Therapeutic targeting of the DNA damage response (DDR), coupled with the implementation of personalised treatment strategies, has the potential to improve the poor survival outcomes of pancreatic ductal adenocarcinoma (PDAC). Many common genetic alterations in PDAC augment replication-associated DNA damage, or replication stress (RS), which increases reliance on the RS-response factor, Ataxia Telangiectasia and Rad3-related (ATR) kinase. Furthermore, many chemotherapies used in the treatment of PDAC increase RS, leading to ATR activation which limits the efficacy of these therapies. Therefore, there is good rationale for targeting ATR as a strategy for treatment of patients with PDAC. In this thesis, I report on investigations into the therapeutic potential of combining the ATR inhibitor, AZD6738, with DNA-damaging drugs and DDR-targeted agents in preclinical models of PDAC. My primary focus was on maximising the efficacy of combined ATR inhibition and gemcitabine (ATRi/gem). I hypothesised that ATRi/gem would most likely benefit specific sub-groups of patients with pre-existing aberrations in DDR pathways (i.e. a precision medicine approach to patient selection). Accordingly, I investigated the potential for deficiency in the double-strand-break master-regulator, Ataxia Telangiectasia Mutated (ATM), to sensitise PDAC models to ATRi/gem. I found that complete loss of ATM function - through kinase inhibition or through CRISPR knockout, but not ATM depletion by RNA interference - sensitised to ATRi and ATRi/gem in PDAC models. Using flow cytometry and quantitative image-based cytometry, I gained insight into the mechanisms by which AZD6738 and gemcitabine synergise, finding evidence for replication catastrophe that was significantly augmented in ATM-deficient cells. In vivo, I demonstrated that low-dose gemcitabine can be used to sensitise to AZD6738, much more effectively in an ATM-deficient setting. My results suggest that ATM-deficiency augments the replication catastrophe-mediated cell death induced by ATRi/gem, thus ATM-loss could predict response to this combination. The preclinical assessments of AZD6738 and gemcitabine that formed part of this project have led to the launch of a phase-I clinical trial (ATRiUM; NCT03669601). My data indicate that ATM status should be carefully assessed in tumours from patients with PDAC, since the distinction between ATM-low and ATM-null could be crucial in maximising the success of trials using ATM expression as a predictive biomarker. In this dissertation, I also present my investigations into the combination of AZD6738 with the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib. While AZD6738 and olaparib synergistically inhibited the growth of PDAC cells proficient in homologous recombination (HR) in vitro, I identified no anti-tumour effect in HR-proficient in vivo models. This could indicate that a DDR deficiency would be necessary for this combination to be most effective in PDAC, a hypothesis that will be tested in the clinic in the Precision-Panc trial, PRIMUS-004.