The researchers evaluated in an ongoing phase II study an ATR inhibitor, ceralasertib alone and in combination with olaparib among patients with ARID1A-deficient and ARID1A -intact solid tumours. They observed antitumour activity with a single agent ceralasertib in ARID1A-deficient solid malignancies, according to Dr. Rahul Aggarwal of UCSF - University of California San Francisco in San Francisco, CA, US, who reported the study findings during the proffered papers session on developmental therapeutics at ESMO 2021 Congress (16-21 September).
Dr. Aggarwal 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.
In this study, the UCSF researchers enrolled the patients with advanced solid tumours. They defined ARID1A deficiency as absence of tumour expression of its gene product BAF250a by immunohistochemical (IHC) staining.
The cohort 1 evaluated the patients with ARID1A-deficient tumours who were treated with ceralasertib monotherapy at 160 mg given orally twice daily from day 1 to 14 in 28 days cycle, while the cohort 2 evaluated the patients with ARID1A-intact tumours who were treated with ceralasertib at 160 mg given twice daily from day 1 to 7 plus olaparib 300 mg given orally twice daily from day 1 to 28.
The study primary endpoint was objective response rate (ORR). Target accrual was 10 patients per cohort. At least 1 objective response was required to proceed to stage 2.
Among screened patients whose tumours harboured 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 2 (range, 0 – 5).
In cohort 1, the ORR was 20% with 2 complete responses (CRs) 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 (SD), for an overall clinical benefit rate of 30% defined as obtained response or SD of duration longer than 6 months in cohort 1.
The percent change from baseline in target lesions is shown for each patient enrolled on cohort 1 (ARID1a-deficient tumours). Two complete and ongoing responses were observed in two patients with ARID1a-deficient endometrial cancer.
© Rahul Aggarwal
In cohort 2, best response of SD 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 ceralsertib monotherapy were thrombocytopenia in 10% of patients and neutropenia in 20%, both of which resolved with temporary dose interruption or dose reduction.
Dr. Aggarwal concluded that they observed in this study antitumour activity of ceralasertib given as a single agent in patients with ARID1A-deficient solid tumours, 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.
This study was funded by AstraZeneca.
Reference
512O – Aggarwal R, Umetsu S, Dhawan M, et al. Interim results from a phase II study of the ATR inhibitor ceralasertib in ARID1A-deficient and ARID1A-intact advanced solid tumor malignancies. ESMO Congress 2021 (16-21 September).