Combining ceralasertib with olaparib as second- or third-line therapy does not improve outcomes for patients with triple-negative breast cancer (TNBC), a phase 2 trial suggests.

The combination did not improve progression-free survival (PFS) or objective response rates (ORR) when compared with olaparib alone. 

The trial also showed that combining adavosertib with olaparib significantly increases the risk of grade 3 or higher adverse events (AEs). 

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These results were presented at ESMO Breast Cancer 2022 by Andrew Tutt, MB ChB, PhD, of the Institute of Cancer Research in London, United Kingdom. 

In the phase 2 VIOLETTE trial ( Identifier: NCT03330847), Dr Tutt and colleagues investigated whether ceralasertib or adavosertib would enhance the efficacy of olaparib. 

The study included 450 patients with metastatic or advanced locoregional TNBC previously treated with 1 to 2 lines of chemotherapy, including platinum chemotherapy. The patients were randomly assigned to receive ceralasertib plus olaparib (n=150), adavosertib plus olaparib (n=150), or olaparib monotherapy (n=150). 

Patients in each arm were divided into 3 groups according to mutation status. The BRCAm group included patients with BRCA1/2 mutations, the non-BRCAm HRRm group included patients with mutations in HRR pathway genes other than BRCA1/2, and the non-HRRm group included patients with no mutations in any of the 15 HRR genes. 


The researchers found that combination adavosertib and olaparib resulted in excess grade 3 or higher AEs, serious AEs, and AEs leading to discontinuation. These results led to early termination of this treatment arm in April 2019.

The entire trial was stopped in November 2020, after the interim analysis of the BRCAm group, because stopping criteria were met. 

The researchers found no significant difference in PFS between patients who received ceralasertib-olaparib and those treated with olaparib alone. The median PFS was 5.3 months and 3.6 months, respectively (hazard ratio [HR], 0.79; 90% CI, 0.59-1.04; P =.1822). 

There was no significant difference in PFS between the ceralasertib and olaparib-alone arms for the BRCAm group (P =.9403), the non-BRCAm HRRm group (P =.1274), or the non-HRRm group (P =.2959). 

Similarly, there was no significant difference in ORR between the ceralasertib and olaparib-alone arms overall (P=.1932), in the BRCAm group (P =.6090), or in the non-BRCAm HRRm group (P =.6769). 

However, in the non-HRRm group, the ORR was significantly higher with ceralasertib than with olaparib alone — 15.4% and 3.9%, respectively (odds ratio, 4.45; P =.0425). 

This improvement in ORR is likely driven by a subset of patients, and it is being explored in an additional analysis, Dr Tutt said. He noted that the clinical significance of the ORR improvement is limited given the lack of PFS benefit.

The safety profiles of ceralasertib-olaparib and olaparib alone were consistent with the known safety profiles of these drugs, according to Dr Tutt.

There were no treatment-related deaths in this trial, and the most common grade 3 or higher AEs in any treatment group were hematologic toxicities.

AEs of special interest included a case of grade 1 pneumonitis in a patient receiving olaparib monotherapy and 2 cases of pneumonitis (grade 1 and 2) in patients receiving ceralasertib plus olaparib. In addition, 2 patients in the ceralasertib arm had new primary malignancies, and 1 patient in the adavosertib arm had myelodysplastic syndrome. 

Dr Tutt noted that the dose of ceralasertib tested in combination with olaparib was lower than the dose being studied with ceralasertib monotherapy. Exploring alternative dose regimens or combinations with other DDR inhibitors may enable higher dosing of ceralasertib. 

Disclosures: This research was supported by AstraZeneca. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Tutt A, Nowecki Z, Szoszkiewicz R, et al. 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). ESMO Breast Cancer 2022; May 3-5, 2022. Abstract 161O.