VIOLETTE: A randomized phase II study to assess the DNA damage response inhibitors AZD6738 or AZD1775 in combination with olaparib (Ola) versus Ola monotherapy in patients (pts) with metastatic, triple-negative breast cancer (TNBC).

TPS1112 Background: TNBC comprises ≈15% of invasive breast cancer cases and alterations in BRCA1/ 2 are associated with ≈5% of all BCs. Ola (a poly ADP-ribose polymerase inhibitor [PARPi]) is approved for treating pts with HER2-negative metastatic BC with a germline BRCA mutation (g BRCAm), demonstrating an improvement in progression-free survival (PFS). Alterations in other non- BRCA1/2 homologous recombination repair (HRR)-related genes (non- BRCA HRRm) may also confer sensitivity to Ola therapy in pts with TNBC. Ola, AZD1775 (a WEE1 checkpoint inhibitor) and AZD6738 (an ataxia telangiectasia and Rad3-related protein inhibitor) target DNA damage repair and cell cycle regulation. Preclinical studies in TNBC models show synergistic antitumor effects of Ola+AZD1775 and Ola+AZD6738, vs Ola monotherapy supporting the clinical evaluation of these combinations. Methods: VIOLETTE is a global, multicenter, open-label, phase II study (NCT03330847) randomising 1:1:1 450 pts with advanced TNBC to 3 treatment arms: 1) Ola 200 mg bid daily + AZD1775 150 mg bid D1-3, D8-10 q21, 2) Ola 300 mg bid daily + AZD6738 160 mg qd D1-7 q28, or 3) Ola 300 mg bid daily q28. All pts will be stratified by prior platinum exposure. Each treatment arm of ≈150 pts will be comprised of 3 biomarker strata of ≈50 pts each (A: BRCAm; B: non- BRCA HRRm; C: non-HRRm). Centralized tumor molecular testing will be deployed to detect mutation(s) in 15 HRR genes. Eligible pts will have received 1-2 prior lines of chemotherapy for metastatic disease, including an anthracycline or taxane. Exclusion criteria include prior PARPi therapy. The primary endpoint is PFS (each combination vs Ola alone) assessed by blinded, independent central review (RECIST v1.1). Secondary endpoints are objective response rate, duration of response, change in tumor size, and overall survival for comparisons between combinations and for each combination vs Ola alone; drug exposure; and safety and tolerability. The first prespecified futility analysis in Stratum C has met the recruitment target and will be assessed by unblinded review April 2019. Clinical trial information: NCT03330847.