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dc.contributor.authorTutt, A.
dc.contributor.authorNowecki, Z.
dc.contributor.authorSzoszkiewicz, R.
dc.contributor.authorIm, S. A.
dc.contributor.authorArkenau, H. T.
dc.contributor.authorArmstrong, Anne C
dc.contributor.authorJacot, W.
dc.contributor.authorKim, J. H.
dc.contributor.authorWebster, M.
dc.contributor.authorBalmana, J.
dc.contributor.authorDelaloge, S.
dc.contributor.authorLukashchuk, N.
dc.contributor.authorOdegbami, R.
dc.contributor.authorCasson, E.
dc.contributor.authorLoembe, A. B.
dc.contributor.authorDrachsler, M. W.
dc.contributor.authorDean, E. J.
dc.contributor.authorPunie, K.
dc.date.accessioned2022-06-22T07:18:38Z
dc.date.available2022-06-22T07:18:38Z
dc.date.issued2022en
dc.identifier.citationTutt 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. en
dc.identifier.doi10.1016/j.annonc.2022.03.180en
dc.identifier.urihttp://hdl.handle.net/10541/625345
dc.description.abstractBackground 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 inhibitor). VIOLETTE (NCT03330847), a phase 2 open-label study, evaluated ola ± cer or ada as 2nd–3rd 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 1–7 + ola 300 mg BID (cer+ola), 28-d cycle; or ada 150 mg BID d 1–3, 8–10 + 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: n=83; HR 1.02 [90% CI 0.63–1.66, P=0.94], HRRm: n=40; 0.54 [0.28–1.03, 0.13], non-HRRm: n=103; 0.76 [0.50–1.14, 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%, n=8) vs ola (4%, n=2) (odds ratio 4.45; 90% CI 1.30–21.20, P=0.04). 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 2nd–3rd 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.en
dc.language.isoenen
dc.relation.urlhttps://dx.doi.org/10.1016/j.annonc.2022.03.180en
dc.titleVIOLETTE: 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)en
dc.typeMeetings and Proceedingsen
dc.contributor.departmentBreast Cancer Research, Institute of Cancer Research and Kings College London, London, UKen
dc.identifier.journalAnnals of Oncologyen
dc.description.noteen]


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