This is a multicenter, prospective, randomized, open-label phase II study evaluating the efficacy and safety of PO→EC as neoadjuvant treatment of operable and locally advanced breast cancer in patients with HR deficiency. Patients will be randomized to receive * paclitaxel 80 mg/m² iv weekly in combination with olaparib tablets 100 mg (4X25mg) twice daily for 12 weeks (65 patients) or * paclitaxel 80 mg/m² iv weekly in combination with carboplatin AUC 2 iv weekly for 12 weeks (37 patients) both followed by 4 cycles of epirubicin 90 mg/m² and cyclophosphamide 600 mg/m² (EC) either every 3 or every 2 weeks followed by surgery. The control arm was chosen to allow direct comparison with one of the currently considered standard of care regimen.
The efficacy of olaparib in germline HRD score high with or without BRCA 1/2 mutation carriers with breast cancer is not well described * The efficacy and safety of olaparib included in a standard of care regimen like paclitaxel weekly followed by epirubicin and cyclophosphamide (Pw--\>EC) is unknown * Carboplatin increased the pCR rate in patients with triple-negative breast cancer (TNBC) in two randomized phase II neoadjuvant studies when added to an anthracycline, cyclophosphamide and paclitaxel (GeparSixto, CALBG 40603). pCR rates were even higher in patients with germline BRCA 1 or 2 mutations (ypT0/is ypN0 65%) and with HRD score high (ypT0/is ypN0 63%). * The TNT study showed a doubling in response rate for patients receiving carboplatin vs docetaxel in patients with germline BRCA 1 or 2 mutations. * There is a high correlation between tumor and germline BRCA 1/2 mutations. * Data from Geparsixto study showed that triple negative breast patients have an HR deficiency in about 70% (67% have a high HRD and 30% have a tBRCA mutation) * About 5% of tBRCA patients have a low HRD score * gBRCA2 patients are older when diagnosed and are more likely to have an HRpos tumor. * The GeparOLA study aims to support the decision for a phase III study exploring the addition of olaparib to a Pw--\>EC schedule by providing an estimate on the pCR rate in the targeted population but also by providing estimate comparison to paclitaxel and carboplatin followed by epirubicin and cyclophosphamide (PCb--\>EC) as carboplatin is more and more considered a standard option of care in HR deficient patients (tBRCA 1/2 mutations and/or HRD score high).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
107
paclitaxel 80 mg/m² iv weekly in combination with olaparib tablets 100 mg twice daily for 12 weeks (PwO) (65 patients)
paclitaxel 80 mg/m² iv weekly in combination with carboplatin AUC 2 iv weekly for 12 weeks (PwCb) (37 patients)
both Arms followed by 4 cycles of epirubicin 90 mg/m² and cyclophosphamide 600 mg/m² (EC) either every 3 or every 2 weeks followed by surgery.
In both study arms, treatment will be given until surgery, disease progression, unacceptable toxicity, or withdrawal of consent of the patients.
Hormone-receptor status (HR+ vs HR-) Age \< 40 years vs \>= 40 years
Kliniken Esslingen, Gynäkologie Onkologie
Esslingen am Neckar, Baden-Wurttemberg, Germany
Universitätsklinikum Erlangen
Erlangen, Bavaria, Germany
Onkologisches Zentrum am Rotkreuzklinikum München
München, Bavaria, Germany
Elisabeth Krankenhaus
Kassel, Hesse, Germany
Sana Klinikum Hameln-Pyrmont
Hamelin, Lower Saxony, Germany
Gemeinschaftspraxis
Hildesheim, Lower Saxony, Germany
Klinikum Südstadt
Rostock, Mecklenburg-Vorpommern, Germany
Marienhospital Witten
Witten, North Rhine-Westphalia, Germany
Martin-Luther-Universität Halle Wittenberg
Halle, Saxony-Anhalt, Germany
Johanniter-Krankenhaus Genthin-Stendal
Stendal, Saxony-Anhalt, Germany
...and 2 more locations
response by pCR =ypT0/is ypN0
Assess the efficacy of olaparib in HER2-negative early Breast Cancer and HRD (BRCA 1/2 mutations and/or HRD positive). Pathological complete response of breast and lymph nodes (ypT0/is ypN0) defined as no microscopic evidence of residual invasive viable tumor cells in all resected specimens of the breast and axilla. Pathological response will be assessed considering all removed breast and lymphatic tissues from all surgeries.
Time frame: 24 weeks
response by pCR =ypT0/is ypN0
To assess the pCR rates of patients receiving PO→EC and the pCR rates of patients receiving paclitaxel and carboplatin followed by EC (PCb→EC)
Time frame: 12 weeks
response by pCR =ypT0/is ypN0 in stratified subgroups
To assess the pCR rates (ypT0/is, ypN0) in the stratified subgroups
Time frame: 24 weeks
response by pCR according to other definitions
To determine other pCR rates (ypT0 ypN0; ypT0 ypN0/+; ypT0/is ypN0/+; ypT(any) ypN0) of patients receiving PO→EC and to compare them with the pCR rates of patients receiving PCb→EC.
Time frame: 24 weeks
response by pCR in HRD high versus tBRCA
To assess the pCR rate in HRD high with vs without tBRCA mutation
Time frame: 24 weeks
Response rate by sono and/or mammo
To determine the response rates of the breast tumor and axillary nodes based on physical examination and imaging tests (sonography, mammography, or MRI) with PO→EC and to compare it with PCb→EC. Clinical (c) and imaging (i) response will be assessed after EC and before surgery by physical examination and imaging tests. Sonography is the preferred examination, however, if sonography appears not to provide valid results or is not performed, other imaging tests will be considered.
Time frame: 12 weeks
Response rate by sono and/or mammo
To determine the response rates of the breast tumor and axillary nodes based on physical examination and imaging tests (sonography, mammography, or MRI) with PO→EC and to compare it with PCb→EC. Clinical (c) and imaging (i) response will be assessed after EC and before surgery by physical examination and imaging tests. Sonography is the preferred examination, however, if sonography appears not to provide valid results or is not performed, other imaging tests will be considered.
Time frame: 24 weeks
Breast Conservation rate
To determine the breast conservation rate with PO→EC and to compare it with PCb→EC. Breast conservation is defined as tumorectomy, segmentectomy or quadrantectomy as a most radical surgery.
Time frame: 24 weeks
Toxicity of treatment
To assess the toxicity and compliance of PO→EC and to compare it with PCb→EC. Tolerability and safety will be assessed on the basis of adverse events, serious adverse events, adverse events of special interest and treatment discontinuations. Safety by toxicity grades is defined by the NCI-CTCAE version 4.0.
Time frame: 24 weeks
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