In an ongoing phase II study, Aggarwal et al evaluated the efficacy of the ATR inhibitor ceralasertib alone and in combination with olaparib in patients with ARID1A-deficient and ARID1A-intact solid tumors. They observed antitumor activity with ceralasertib monotherapy in ARID1A-deficient solid malignancies, according to findings presented at the European Society for Medical Oncology (ESMO) Congress 2021 (Abstract 512O).
The research team explained that a loss of ARID1A leads to increased reliance on ataxia telangiectasia and Rad3-related (ATR) kinase. ATR inhibition induces synthetic lethality in ARID1A-deficient preclinical models.
Study Methods
In this study, the researchers defined ARID1A deficiency as the absence of tumor expression of its gene product BAF250a by immunohistochemical (IHC) staining.
Cohort 1 evaluated patients with ARID1A-deficient tumors who were treated with ceralasertib monotherapy at 160 mg given orally twice daily from day 1 to 14 in a 28-day cycle, while cohort 2 evaluated patients with ARID1A-intact tumors who were treated with ceralasertib at 160 mg given twice daily from day 1 to 7 plus olaparib at 300 mg given orally twice daily from day 1 to 28.
The primary endpoint of the study was objective response rate. Target accrual was 10 patients per cohort. At least one objective response was required to proceed to stage 2.
Among screened patients whose tumors harbored pathogenic mutations in ARID1A, 28 of 42 patients (67%) had BAF250a loss of expression detected by IHC. In total, 20 patients were enrolled, 10 in each cohort. The median number of prior lines of therapy was two (range = 0–5).
Objective Response Rate
In cohort 1, the objective response rate was 20%, with two complete responses observed. Both patients remained on treatment for 21.3+ and 16.3+ months, respectively, with ongoing complete responses. One additional patient remained on treatment for 8.8 months with stable disease, for an overall clinical benefit rate of 30% defined as obtained response or stable disease of duration longer than 6 months in cohort 1.
In cohort 2, a best response of stable disease was observed in 4 of 10 patients (40%). No objective responses were observed in that cohort.
Overall, the median duration of treatment on study was 1.4 months (range = 0.9–19.8+).
The researchers reported that the most common grade ≥ 3 adverse events with ceralasertib monotherapy were thrombocytopenia in 10% of patients and neutropenia in 20%, both of which resolved with temporary dose interruption or dose reduction.
The study authors concluded that they observed antitumor activity with ceralasertib given as a single agent in patients with ARID1A-deficient solid tumors, including two patients with durable and ongoing complete responses. Accrual is currently ongoing in stage 2 of cohort 1 using the absence of BAF250a expression by IHC for patient selection.
Disclosure: This study was funded by AstraZeneca. For full disclosures of the study authors, visit oncologypro.esmo.org.
