Neoadjuvant PARP inhibitor scheduling in BRCA1 and BRCA2 related breast cancer: PARTNER, a randomized phase II/III trial
Abstract Poly (ADP-ribose) polymerase inhibitors (PARPi) exploit DNA repair deficiency in germline BRCA1 and BRCA2 pathogenic variant (gBRCAm) cancers. Haematological toxicity limits chemotherapy-PARPi treatment combinations. In preclinical models we identified a schedule combining olaparib and carb...
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2025-05-01
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| Online Access: | https://doi.org/10.1038/s41467-025-59151-0 |
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| author | Jean E. Abraham Lenka Oplustil O’Connor Louise Grybowicz Karen Pinilla Alba Alimu Dayimu Nikolaos Demiris Caron Harvey Lynsey M. Drewett Rebecca Lucey Alexander Fulton Anne N. Roberts Joanna R. Worley Ms Anita Chhabra Wendi Qian Jessica Brown Richard Hardy Anne-Laure Vallier Steve Chan Maria Esther Una Cidon Elizabeth Sherwin Amitabha Chakrabarti Claire Sadler Jen Barnes Mojca Persic Sarah Smith Sanjay Raj Annabel Borley Jeremy P. Braybrooke Emma Staples Lucy C. Scott Cheryl A. Palmer Margaret Moody Mark J. Churn Domenic Pilger Guido Zagnoli-Vieira Paul W. G. Wijnhoven Mukesh B. Mukesh Rebecca R. Roylance Philip C. Schouten Nicola C. Levitt Karen McAdam Anne C. Armstrong Ellen R. Copson Emma McMurtry Susan Galbraith Marc Tischkowitz Elena Provenzano Mark J. O’Connor Helena M. Earl PARTNER Trial Group |
| author_facet | Jean E. Abraham Lenka Oplustil O’Connor Louise Grybowicz Karen Pinilla Alba Alimu Dayimu Nikolaos Demiris Caron Harvey Lynsey M. Drewett Rebecca Lucey Alexander Fulton Anne N. Roberts Joanna R. Worley Ms Anita Chhabra Wendi Qian Jessica Brown Richard Hardy Anne-Laure Vallier Steve Chan Maria Esther Una Cidon Elizabeth Sherwin Amitabha Chakrabarti Claire Sadler Jen Barnes Mojca Persic Sarah Smith Sanjay Raj Annabel Borley Jeremy P. Braybrooke Emma Staples Lucy C. Scott Cheryl A. Palmer Margaret Moody Mark J. Churn Domenic Pilger Guido Zagnoli-Vieira Paul W. G. Wijnhoven Mukesh B. Mukesh Rebecca R. Roylance Philip C. Schouten Nicola C. Levitt Karen McAdam Anne C. Armstrong Ellen R. Copson Emma McMurtry Susan Galbraith Marc Tischkowitz Elena Provenzano Mark J. O’Connor Helena M. Earl PARTNER Trial Group |
| author_sort | Jean E. Abraham |
| collection | DOAJ |
| description | Abstract Poly (ADP-ribose) polymerase inhibitors (PARPi) exploit DNA repair deficiency in germline BRCA1 and BRCA2 pathogenic variant (gBRCAm) cancers. Haematological toxicity limits chemotherapy-PARPi treatment combinations. In preclinical models we identified a schedule combining olaparib and carboplatin that avoids enhanced toxicity but maintains anti-tumour activity. We investigated this schedule in a neoadjuvant, phase II-III, randomised controlled trial for gBRCAm breast cancers (ClinicalTrials.gov ID:NCT03150576; PARTNER). The research arm included carboplatin (Area Under the Curve 5, 3-weekly); paclitaxel (80 mg/m2, weekly) day 1, plus olaparib (150 mg twice daily) day 3-14 (4 cycles), followed by anthracycline-containing chemotherapy (3 cycles); control arm gave chemotherapy alone. The primary endpoint, pathological complete response rate, showed no statistical difference between research 64.1% (25/39); control 69.8% (30/43) (p = 0.59). However, estimated survival outcomes at 36-months demonstrated improved event-free survival: research 96.4%, control 80.1% (p = 0.04); overall survival: research 100%, control 88.2% (p = 0.04) and breast cancer specific survival: research 100%, control 88.2% (p = 0.04). There were no statistical differences in relapse-free survival and distant disease-free survival, both were: research 96.4%, control 87.9% (p = 0.20). Similarly, local recurrence-free survival and time to second cancer were both: research 96.4%, control 87.8% (p = 0.20). The PARTNER trial identified a safe, tolerable schedule combining neoadjuvant chemotherapy with olaparib. This combination demonstrated schedule-dependent overall survival benefit in early-stage gBRCAm breast cancer. This result needs confirmation in larger trials. |
