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

Author

Listed:
  • Jean E. Abraham

    (University of Cambridge
    University of Cambridge)

  • Lenka Oplustil O’Connor

    (AstraZeneca)

  • Louise Grybowicz

    (Cambridge University Hospitals NHS Foundation Trust)

  • Karen Pinilla Alba

    (University of Cambridge
    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
    University of Cambridge)

  • Alexander Fulton

    (University of Cambridge
    University of Cambridge)

  • Anne N. Roberts

    (Cambridge University Hospitals NHS Foundation Trust)

  • Joanna R. Worley

    (University of Cambridge
    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
    University of Nottingham)

  • 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
    Hampshire Hospitals 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)

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.

Suggested Citation

  • 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. Robe, 2025. "Neoadjuvant PARP inhibitor scheduling in BRCA1 and BRCA2 related breast cancer: PARTNER, a randomized phase II/III trial," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59151-0
    DOI: 10.1038/s41467-025-59151-0
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    References listed on IDEAS

    as
    1. Jean E. Abraham & Karen Pinilla & Alimu Dayimu & Louise Grybowicz & Nikolaos Demiris & Caron Harvey & Lynsey M. Drewett & Rebecca Lucey & Alexander Fulton & Anne N. Roberts & Joanna R. Worley & Anita , 2024. "The PARTNER trial of neoadjuvant olaparib with chemotherapy in triple-negative breast cancer," Nature, Nature, vol. 629(8014), pages 1142-1148, May.
    2. Stephen J. Pettitt & Dragomir B. Krastev & Inger Brandsma & Amy Dréan & Feifei Song & Radoslav Aleksandrov & Maria I. Harrell & Malini Menon & Rachel Brough & James Campbell & Jessica Frankum & Michae, 2018. "Genome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    3. Hannah Farmer & Nuala McCabe & Christopher J. Lord & Andrew N. J. Tutt & Damian A. Johnson & Tobias B. Richardson & Manuela Santarosa & Krystyna J. Dillon & Ian Hickson & Charlotte Knights & Niall M. , 2005. "Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy," Nature, Nature, vol. 434(7035), pages 917-921, April.
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