Homologous Repair‐Deficient Pancreatic Cancer: Refined Targeting of DNA Damage Response is an Effective Therapeutic Strategy

ABSTRACT Background Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with a high mortality rate. While up to 20% of PDAC patients harbor mutations in genes involved in homologous recombination (HR) repair, only 5% of germline BRCA1/2 mutation carriers have an approved treatment option with the PARP inhibitor (PARPi) olaparib. Characterizing HR‐deficient (HRD) genotypes beyond g BRCA1/2 that are susceptible to PARPi has potential to substantially broaden the eligible patient population, and defining the optimal inhibitor may further optimize treatment strategies to advance personalized medicine in PDAC. Objective Our previous preclinical work showed synthetic lethality of a multi‐pronged DNA damage repair interference strategy using the PARPi olaparib, ATR inhibitor VE‐822, and DNA‐PK inhibitor CC‐115 (termed PAD) in ATM deficiency. In the present study, we challenged the role of olaparib in our PAD combination and assessed the regimen's efficacy across various HRD genotypes. Methods We assessed a spectrum of DNA damage repair‐interfering drugs to identify the most potent inhibitor in HRD. Using ATM , BRCA1 , BRCA2 and PALB2 ‐defective versus HR‐proficient murine PDAC cells, we systematically investigated the feasibility of expanding an optimized PAD regimen within defined HRD genotypes in vitro and in vivo. The regimen's efficacy was validated in PDAC patient‐derived organoids with and without deleterious class IV/V alterations in HRD genes. Results and Conclusion Here, we demonstrate a remarkable potency of the PARPi talazoparib in HRD PDAC. Substituting olaparib, currently the only approved inhibitor in PDAC, with talazoparib in our PAD regimen enhanced its efficacy while maintaining comparable tolerability in vivo. Importantly, we show that PAD is an effective therapeutic regimen that can be extended to the most prevalent HR‐defective genotypes in PDAC including ATM , BRCA1 , BRCA2 and PALB2 in a preclinical setting. Collectively, these data provide a strong rationale to implement the refined regimen, talazoparib‐based PAD, as a therapeutic concept tailored for HRD PDAC patients.