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
- Helena M. Earl
2025-05-13
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 2 , 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.