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

Abstract

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 triple-negative breast cancer (TNBC) or cT1c and Ki-67>20% BC with HRD were randomised either to paclitaxel (P) 80 mg/m2 weekly plus olaparib (O) 100 mg twice daily for 12 weeks or P plus carboplatinum (Cb) area under the curve 2 weekly for 12 weeks, both followed by epirubicin/cyclophosphamide (EC). Stratification factors were hormone receptor (HR) status (HR+ versus HR-) and age (<40 versus ≥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 the PO-EC arm. Secondary end points were other pCR definitions, breast conservation rate, clinical/imaging response, tolerability and safety.

Results: A total of 107 patients were randomised between September 2016 and July 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; grade 3 tumours: 86.8%; Ki-67>20%: 89.6%; TNBC: 72.6%; confirmed gBRCA1/2 mutation: 56.2%. The pCR rate with PO was 55.1% [90% confidence interval (CI) 44.5% to 65.3%] versus PCb 48.6% (90% CI 34.3% to 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.

Conflict of interest statement

Disclosure PAF reports grants from Novartis, BioNtech, personal fees from Novartis, Roche, Pfizer, Celgene, Daiichi Sankyo, AstraZeneca, MacroGenics, Eisai, Merck Sharp & Dohme, grants from Cepheid, personal fees from Lilly, during the conduct of the study. TL reports non-financial support from Pharma Mar, Daiichi Sankyo, Celgene; personal fees and non-financial support from MSD, Pfizer, Roche, Clovis; personal fees from Amgen, Novartis, Teva, Tesaro. AS reports grants from Celgene, Roche, AbbVie, Molecular Partners, expert testimony from Roche and AstraZeneca; travel expenses from Celgene, Roche and Pfizer, honoraria from Roche, Celgene, Pfizer, Novartis, AstraZeneca, MSD, Tesaro and Lilly, outside the submitted work. CJ reports personal fees from AstraZeneca and Roche during the conduct of the study. JH reports personal fees and travel expenses from Pfizer, Roche, AstraZeneca; personal fees from Lilly, Celgene, MSD, AbbVie, Eisai; grants from Hexal, Celgene; grants and personal fees from Novartis, travel expenses from Daiichi Sankyo, outside the submitted work. WDS reports grants from German Breast Group, during the conduct of the study; personal fees from AstraZeneca, outside the submitted work. SaS reports other from AstraZeneca during the conduct of the study; personal fees and advisory boards from Amgen, Hexal, Roche, Mundipharma; travel expenses from Novartis, outside the submitted work. CD reports personal fees from Novartis, Roche, MSD Oncology, Daiichi Sankyo, grants from Myriad Genetics, other from Sividon Diagnostics/Myriad outside the submitted work and has a patent EP18209672 pending, a patent EP20150702464 pending, and a patent software (VMscope digital pathology) pending. CH reports personal fees from Roche, Celgene, Pfizer, Lilly, AstraZeneca, Novartis outside the submitted work. KR reports personal fees from AstraZeneca, Tesaro, Pfizer outside the submitted work. RS reports grants from Cologne Furtune during the conduct of the study. J-UB reports personal fees from Amgen, AstraZeneca, MSD, Novartis, Pfizer, Roche, SonoScape, outside the submitted work. MU reports personal fees and non-financial support to the institute from AbbVie, Amgen GmbH, AstraZeneca, Celgene GmbH, Daiichi Sankyo, Eisai GmbH, MSD, Mundipharma, Myriad Genetics, Odonate, Pfizer GmbH, Roche, Sanofi Aventis Deutschland GmbH; Teva Pharmaceuticals Ind Ltd, Novartis, Clovis Oncology; personal fees and others from BMS, Lilly; personal fees from Puma Biotechnology, Pierre Fabre outside the submitted work. SL reports grants and honoraria from AstraZeneca during the conduct of the study; grants and honoraria from AbbVie, Amgen, Celgene, Novartis, Pfizer, Roche, other from Seattle Genetics, PriME/ Medscape; personal fees and lecture honoraria from Chugai, grants from Teva, Vifor, Immunomedics grants and honoraria from Daiichi Sankyo, honoraria from Lilly, Samsung, Eirgenix, BMS, Puma, MSD, outside the submitted work and has a patent EP14153692.0 pending. All other authors declare no conflict of interest.

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