乌鸦传媒

The combination of olaparib (Lynparza) and ceralasertib, an ataxia telangiectasia and RAD3-related inhibitor, did not improve outcomes in previously treated metastatic triple-negative breast cancer versus the PARP inhibitor alone, according to results from the randomized trial.

Among 226 patients, no significant difference in progression-free survival (PFS) was observed between the two regimens, with a median PFS of 5.3 months with the combination compared to 3.6 months with olaparib alone (HR 0.79, 90% CI 0.59-1.04, P=0.18), reported Andrew Tutt, MBChB, PhD, of Kings College London, at the in Berlin.

None of the three distinct cohorts in the phase II trial -- those with BRCA mutations, those with non-BRCA homologous recombination repair (HRR) pathway mutations, or those without any HRR mutations -- significantly benefited from the addition of the novel drug versus olaparib monotherapy:

• BRCA mutations: median 7.4 vs 7.3 months, respectively (HR 1.02, 90% CI 0.63-1.66, P=0.94)
• Non-BRCA HRR mutations: 3.9 vs 1.9 months (HR 0.54, 90% CI 0.28-1.03, P=0.13)
• No HRR mutations: 3.6 vs 1.9 months (HR 0.76, 90% 0.50-1.14, P=0.30)

For the secondary endpoint of objective response, Tutt reported no significant differences with the combination versus olaparib alone for the BRCA mutation group (50% vs 44%) and non-BRCA HRR mutation group (20% vs 15%).

Responses were higher with the combination, however, in the cohort without any HRR mutations (15.4% vs 3.9%; OR 4.45, 90% 1.30-21.20, P=0.04).

"But given the lack of statistically significant difference in PFS, the clinical significance of that difference has to be questioned," Tutt said. He added that this signal of response "is likely to be driven by a biology-driven subset of patients" and is being explored in translational analyses.

Duration of response in the olaparib-ceralasertib and olaparib arms was 32 months versus 20 months in the cohort with BRCA mutations, 17.1 months versus 16.8 months in the non-BRCA HRR group, and 24.1 months versus 11.4 months in patients without any HRR mutations.

The most common adverse events (AEs) reported were anemia and neutropenia. Grade ≥3 AEs were seen in 46.8% of patients receiving the combination therapy and 35.5% of patients receiving olaparib monotherapy.

VIOLETTE included 112 patients with previously treated metastatic triple-negative breast cancer who received olaparib-ceralasertib, 114 who received olaparib alone, and 47 treated with olaparib plus the WEE1 inhibitor adavosertib -- a third arm of the trial discontinued early due to greater than anticipated grade ≥3 hematological toxicity. Among the olaparib-ceralasertib and olaparib-alone groups, 83 had BRCA mutations, 40 had non-BRCA HRR mutations, and 103 had no HRR mutations.

The trial was stopped after an interim analysis of the BRCA mutation group suggested no benefit with the combination, and thus is underpowered relative to its statistical analysis plan, Tutt noted.

While VIOLETTE was a negative trial, Tutt observed that olaparib plus ceralasertib had previously demonstrated encouraging efficacy data in the setting of PARP inhibitor resistance in ovarian cancer, "suggesting further exploration of this combination, with perhaps different doses and schedules in [the] settings of relapse on or after PARP inhibitors."

"I think we can learn very important information from a negative trial," said discussant Valentina Guarneri, MD, PhD, of the University of Padova in Italy.

She noted the higher incidence of brain metastases in the cohort with BRCA mutations (10.4%) versus the other two cohorts (2% to 3%).

"We already know that patients with germline BRCA mutations have a higher risk of developing brain metastases," she said. "So this data is really important when considering which is the optimal work-up staging for patients with triple-negative breast cancer, particularly in the case of BRCA mutations."

Comment