PARPis and Other Novel, Targeted Therapeutics in Pancreatic Adenocarcinoma

Although the prognosis for patients with PDAC remains poor, there has been progress in the development of novel, biomarker-directed therapies for subgroups of patients. Patients with HRD derive benefit from platinum-based chemotherapy, and olaparib maintenance treatment is associated with improved PFS among patients with gBRCA1/2 pathogenic variants. Ongoing trials aim to investigate PARPi in other set-tings for the treatment of PDAC, to identify patients beyond those with gBRCA1/2 or gPALB2 pathogenic variants who may have a HRD phenotype and benefit from PARPi, and to evaluate combinations with PARPi that may improve clinical efficacy. The best way to clinically identify HRD in PDAC patients remains elusive, with substan-tial effort geared toward answering this question. Biomarker-directed therapies, including pembrolizumab for patients with MMRd and larotrectinib and entrectinib for patients with NTRK fusions, have been approved in a disease agnostic fashion. Additional promising biomarker-directed therapies for tumors with NRG1 fusions and KRAS p.G12C mutations remain under development.