512O - Interim results from a phase II study of the ATR inhibitor ceralasertib in ARID1A-deficient and ARID1A-intact advanced solid tumor malignancies

Background

Loss of ARID1A leads to increased reliance on ATR (Ataxia Telangiectasia and Rad3 Related) kinase. ATR inhibition induces synthetic lethality in ARID1A-deficient preclinical models. We evaluated ceralasertib, an ATR inhibitor, alone and in combination with Olaparib, in patients harboring ARID1A-deficient and -intact solid tumors, respectively.

Methods

Patients (pts) with advanced solid tumor malignancies were enrolled. ARID1A deficiency was defined as absence of tumor expression of its gene product BAF250a by immunohistochemical (IHC) staining. Two cohorts were evaluated: Cohort 1) ARID1A-deficient pts treated with ceralasertib monotherapy at 160 mg PO BID days 1-14 of 28 day cycle; Cohort 2) ARID1A-intact pts treated with ceralasertib 160 mg BID days 1-7 plus olaparib 300 mg PO BID days 1-28. The primary endpoint was objective response rate (ORR). Target accrual was 10 patients/cohort; ≥ 1 objective response (OR) was required to proceed to stage 2.

Results

Of screened pts whose tumors harbored pathogenic mutations in ARID1A, 28/42 (67%) had BAF250a loss of expression by IHC. Twenty pts were enrolled (10/cohort). The median number of lines of prior therapy was 2 (range 0 – 5). In Cohort 1, the ORR was 20%. Two complete responses (CRs) were observed, and both pts remain on treatment for 19.8+ and 14.7+ months duration, respectively, with ongoing CRs. One additional patient remained on treatment for 8.8 months with stable disease (SD), for an overall clinical benefit rate (response or SD > 6 months) of 30% in Cohort 1. In Cohort 2, best response of SD was observed in 4/10 pts (40%); no ORs were observed. Overall, the median duration of treatment on study was 1.4 months (range 0.9 – 19.8+). The most common Grade ≥ 3 adverse events with ceralsertib monotherapy were thrombocytopenia (20%) and neutropenia (20%), both of which resolved with temporary dose interruption/reduction.

Conclusions

We observed anti-tumor activity with single agent ceralasertib in ARID1A-deficient solid tumors, including two patients with durable and ongoing complete responses. Accrual is ongoing in stage 2 using absence of BAF250a expression by IHC for patient selection.

Clinical trial identification

NCT03682289.

Editorial acknowledgement

Legal entity responsible for the study

University of California San Francisco.

Funding

AstraZeneca.

Disclosure

S. Smith: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. N. Shah: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. E. Dean: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. All other authors have declared no conflicts of interest.