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<p>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/m<sup>2</sup>, 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) (<i>p</i> = 0.59). However, estimated survival outcomes at 36-months demonstrated improved event-free survival: research 96.4%, control 80.1% (<i>p</i> = 0.04); overall survival: research 100%, control 88.2% (<i>p</i> = 0.04) and breast cancer specific survival: research 100%, control 88.2% (<i>p</i> = 0.04). There were no statistical differences in relapse-free survival and distant disease-free survival, both were: research 96.4%, control 87.9% (<i>p</i> = 0.20). Similarly,&#xa0;local recurrence-free survival and time to second cancer were both: research 96.4%, control 87.8% (<i>p</i> = 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月13日

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  • 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

摘要

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.