Background: RANK ligand (RANKL) functions via its receptor RANK and pharmacologic inhibition attenuates breast cancer (BC) development and metastatic progression. High RANK expression is associated in hormone receptor negative (HR-) BC with higher pathological complete response (pCR) rates. Denosumab, an antibody against RANKL, will be tested in patients with HR- primary BC in addition to neoadjuvant chemotherapy (NACT). Methods: GeparX will randomize 778 patients to NACT +/- denosumab (120mg sc every 4 weeks for 6 cycles), stratified by lymphocyte predominant BC ( ≤ 50% vs > 50% stromal tumor infiltrating lymphocytes [TILs]), HER2 status, and epirubicin/cyclophosphamide (EC, q2w vs q3w). Secondarily patients will be randomized to the backbone treatment of nab-paclitaxel (nP) 125mg/m² weekly + EC or nP 125mg/m² day 1,8 q22 + EC, stratified by the first randomization. Carboplatin will be given in triple negative (TNBC) and trastuzumab + pertuzumab in HER2+ BC. Patients with primary cT1c-cT4a-d BC, centrally confirmed HR- and centrally assessed HER2, Ki-67, TIL and RANK status on core biopsy can be enrolled. Primary objective is to compare pCR (ypT0 ypN0) rates of NACT +/- denosumab plus backbone treatment and of backbone treatment alone. Secondary objectives are interaction of denosumab treatment with RANK expression; pCR rates per arm for both randomizations in TNBC and HER2+ BC; pCR rates in RANK high vs low; other pCR definitions for both randomizations; response rates; breast conservation rates; toxicity and compliance; and survival. A large translational program is also planned. Sample size (primary endpoint) planning assumed a pCR improvement by denosumab from 54% to 65% (OR = 1.58; 2-sided α = 0.10; 92% power) and by different NACT schedule from 55% to 64% (OR = 1.45; 2-sided α = 0.10; 80% power; overall α = 0.20), requiring 778 patients. Results: Recruitment will start in QII/2016 and is planned for 18 months in 60 sites in Germany. Conclusions: GeparX investigates if the addition of denosumab to standard NACT will increase the pCR rate and which nab-paclitaxel schedule to prefer in primary BC. Clinical trial information: EudraCT No.: 2015-001755-72.