GeparOLA: A randomized phase II trial to assess the efficacy of paclitaxel and olaparib in comparison to paclitaxel/carboplatin followed by epirubicin/cyclophosphamide as neoadjuvant chemotherapy in patients (pts) with HER2-negative early breast cancer (BC) and homologous recombination deficiency (HRD).

Abstract

506 Background: The efficacy and toxicity of olaparib in early BC pts with homologous DNA repair deficiency (here defined as HRD score high tumors +/- germline (g) or tumor (t) BRCA mutation) is not well described. GeparOLA investigates olaparib in HER2 negative early BC with HRD. Methods: GeparOLA (NCT02789332) randomized 102 pts to either paclitaxel 80 mg/m² weekly (Pw) plus olaparib 100 mg twice daily for 12 weeks (PwO n = 65) or Pw plus carboplatin (Cb) AUC2 weekly for 12 weeks (PwCb n = 37), both followed by EC. Randomization was stratified by hormone receptor-status (HR+ vs HR-) and age ( < 40 vs ≥40 years). Pts with untreated primary cT2 - cT4a-d or cT1c with either cN+ or pNSLN+ or triple negative or Ki-67 > 20% were included, with either g/t BRCA mutation and/or high HRD score. The primary endpoint is pathological complete response (pCR; ypT0/is ypN0). A one group χ2-test was planned to exclude the pCR rate of ≤55% in PwO→EC arm. Secondary endpoints are other pCR definitions, breast conservation rate, clinical and imaging response, tolerability and safety. Results: A total of 107 pts were randomized between 9/2016 and 7/2018; 106 started treatment. Median age was 47.0 years [range 25.0-71.0]; 36.2% of pts had cT1, 61.0% cT2, 2.9% cT3, and 31.8% cN-positive tumors; G3: 86.8%; Ki-67 > 20%: 89.6%; TNBC 72.6%; confirmed g /tBRCA 1/2 mutation: 60.4%. pCR rate with PwO was 55.1% (90%CI 44.5%-65.3%) vs PwCb 48.6% (90%CI 34.3%-63.2%). Analysis for the stratified subgroups showed higher pCR rates with PwO in the cohorts of pts < 40 years and HR+ pts Clinical trial information: NCT02789332. Conclusions: GeparOla could not exclude a pCR rate of ≤55% in the PwO arm. Subgroup analysis is hypothesis generating and need further confirmation.[Table: see text]

Neoadjuvant Treatment for Triple Negative Breast Cancer: Recent Progresses and Challenges

“…A confirmatory trial is currently ongoing in order to verify the benefit of single agent talazoparib (NCT02401347). GeparOLA trial (NCT02789332) is a phase II randomized trial to evaluate neoadjuvant paclitaxel and olaparib in patients with HRD [71]. The study randomized 107 patients, including 77 TNBC, to either weekly paclitaxel and daily olaparib or weekly paclitaxel and carboplatin for 12 weeks, and then followed with EC.…”

Practical classification of triple-negative breast cancer: intratumoral heterogeneity, mechanisms of drug resistance, and novel therapies

“…When head-to-head comparisons have been performed across different agents, data suggest that the selection for HRD can predict equally a benefit to DNA-disrupting agents, regardless of their pharmacological class. The phase II trial GeparOLA assessed the efficacy of neoadjuvant paclitaxel and olaparib vs. paclitaxel and carboplatin in patients with HRD: overall, the study failed to show a difference in terms of pCR 109 . Eventually, the combination of PARPis and carboplatin did not result in a synergistic activity, across different settings of care, providing none or narrow added clinical benefit, at the cost of increased toxicity 110,111 .…”

Personalized treatment in metastatic triple‐negative breast cancer: The outlook in 2020

“…Whether the addition of PARPi to platinum‐ or nonplatinum‐based chemotherapy would further improve the treatment outcome in patients with gBRCA mutations or HR defects, is an area of active research. The recently presented GeparOLA study and BROCADE‐3 study have already shown the feasibility of this approach, with quite encouraging efficacy results. Likewise, the combination of PARPi and anti‐PD‐1/ PD‐L1 agents looks quite effective in pre‐clinical models .…”