Phase II trial of olaparib and ceralasertib in patients with recurrent osteosarcoma: Lung-only resectable cohort efficacy and correlative biomarker results.

10015 Background: Patients with osteosarcoma recurrence have limited treatment options and 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: We conducted a phase II trial of olaparib and ceralasertib in patients aged 12-40 with recurrent osteosarcoma. The primary endpoint for patients with resectable disease limited to the lung (Cohort 2) was submission of paired pre- and post-treatment tumor samples. Secondary endpoints for Cohort 2 included event-free status at 12-months, event-free survival (EFS) and overall survival (OS). 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. Patients with unilateral disease received 2 cycles of treatment prior to surgery. Patients with bilateral disease had one side resected, then received 2 cycles of treatment followed by surgery of the contralateral side. Tumor, blood and plasma samples were obtained from Cohort 1 (measurable unresectable disease, efficacy results previously reported) and Cohort 2 patients for correlative studies. Results: Between 3/2021-9/2024, 10 patients from 4 centers were enrolled in Cohort 2. Four patients had bilateral and six had unilateral lung metastases. Median age was 19.3 (range 15.7-24.6). Patients had received a median of three prior therapy regimens. Seven patients (70%, 95%CI: 35%-93%) underwent planned thoracic surgery and had paired pre- and post-treatment tumor samples submitted for correlative studies. Four patients (40%, 95%CI: 12%-74%) were event-free at 12 months and received >12 cycles of olaparib and ceralasertib. The 12-month EFS±SE and OS±SE were 40±15.5% and 90±9.5%, respectively. Initial review of clinical sequencing on a subset of Cohort 1 and 2 patients suggests therapy resistance may be associated with high-risk genomic features, like MYC amplification. Conclusions: Patients with recurrent resectable osteosarcoma limited to the lung parenchyma can be included as a separate cohort in phase II trials of novel agents. In this cohort, it is feasible to incorporate pre-surgical treatment with experimental agents followed by surgical resection of pulmonary nodules and collection of pre- and post-treatment tumor samples, enabling correlative biology. 12-month EFS was 40% but with a wide confidence interval crossing the confidence interval of historical 12-month EFS of 20% from prior COG studies. Sequencing and ctDNA analyses for all enrolled patients (both cohorts) with available samples (N=40 patients with tumor samples and N=48 patients with ctNDA samples) are underway to further assess potential biomarkers of treatment response. Clinical trial information: NCT04417062 .