A phase II study of niraparib and dostarlimab with radiation in patients with metastatic pancreatic cancer.

564 Background: PARP inhibitors have activity as monotherapy in BRCA1/2 mutated metastatic pancreatic cancer; however, several other genes and associated proteins exist in the homologous recombination repair (HRR) pathway promoting resistance to chemotherapy and radiation-induced damage. Tumors with HRR deficiency have an impaired ability to repair themselves and are susceptible to PARP inhibition, but ionizing radiation can also induce DNA breaks. Ongoing research suggests that PARP inhibitors may cause radio-sensitization and may also enhance sensitivity to immunotherapy. We conducted a phase 2 study of niraparib and dostarlimab with radiation in a biomarker unselected PDAC population given PARP inhibitors' immunomodulatory and radiosensitizing effects. Methods: In this open-label, single-arm, phase-2 study, eligible patients had histologically confirmed MSS PDAC, ECOG PS 0-1, and progressed on at least one line of jm. Treatment consisted of niraparib 200 mg daily on a 21-day cycle, dostarlimab 500 mg every 3 weeks every 4 weeks for the first four doses, then 1000 mg every 6 weeks, and 3 fractions of 8 Gy at Cycle 2. Treatment continued until progressive disease, discontinuation, or withdrawal. The primary endpoint was DCR by RECIST 1.1 with radiological evaluations every 3 months. Secondary endpoints included DCR by irRECIST, PFS, OS, and safety. Responses were defined as disease control outside the radiation field. We obtained serial tumor biopsies, including pre-treatment. A two-stage design was used, requiring disease control in at least one of the first 15 patients before proceeding to the full accrual of 25 patients. Intention to treat analysis included all patients receiving at least one dose of any study agent. Results: We enrolled and treated 15 pts (median age 60 years [range 37-77], 53% male) from 08/2020 to 05/2021. Overall, DCR was 0/15 (95% CI: 0-22%), median PFS was 1.6 months (95% CI: 1.1-2.7), and median OS 3.1 months (95% CI: 1.5-7.7). Among 27 treatment-related serious adverse events, 15 (56%) were grade 3, including decreased CD4 lymphocytes, thrombocytopenia, anemia, and fatigue being the most common. Conclusions: The combination of niraparib and dostarlimab with radiation did not meet the pre-specified criteria for expansion to full accrual. Further analyses of dose intensity in this heavily pretreated and evaluation of in-field responses are underway. Further investigation of the combination with biomarker selection is warranted. Clinical trial information: NCT04409002.