ATR Inhibitor Ceralasertib Paired With Olaparib Shows Promise in BRCA-Mutant Breast Cancer

Cancer researchers have long sought ways to attack tumours through the machinery they use to repair their own DNA, and one of the most ambitious strategies involves deliberately overwhelming that machinery from two directions at once. A new Phase 1 clinical trial has now tested that idea in patients, combining ceralasertib, an inhibitor of the ATR kinase, with olaparib, a widely used PARP inhibitor. The study, published in the British Journal of Cancer, enrolled 142 patients with advanced solid tumours and reports a generally manageable safety profile alongside encouraging preliminary activity in a carefully selected group of women with BRCA1/2-mutated, HER2-negative breast cancer who had never previously received a PARP inhibitor.

The biological rationale behind the combination rests on how cancer cells cope with DNA damage. ATR, or ataxia telangiectasia and Rad3-related protein kinase, is a central regulator of the DNA damage response. When replication stress causes DNA replication forks to stall, ATR stabilises those forks, delays the firing of late replication origins and activates S-phase and G2-M checkpoints, buying the cell time to repair damage before it divides. Blocking ATR therefore allows double-strand DNA breaks to accumulate, driving genomic instability and ultimately cell death. PARP1, meanwhile, is involved in repairing single-strand breaks during base excision repair, and PARP inhibitors such as olaparib work partly by trapping PARP1 on DNA, causing stalled replication forks to collapse into double-strand breaks.

Those double-strand breaks are normally repaired by the homologous recombination repair pathway, in which the tumour suppressor proteins BRCA1 and BRCA2 play key roles. In tumours carrying BRCA1/2 mutations, homologous recombination is defective, so PARP inhibitors kill the cells through synthetic lethality: two independent weaknesses that are individually survivable but lethal together. PARP inhibition also increases replication stress, making tumour cells increasingly dependent on ATR for survival. Preclinical work had shown selective synergy between ceralasertib and olaparib in BRCA-deficient and ATM-deficient models, and in most models of acquired PARP inhibitor resistance, raising hopes that the pairing could both deepen responses and overcome resistance in the clinic.

The trial, registered as NCT02264678, was a modular, open-label, multicentre study. In the dose-escalation phase, Part A1 tested ceralasertib alone at 80 mg twice daily or 160 mg once daily in 13 patients, while Part A2 escalated ceralasertib in combination with olaparib across 67 patients with advanced solid tumours. Dose expansion then followed in two breast cancer cohorts: Part B3 enrolled 37 patients with BRCA1/2-mutated, HER2-negative breast cancer who were PARP inhibitor-naive, and Part B4 enrolled 25 patients with BRCA1/2 wild-type triple-negative breast cancer. All expansion patients received the recommended Phase 2 dose until disease progression or discontinuation criteria were met.

The safety findings shaped the final dosing regimen. No dose-limiting toxicities occurred with ceralasertib monotherapy, but haematological toxicity emerged as the limiting factor when the two drugs were combined. Dose-limiting toxicities appeared in several escalation cohorts, predominantly involving neutropenia and thrombocytopenia, and attempts to push the ceralasertib dose higher or extend the number of dosing days proved intolerable. The recommended Phase 2 dose was set at ceralasertib 160 mg once daily on days 1 to 7 of each 28-day cycle, plus olaparib 300 mg twice daily given continuously. At this schedule, tolerability was illustrated by limited dose reductions and discontinuations, with a median relative dose intensity of 100 percent for ceralasertib in the expansion cohorts.

Across the expansion cohorts, treatment-emergent adverse events were nearly universal, affecting 97.3 percent of patients in Part B3 and 96.0 percent in Part B4, but grade 3 or worse events were less frequent, at 43.2 percent and 36.0 percent respectively. The most common severe toxicities were haematological: anaemia and neutropenia predominated in the BRCA-mutant cohort, while anaemia, thrombocytopenia and neutropenia appeared in the triple-negative cohort. Adverse events led to discontinuation in only a small minority of patients, two of 37 in Part B3 and one of 25 in Part B4, and no deaths from adverse events occurred in Part B3. The investigators concluded that no new safety signals were observed beyond those already known for each drug class.

