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)

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.