| format | Article |
| id | doaj-art-e2af581ec0d74236a2b8a7f93547802e |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-e2af581ec0d74236a2b8a7f93547802e2025-08-20T03:53:58ZengNature PortfolioNature Communications2041-17232025-05-0116111510.1038/s41467-025-59151-0Neoadjuvant PARP inhibitor scheduling in BRCA1 and BRCA2 related breast cancer: PARTNER, a randomized phase II/III trialJean E. Abraham0Lenka Oplustil O’Connor1Louise Grybowicz2Karen Pinilla Alba3Alimu Dayimu4Nikolaos Demiris5Caron Harvey6Lynsey M. Drewett7Rebecca Lucey8Alexander Fulton9Anne N. Roberts10Joanna R. Worley11Ms Anita Chhabra12Wendi Qian13Jessica Brown14Richard Hardy15Anne-Laure Vallier16Steve Chan17Maria Esther Una Cidon18Elizabeth Sherwin19Amitabha Chakrabarti20Claire Sadler21Jen Barnes22Mojca Persic23Sarah Smith24Sanjay Raj25Annabel Borley26Jeremy P. Braybrooke27Emma Staples28Lucy C. Scott29Cheryl A. Palmer30Margaret Moody31Mark J. Churn32Domenic Pilger33Guido Zagnoli-Vieira34Paul W. G. Wijnhoven35Mukesh B. Mukesh36Rebecca R. Roylance37Philip C. Schouten38Nicola C. Levitt39Karen McAdam40Anne C. Armstrong41Ellen R. Copson42Emma McMurtry43Susan Galbraith44Marc Tischkowitz45Elena Provenzano46Mark J. O’Connor47Helena M. Earl48PARTNER Trial GroupPrecision Breast Cancer Institute, Department of Oncology, University of CambridgeAstraZenecaCambridge Cancer Trials Centre, Cambridge University Hospitals NHS Foundation TrustPrecision Breast Cancer Institute, Department of Oncology, University of CambridgeCambridge Clinical Trials Centre, Cancer Theme, University of CambridgeDepartment of Statistics, Athens University of Economics and BusinessCambridge Cancer Trials Centre, Cambridge University Hospitals NHS Foundation TrustRoyal Devon University Healthcare NHS Foundation TrustPrecision Breast Cancer Institute, Department of Oncology, University of CambridgePrecision Breast Cancer Institute, Department of Oncology, University of CambridgeCambridge Cancer Trials Centre, Cambridge University Hospitals NHS Foundation TrustPrecision Breast Cancer Institute, Department of Oncology, University of CambridgeCambridge University Hospitals NHS Foundation TrustCambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation TrustAstraZenecaCambridge Clinical Trials Centre, Cancer Theme, University of CambridgeCambridge Cancer Trials Centre, Cambridge University Hospitals NHS Foundation TrustThe City Hospital, Nottingham University Hospitals NHS TrustRoyal Bournemouth General Hospital, University Hospitals Dorset NHS Foundation TrustIpswich Hospital, East Suffolk and North Essex NHS Foundation TrustUniversity Hospitals Dorset NHS Foundation TrustApconix Ltd, Alderley EdgeAstraZenecaUniversity Hospital of Derby and BurtonBedford Hospital, Bedfordshire Hospitals NHS Foundation TrustUniversity Hospital Southampton NHS Foundation TrustVelindre Cancer CentreUniversity Hospitals Bristol and Weston NHS Foundation TrustQueens Hospital, Barking, Havering and Redbridge University Hospitals NHS TrustBeatson West Of Scotland Cancer CentreHinchingbrooke Hospital, North West Anglia NHS Foundation TrustMacmillan Unit, West Suffolk Hospital NHS Foundation TrustWorcestershire Acute Hospitals NHS TrustAstraZenecaAstraZenecaAstraZenecaColchester General Hospital, East Suffolk & North Essex NHS TrustUniversity College London Hospitals NHS Foundation TrustDepartment of Histopathology, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation TrustOxford University Hospital NHS Foundation TrustPeterborough City Hospital, North West Anglia NHS Foundation TrustThe Christie NHS Foundation TrustCancer Sciences Academic Unit, University of SouthamptonEMC2 Clinical Consultancy LtdAstraZenecaDepartment of Genomic Medicine, National Institute for Health