The efficacy results revealed a striking split between the two expansion cohorts. In Part B3, 14 of 37 patients, or 37.8 percent, achieved a confirmed objective response, comprising one complete response and 13 partial responses, with a median duration of response of 9.8 months. Among the 30 patients whose BRCA1/2 mutation was centrally confirmed by next-generation sequencing, the response rate rose to 40.0 percent, the median duration of response reached 11.0 months, and median progression-free survival was 9.0 months. Median overall survival in this centrally confirmed group was 26.2 months. In sharp contrast, Part B4 produced no objective responses at all among patients with BRCA wild-type triple-negative breast cancer lacking homologous recombination repair mutations, with median progression-free survival of just 3.1 months.

Pharmacokinetic and pharmacodynamic analyses added mechanistic texture to the clinical findings. Ceralasertib was rapidly absorbed, reaching peak plasma concentrations within about an hour and a half, and exposures at both 160 mg once daily and 80 mg twice daily provided 24-hour coverage over the concentration required for 90 percent ATR inhibition. When the drugs were combined, single-dose ceralasertib exposure was modestly reduced compared with monotherapy, and ceralasertib did not accumulate at steady state. In paired tumour biopsies, levels of phosphorylated RAD50, a pharmacodynamic biomarker of DNA damage response activation, increased on treatment in all three evaluable samples, alongside rises in the DNA damage markers gamma-H2AX and phosphorylated CHK1, confirming target engagement, although the small sample size limited interpretation.

Exploratory biomarker work examined whether ATM status or expression of Schlafen-11, an emerging predictor of sensitivity to DNA-damaging therapy, could identify responders. Responders showed a higher proportion of ATM-low tumours than non-responders, and median SLFN11 H-scores were lower in patients achieving complete or partial responses than in those with stable or progressive disease, with 85.7 percent of responders classified as SLFN11-low. However, neither marker was strongly associated with clinical outcome, and the authors note that predictive biomarkers for ceralasertib remain to be elucidated, partly because replication stress, the key hypothesised predictor of ATR inhibitor sensitivity, still cannot be measured accurately in clinical tissue samples.

The authors place their findings in context by comparing them with landmark PARP inhibitor monotherapy trials in BRCA-mutated metastatic breast cancer, where median progression-free survival has ranged from 4.0 to 8.6 months and response rates have varied widely depending on prior platinum exposure. Without a monotherapy comparator arm, the contribution of ceralasertib to the observed activity cannot be conclusively determined, and the parallel randomised VIOLETTE study found no significant progression-free survival benefit from adding ceralasertib to olaparib in triple-negative breast cancer, possibly because haematological toxicity forced a relatively low ceralasertib dose. Nevertheless, the combination demonstrated preliminary activity with manageable safety in PARP inhibitor-naive patients with BRCA1/2-mutated HER2-negative breast cancer, and the authors argue that further work should identify which patient groups, defined by prior PARP exposure, specific mutations or biomarkers, are most likely to benefit from adding ATR inhibition to PARP therapy.

Subject of Research: Phase 1 trial of the ATR inhibitor ceralasertib combined with the PARP inhibitor olaparib in advanced solid tumours and breast cancer

Article Title: Safety and efficacy of ceralasertib, an ATR kinase inhibitor, combined with olaparib: dose escalation in advanced solid tumours and dose expansion in advanced breast cancer

Article References: Lopez, J. S., Im, S.-A., Postel-Vinay, S., Campone, M., El-Khoueiry, A. B., Abida, W., Arkenau, T., Lee, K.-W., Rha, S. Y., Jodrell, D. I., Roylance, R., Irurzun-Arana, I., Jones, G. N., Lukashchuk, N., Stephens, C., Norris, C., Loembé, A.-B., Dean, E., & Krebs, M. G. (2026). Safety and efficacy of ceralasertib, an ATR kinase inhibitor, combined with olaparib: dose escalation in advanced solid tumours and dose expansion in advanced breast cancer. British Journal of Cancer. https://doi.org/10.1038/s41416-026-03601-z

Image Credits: AI Generated

DOI: 10.1038/s41416-026-03601-z

Keywords: ceralasertib, olaparib, ATR inhibitor, PARP inhibitor, BRCA1/2, breast cancer, triple-negative breast cancer, DNA damage response, replication stress, Phase 1 trial, synthetic lethality, targeted therapy