Neoadjuvant paclitaxel/olaparib in comparison to paclitaxel/carboplatinum in patients with HER2-negative breast cancer and homologous recombination deficiency (GeparOLA study)

Background: The efficacy and toxicity of olaparib as combination therapy in early breast cancer (BC) patients with homologous recombinant deficiency (HRD score high and/or germline (g) or tumour (t) BRCA1/2 mutation) is not well described. GeparOLA (ClinicalTrials.gov, NCT02789332) investigated olaparib in combination with paclitaxel in HER2-negative early BC with HRD.

Patients and methods: Patients with untreated primary HER2-negative cT2-cT4a-d or cT1c with either cN+ or pNSLN+ or cT1c and TNBC or cT1c and Ki-67>20% BC with HRD were randomised either to paclitaxel (P) 80mg/m2 weekly plus olaparib (O) 100mg twice daily for 12 weeks or P plus carboplatinum (Cb) AUC2 weekly for 12 weeks, both followed by epirubicin/cyclophosphamide (EC). Stratification factors were hormone receptor (HR) status (HR+ vs HR-) and age (<40 vs ≥40 years). The primary endpoint was pathological complete response (pCR; ypT0/is ypN0). A two-sided one group χ2-test was planned to exclude a pCR rate of ≤55% in PO-EC arm. Secondary endpoints were other pCR definitions, breast conservation rate, clinical/imaging response, tolerability and safety.

Results: A total of 107 patients were randomised between 09/2016 and 07/2018; 106 (PO N=69; PCb N=37) started treatment. Median age was 47.0 years [range 25.0-71.0]; 36.2% had cT1, 61.0% cT2, 2.9% cT3, and 31.8% cN-positive tumours; G3: 86.8%; Ki-67>20%: 89.6%; TNBC: 72.6%; confirmed gBRCA1/2 mutation: 56.2%. pCR rate with PO was 55.1% (90%CI 44.5%-65.3%) vs PCb 48.6% (90%CI 34.3%-63.2%). Analysis for the stratified subgroups showed higher pCR rates with PO in the cohorts of patients <40 years and HR+ patients.

Conclusion: GeparOLA could not exclude a pCR rate of ≤55% in the PO arm. PO was significantly better tolerated and the combination merits further evaluation.

Keywords: HER2-negative breast cancer; HRD; PARP inhibitor; carboplatinum; neoadjuvant therapy; olaparib.