of denosumab treatment with RANK expression; pCR per arm for both randomizations in TNBC and HER2+ BC; pCR in RANK high vs low; other pCR definitions for both randomizations; response rates; breast conservation rates; toxicity and compliance; survival. The biosimilar substudy evaluates safety and efficacy of the biosimilar trastuzumab ABP 980 in combination with pertuzumab for HER2+ positive BC. Sample size (primary endpoint) planning assumed a pCR improvement by denosumab from 35% to 46% (OR=1.58; 2-sided α=0.10; 92% power) and by different nab-paclitaxel schedule from 36% to 45% (OR=1.45; 2-sided α=0.10; 80% power; overall α=0.20), requiring 778 patients (2-sided α=0.10; 80% power). Results A total of 780 patients were randomized between 2/2017 and 3/2019. Baseline characteristics were well balanced. Median age was 49.0 years [range 22-80]; 37.7% of patients had cT1, 56.3% cT2, 6.0% cT3/ T4, and 38.1% were cN+; G3 was reported in 66.5% and Ki-67 &gt;20% in 83.1%; 7.9% of tumors showed &gt;50% sTILs. 40.6% of patients had TNBC, 39.7% HER2/HR+ BC and 19.6% HER2+ BC. 343 serious adverse events (SAEs) in a total of 214 patients were reported. The rate of patients with at least one SAE was higher with nab-paclitaxel 125mg/m² weekly than in 2/3 weeks (30.8% vs 24.1%) irrespective of the addition of denosumab. The last patient will be operated at the beginning of October 2019. Conclusions The results of the primary endpoints and selected secondary endpoints will be presented at the meeting. Funding: The trial was financially supported by Amgen and Celgene
Citation Format: Jens-Uwe Blohmer, Theresa Link, Sherko Kümmel, Michael Untch, Marianne Just, Peter A Fasching, Andreas Schneeweiss, Pauline Wimberger, Oliver Stötzer, Jens Huober, Marc Thill, Christian Jackisch, Kerstin Rhiem, Claus Hanusch, Carsten Denkert, Knut Engels, Valentina Nekljudova, Sibylle Loibl. Investigating denosumab as an add-on treatment to neoadjuvant chemotherapy and two different nab-paclitaxel schedules in a 2x2 design in primary breast cancer - First results of the GeparX study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS3-01.