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    VIOLETTE: Randomised phase II study of olaparib (ola) plus ceralasertib (cer) or adavosertib (ada) vs ola alone in patients (pts) with metastatic triple-negative breast cancer (mTNBC)

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    Authors
    Tutt, A.
    Nowecki, Z.
    Szoszkiewicz, R.
    Im, S. A.
    Arkenau, H. T.
    Armstrong, Anne C
    Jacot, W.
    Kim, J. H.
    Webster, M.
    Balmana, J.
    Delaloge, S.
    Lukashchuk, N.
    Odegbami, R.
    Casson, E.
    Loembe, A. B.
    Drachsler, M. W.
    Dean, E. J.
    Punie, K.
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    Affiliation
    Breast Cancer Research, Institute of Cancer Research and Kings College London, London,
    Issue Date
    2022
    
    Metadata
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    Abstract
    Background: Combining DNA damage response (DDR) inhibitors to inhibit multiple DDR pathways may enhance tumour cell death. Preclinical models show synergistic antitumour effects of ola (PARP1 inhibitor) + cer (ATR inhibitor) or ada (WEE1 in- hibitor). VIOLETTE (NCT03330847), a phase 2 open-label study, evaluated ola cer or ada as 2nde3rd line in pts with mTNBC. Methods: Randomisation was stratified within each arm by mutation status (BRCAm, non-BRCAm homologous recombination repair pathway mutations [HRRm], or no HRRm [non-HRRm]) based on a prospective central tumour test and prior platinum therapy. Pts received ola 300 mg BID, 28-d cycle; cer 160 mg d 1e7 + ola 300 mg BID (cer+ola), 28-d cycle; or ada 150 mg BID d 1e3, 8e10 + ola 200 mg BID (ada+ola), 21- d cycle. Primary study endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), safety, and tolerability. Ada+ola was discontinued early due to higher than expected grade 3 haematologic toxicity, which limited its interpretation. We focus on cer+ola vs ola. The sponsor stopped VIOLETTE after reviewing BRCAm stratum efficacy data. Results: Of 273 pts (450 planned; median age: 53 y), 114 received ola, 112 cer+ola, and 47 ada+ola. Primary analyses showed no statistically significant difference in PFS for cer+ola vs ola (BRCAm: n¼83; HR 1.02 [90% CI 0.63e1.66, P¼0.94], HRRm: n¼40; 0.54 [0.28e1.03, 0.13], non-HRRm: n¼103; 0.76 [0.50e1.14, 0.30]). No statistically significant difference in ORR was seen for cer+ola vs ola in BRCAm (50% vs 44%) or HRRm (20% vs 15%). ORR was higher in non-HRRm for cer+ola (15%, n¼8) vs ola (4%, n¼2) (odds ratio 4.45; 90% CI 1.30e21.20, P¼0.04). In all pts, nausea and anaemia were the most common adverse events (AEs). Grade 3 AEs: 36% ola, 47% cer+ola, 78% ada+ola. Details of exploratory and subgroup analyses will be presented. Conclusions: Cer+ola did not improve PFS vs ola as 2nde3rd line for mTNBC. Clinical significance of higher ORR with cer+ola in non-HRRm pts is unclear. Cer+ola had a manageable safety profile consistent with known profiles of each. Further analyses may identify pts likely to benefit from each treatment.
    Citation
    Tutt A, Nowecki Z, Szoszkiewicz R, Im SA, Arkenau HT, Armstrong A, et al. 161O VIOLETTE: Randomised phase II study of olaparib (ola) + ceralasertib (cer) or adavosertib (ada) vs ola alone in patients (pts) with metastatic triple-negative breast cancer (mTNBC). Vol. 33, Annals of Oncology. Elsevier BV; 2022. p. S194–5.
    Journal
    Annals of Oncology
    URI
    http://hdl.handle.net/10541/625395
    DOI
    10.1016/j.annonc.2022.03.180
    Additional Links
    https://dx.doi.org/10.1016/j.annonc.2022.03.180
    Type
    Meetings and Proceedings
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.annonc.2022.03.180
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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