Neoadjuvant PARP inhibitor scheduling in BRCA1 and BRCA2 related breast cancer: PARTNER, a randomized phase II/III trial
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.
Article Details
Authors (49)
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