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Neoadjuvant PARP inhibitor scheduling in BRCA1 and BRCA2 related breast cancer: PARTNER, a randomized phase II/III trial

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 and Helena M. Earl
Additional contact information
Jean E. Abraham: University of Cambridge
Lenka Oplustil O’Connor: AstraZeneca
Louise Grybowicz: Cambridge University Hospitals NHS Foundation Trust
Karen Pinilla Alba: University of Cambridge
Alimu Dayimu: University of Cambridge
Nikolaos Demiris: Athens University of Economics and Business
Caron Harvey: Cambridge University Hospitals NHS Foundation Trust
Lynsey M. Drewett: Royal Devon University Healthcare NHS Foundation Trust
Rebecca Lucey: University of Cambridge
Alexander Fulton: University of Cambridge
Anne N. Roberts: Cambridge University Hospitals NHS Foundation Trust
Joanna R. Worley: University of Cambridge
Ms Anita Chhabra: Cambridge University Hospitals NHS Foundation Trust
Wendi Qian: Cambridge University Hospitals NHS Foundation Trust
Jessica Brown: AstraZeneca
Richard Hardy: University of Cambridge
Anne-Laure Vallier: Cambridge University Hospitals NHS Foundation Trust
Steve Chan: Nottingham University Hospitals NHS Trust
Maria Esther Una Cidon: University Hospitals Dorset NHS Foundation Trust
Elizabeth Sherwin: East Suffolk and North Essex NHS Foundation Trust
Amitabha Chakrabarti: University Hospitals Dorset NHS Foundation Trust
Claire Sadler: Alderley Edge
Jen Barnes: AstraZeneca
Mojca Persic: University Hospital of Derby and Burton
Sarah Smith: Bedfordshire Hospitals NHS Foundation Trust
Sanjay Raj: University Hospital Southampton NHS Foundation Trust
Annabel Borley: Velindre Cancer Centre
Jeremy P. Braybrooke: University Hospitals Bristol and Weston NHS Foundation Trust
Emma Staples: Havering and Redbridge University Hospitals NHS Trust
Lucy C. Scott: Beatson West Of Scotland Cancer Centre
Cheryl A. Palmer: North West Anglia NHS Foundation Trust
Margaret Moody: West Suffolk Hospital NHS Foundation Trust
Mark J. Churn: Worcestershire Acute Hospitals NHS Trust
Domenic Pilger: AstraZeneca
Guido Zagnoli-Vieira: AstraZeneca
Paul W. G. Wijnhoven: AstraZeneca
Mukesh B. Mukesh: East Suffolk & North Essex NHS Trust
Rebecca R. Roylance: University College London Hospitals NHS Foundation Trust
Philip C. Schouten: Cambridge University Hospitals NHS Foundation Trust
Nicola C. Levitt: Oxford University Hospital NHS Foundation Trust
Karen McAdam: North West Anglia NHS Foundation Trust
Anne C. Armstrong: The Christie NHS Foundation Trust
Ellen R. Copson: University of Southampton
Emma McMurtry: EMC2 Clinical Consultancy Ltd
Susan Galbraith: AstraZeneca
Marc Tischkowitz: University of Cambridge
Elena Provenzano: Cambridge University Hospitals NHS Foundation Trust
Mark J. O’Connor: AstraZeneca
Helena M. Earl: University of Cambridge

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59151-0

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