Research Cambridge Biomedical Research Centre, University of CambridgeDepartment of Histopathology, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation TrustAstraZenecaDepartment of Oncology, University of CambridgeAbstract Poly (ADP-ribose) polymerase inhibitors (PARPi) exploit DNA repair deficiency in germline BRCA1 and BRCA2 pathogenic variant (gBRCAm) cancers. Haematological toxicity limits chemotherapy-PARPi treatment combinations. In preclinical models we identified a schedule combining olaparib and carboplatin that avoids enhanced toxicity but maintains anti-tumour activity. We investigated this schedule in a neoadjuvant, phase II-III, randomised controlled trial for gBRCAm breast cancers (ClinicalTrials.gov ID:NCT03150576; PARTNER). The research arm included carboplatin (Area Under the Curve 5, 3-weekly); paclitaxel (80 mg/m2, weekly) day 1, plus olaparib (150 mg twice daily) day 3-14 (4 cycles), followed by anthracycline-containing chemotherapy (3 cycles); control arm gave chemotherapy alone. The primary endpoint, pathological complete response rate, showed no statistical difference between research 64.1% (25/39); control 69.8% (30/43) (p = 0.59). However, estimated survival outcomes at 36-months demonstrated improved event-free survival: research 96.4%, control 80.1% (p = 0.04); overall survival: research 100%, control 88.2% (p = 0.04) and breast cancer specific survival: research 100%, control 88.2% (p = 0.04). There were no statistical differences in relapse-free survival and distant disease-free survival, both were: research 96.4%, control 87.9% (p = 0.20). Similarly, local recurrence-free survival and time to second cancer were both: research 96.4%, control 87.8% (p = 0.20). The PARTNER trial identified a safe, tolerable schedule combining neoadjuvant chemotherapy with olaparib. This combination demonstrated schedule-dependent overall survival benefit in early-stage gBRCAm breast cancer. This result needs confirmation in larger trials.https://doi.org/10.1038/s41467-025-59151-0 |
| spellingShingle | Jean E. Abraham Lenka Oplustil O’Connor Louise Grybowicz Karen Pinilla Alba Alimu Dayimu Nikolaos Demiris Caron Harvey Lynsey M. Drewett Rebecca Lucey Alexander Fulton Anne N. Roberts Joanna R. Worley Ms Anita Chhabra Wendi Qian Jessica Brown Richard Hardy Anne-Laure Vallier Steve Chan Maria Esther Una Cidon Elizabeth Sherwin Amitabha Chakrabarti Claire Sadler Jen Barnes Mojca Persic Sarah Smith Sanjay Raj Annabel Borley Jeremy P. Braybrooke Emma Staples Lucy C. Scott Cheryl A. Palmer Margaret Moody Mark J. Churn Domenic Pilger Guido Zagnoli-Vieira Paul W. G. Wijnhoven Mukesh B. Mukesh Rebecca R. Roylance Philip C. Schouten Nicola C. Levitt Karen McAdam Anne C. Armstrong Ellen R. Copson Emma McMurtry Susan Galbraith Marc Tischkowitz Elena Provenzano Mark J. O’Connor Helena M. Earl PARTNER Trial Group Neoadjuvant PARP inhibitor scheduling in BRCA1 and BRCA2 related breast cancer: PARTNER, a randomized phase II/III trial Nature Communications |
| title | Neoadjuvant PARP inhibitor scheduling in BRCA1 and BRCA2 related breast cancer: PARTNER, a randomized phase II/III trial |
| title_full | Neoadjuvant PARP inhibitor scheduling in BRCA1 and BRCA2 related breast cancer: PARTNER, a randomized phase II/III trial |
| title_fullStr | Neoadjuvant PARP inhibitor scheduling in BRCA1 and BRCA2 related breast cancer: PARTNER, a randomized phase II/III trial |
| title_full_unstemmed | Neoadjuvant PARP inhibitor scheduling in BRCA1 and BRCA2 related breast cancer: PARTNER, a randomized phase II/III trial |
| title_short | Neoadjuvant PARP inhibitor scheduling in BRCA1 and BRCA2 related breast cancer: PARTNER, a randomized phase II/III trial |
| title_sort | neoadjuvant parp inhibitor scheduling in brca1 and brca2 related breast cancer partner a randomized phase ii iii trial |
| url | https://doi.org/10.1038/s41467-025-59151-0 |
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