Results of a phase II trial of olaparib in combination with ceralasertib in patients with recurrent and unresectable osteosarcoma.

10005 Background: Osteosarcoma is the most common bone tumor of children, adolescents, and young adults and patients with recurrent osteosarcoma have very poor outcomes. The observed response to cisplatin in osteosarcoma, in vitro susceptibility of osteosarcoma cell lines to ATR and PARP inhibitors, and the presence of mutations in genes involved in DDR served as the basis for the development of this trial. Methods: In this single arm, open label phase II trial of olaparib and ceralasertib patients aged 12-40 weighing > 40 Kg with recurrent osteosarcoma and measurable unresectable disease were eligible for Cohort 1. The primary endpoint for Cohort 1 was event-free status at 4-months. Secondary endpoints included objective response rate (ORR) and event-free survival (EFS). After an early study amendment changing the dosing strategy based on clinical data generated from other trials, patients received Olaparib 150mg twice a day on days 1-28 and ceralasertib 80mg twice a day on days 1-14 of a 28-day cycle. Using a two-stage design and a planned sample size of 34 evaluable Cohort 1 patients receiving the amended dosing strategy there is 90% power to detect a 20% increase (39% vs 19%, selected based on a historical benchmark) in the proportion of patients who are event-free at 4-months. Interim analysis required ≥2 of 15 patients to be 4-months event-free to proceed to Stage 2; at Stage 2, ≥11 of 34 patients 4-months event-free for evidence of efficacy. Results: The study proceeded to full accrual based on the interim analysis. As of 1/21/2025 data-cut off, 38 patients from four centers were enrolled in Cohort 1 between November 2020 and November 2024; 37 were eligible and evaluable for safety, objective response, and survival analyses. Excluding four patients enrolled before the study amendment updating dosing, 33 patients were evaluable for the primary objective. Median age was 19.6 years (range 12.7-38.2). Patients received an average of 4.2 (range 1-9) prior therapy regimens, including 26 (70%) patients with prior multi-tyrosine kinase inhibitor treatment. Four of the 33 evaluable were event-free at 4-months (12%; 95% CI: 4%-29%). One of 37 patients had an objective response (ORR: 2.7%; 95% CI: 0.14%-16%). The 4-month EFS±SE was 13.5±5.6% (n = 37). The most common ≥ grade 3 adverse events were platelet count decreased and anemia (38% and 27%, respectively). Conclusions: The study did not meet the predetermined threshold for efficacy for Cohort 1; however, a subset of patients may be benefit from this combination treatment. Results of Cohort 2 (resectable osteosarcoma limited to the lung parenchyma) will be reported separately. Assessment of potential biomarkers of response is underway. Clinical trial information: NCT04417062 .