Phase II study of olaparib in patients with advanced pancreatic acinar cell carcinoma.

TPS789 Background: Pancreatic Acinar Cell Carcinoma (PACC) is a rare and biologically distinct subtype of pancreatic cancer, representing 0.5-1% of all pancreatic malignancies, with a median overall survival of 15-20 months. Significant serum CA 19-9 elevation is uncommon, while elevation of serum lipase is observed in at least 50% of patients. Most patients present at advanced stages and treatment with combination chemotherapies extrapolated from other GI malignancies leads to low response rates. No clinical treatment trials specific for PACC have ever been reported. PACC tumors from patients show evidence of high chromosomal instability, a hallmark of DNA repair deficiency. ID3 is ubiquitously downregulated and was recently shown to play a significant role in homologous recombination repair (HRR). Recent genomic profiling of larger PACC patient cohorts has revealed a high prevalence of mutations in HRR genes, including BRCA1, BRCA2, and PALB2. Olaparib is a Poly-ADP ribose polymerase (PARP)-1 inhibitor that has been FDA approved for treatment of BRCA-mutant HRR deficient cancers. We hypothesize that PACC will be sensitive to PARP inhibition with olaparib. Methods: This is an open label, single arm, single center, phase II study of olaparib in patients with advanced previously treated PACC. The primary objective of the trial is to evaluate anti-tumor activity of olaparib (objective response rate). Secondary objectives assess the safety (CTCAE v. 5.0) and alternative measures of efficacy such as clinical outcomes and blood biomarkers (disease control rate, median progression-free survival, median overall survival, best response in serum lipase). Key eligibility criteria include histologic diagnosis of PACC, receipt of at least one line of combination chemotherapy, presence of RECIST measurable disease and adequate organ and bone marrow function. A fixed dose of olaparib at 300 mg will be given orally continuously twice daily during a 28-day cycle, for up to 2 years or until disease progression or intolerable toxicities. In person visits to assess toxicity are required every 4 weeks, and response is determined through serial imaging every 8 weeks (CT or MRI). Exploratory objectives include acquisition of tumor tissue for establishment of new PACC preclinical models, assessment of genetic alterations through genetic mapping technique, assessment of HRR-related gene products as a predictive biomarker, assessment of ID3 protein levels, and assessment of treatment response to tumor profile. Up to 13 evaluable participants will be enrolled. Three participants have been enrolled as of Sep 19, 2024. Clinical trial information: NCT05286827 .