Safety and Efficacy of Ceralasertib plus Olaparib for Advanced/Metastatic Triple-Negative Breast Cancer in Three Molecular Strata: The Phase II VIOLETTE Study.

PURPOSE: VIOLETTE (NCT03330847) assessed olaparib alone or with ceralasertib (ATR inhibitor) or adavosertib (WEE1 inhibitor) as second-/third-line treatment in three molecular strata of patients with previously treated, PARP inhibitor-naïve, advanced triple-negative breast cancer (TNBC). PATIENTS AND METHODS: Patients were randomized 1:1:1 to olaparib 300 mg twice daily (BD), ceralasertib 160 mg once daily (Days 1-7; 28-day cycles) + olaparib 300 mg BD, or adavosertib 150 mg BD (Days 1-3, 8-10; 21-day cycles) + olaparib 200 mg BD. Patients were stratified by presence of tumoral homologous recombination repair (HRR) pathway mutations (m): BRCA1/2m, non-BRCA1/2m HRRm, or non-HRRm. Primary endpoint was progression-free survival (PFS) by blinded independent central review. RESULTS: 273 patients were randomized: 114, 112, and 47 to the olaparib, ceralasertib + olaparib, and adavosertib + olaparib arms, respectively. The adavosertib + olaparib arm was terminated early due to unacceptable toxicity. Median PFS of ceralasertib + olaparib was 7.4, 3.9, and 3.6 months in the BRCA1/2m, non-BRCA1/2m HRRm, and non-HRRm strata, respectively, and did not differ significantly from olaparib (HR 1.02 [90% CI, 0.63-1.66], 0.54 [90% CI, 0.28-1.03], and 0.76 [90% CI, 0.50-1.14], respectively). In the non-HRRm group objective response rates (ORR) were significantly improved for ceralasertib + olaparib (15.4%) vs. olaparib (3.9%; OR, 4.45; 90% CI, 1.30‒21.20; P = 0.0425). No unexpected safety signals were reported for ceralasertib or olaparib. CONCLUSIONS: In patients with advanced PARP inhibitor-naïve non-HRRm TNBC, ceralasertib + olaparib significantly improved ORR versus olaparib. However, clinical significance is limited without improvement in PFS.