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Neoadjuvant PARP inhibitor scheduling in BRCA1 and BRCA2 related breast cancer: PARTNER, a randomized phase II/III trial
Abraham, J. E. O'Connor, L. O. Grybowicz, L. Alba, K. P. Dayimu, A. Demiris, N. Harvey, C. Drewett, L. M. Lucey, R. Fulton, A.
Abraham, J. E.
O'Connor, L. O.
Grybowicz, L.
Alba, K. P.
Dayimu, A.
Demiris, N.
Harvey, C.
Drewett, L. M.
Lucey, R.
Fulton, A.
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/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.
Authors
Abraham, J. E.
O'Connor, L. O.
Grybowicz, L.
Alba, K. P.
Dayimu, A.
Demiris, N.
Harvey, C.
Drewett, L. M.
Lucey, R.
Fulton, A.
Roberts, A. N.
Worley, J. R.
Chhabra, M. A.
Qian, W.
Brown, J.
Hardy, R.
Vallier, A. L.
Chan, S.
Cidon, M. E. U.
Sherwin, E.
Chakrabarti, A.
Sadler, C.
Barnes, J.
Persic, M.
Smith, S.
Raj, S.
Borley, A.
Braybrooke, J. P.
Staples, E.
Scott, L. C.
Palmer, C. A.
Moody, M.
Churn, M. J.
Pilger, D.
Zagnoli-Vieira, G.
Wijnhoven, P. W. G.
Mukesh, M. B.
Roylance, R. R.
Schouten, P. C.
Levitt, N. C.
McAdam, K.
Armstrong, A. C.
Copson, E. R.
McMurtry, E.
Galbraith, S.
Tischkowitz, M.
Provenzano, E.
O'Connor, M. J.
Earl, H. M.
O'Connor, L. O.
Grybowicz, L.
Alba, K. P.
Dayimu, A.
Demiris, N.
Harvey, C.
Drewett, L. M.
Lucey, R.
Fulton, A.
Roberts, A. N.
Worley, J. R.
Chhabra, M. A.
Qian, W.
Brown, J.
Hardy, R.
Vallier, A. L.
Chan, S.
Cidon, M. E. U.
Sherwin, E.
Chakrabarti, A.
Sadler, C.
Barnes, J.
Persic, M.
Smith, S.
Raj, S.
Borley, A.
Braybrooke, J. P.
Staples, E.
Scott, L. C.
Palmer, C. A.
Moody, M.
Churn, M. J.
Pilger, D.
Zagnoli-Vieira, G.
Wijnhoven, P. W. G.
Mukesh, M. B.
Roylance, R. R.
Schouten, P. C.
Levitt, N. C.
McAdam, K.
Armstrong, A. C.
Copson, E. R.
McMurtry, E.
Galbraith, S.
Tischkowitz, M.
Provenzano, E.
O'Connor, M. J.
Earl, H. M.
Description
Date
2025
Publisher
Collections
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Keywords
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Article
Citation
Abraham JE, O'Connor LO, Grybowicz L, Alba KP, Dayimu A, Demiris N, et al. Neoadjuvant PARP inhibitor scheduling in BRCA1 and BRCA2 related breast cancer: PARTNER, a randomized phase II/III trial. Nature communications. 2025 May 13;16(1):4269. PubMed PMID: 40360463. Pubmed Central PMCID: PMC12075821 in the study design, data collection, analysis, interpretation, or writing of the report. The authors declare the existence of the following competing interests: J.E.A. reports honoraria, conference attendance, travel support, and a grant from AstraZeneca; and honoraria from Esai and Pfizer for lectures. L.O.O.C. reports employment and shares in AstraZeneca. J.B. reports employment and stock in AstraZeneca. C.S. reports former employment and stock in AstraZeneca. J. Ba reports former employment and stock in AstraZeneca. M.M. reports shares in AstraZeneca. D.P. reports employment and shares in AstraZeneca. G.Z.V. reports employment and shares in AstraZeneca. P.W. reports employment and shares in AstraZeneca. M.B.M. reports advisory board membership in Roche, Pfizer, MSD, Daiichi-Sankyo, Gilead, AstraZeneca, Novartis, Menarini group, Genomic Health (Precision Medicine) & Seagen; speaker honoraria from Roche, BMS, Seagen, Pfizer, Daiichi-Sankyo, AstraZeneca, Lilly, MSD, Genomic Health (Precision Medicine), Eisai & Novartis; and meeting expenses from Roche, Eli Lilly, Novartis and MSD. R.R.R. reports honoraria from Daiichi-Sankyo, AstraZeneca, Novartis, Pfizer; membership in advisory boards for Daiichi-Sankyo, Eli Lilly, Pfizer, AstraZeneca; and travel/conference attendance for BMS, Pfizer, Roche. PCS reports that their partner is employed by AstraZeneca. N.C.L. reports shares in AstraZeneca. A.C.A. reports research funding paid to the Institution from AstraZeneca; conference fees and travel expenses from Roche and Novartis; conference fees from M.S.D.; membership on Roche and AstraZeneca advisory boards; and a grant for an educational project from Gilead. ERC reports honoraria from AstraZeneca, Eli Lilly, Novartis, Pfizer, Roche; membership in advisory boards for AstraZeneca, Eli Lilly, Pfizer, Menarini Stemline UK, Novartis; consultancy for Pfizer, conference fees/travel/accommodation from Roche, Novartis; an educational grant from Daiichi-Sankyo; and research funding and support from SECA, AstraZeneca. S.G. reports employment and stock in AstraZeneca. EP reports honoraria from Roche, Novartis, and AstraZeneca. M.J.O.C. reports employment and shares in AstraZeneca. Epub 2025/05/14. eng.