A well-established strategy for multimodal tumour attack is the use of oncolytic adenoviruses armed with therapeutic transgenes. In the present work we explored the multimodal approach that combines the lytic effects of the oncolytic adenovirus AdNuPAR with the cytotoxic activity of a gene-directed enzyme prodrug therapy (GDEPT). This system uses the purine nucleoside 2´-deoxyribosyltransferase (PDT) transgene, which encodes for an enzyme that converts the prodrug 2-fluoro-2’-desoxiadenosine (FdAdo) into the cytotoxic drug 2-fluoroadenine (FAde). To have a good balance between viral fitness and the GDEPT system we generated AdNuPAR viruses armed with PDTs transgenes that differ in their codon usage (AdNuPAR-wtPDT, AdNuPAR-iPDT and AdNuPAR-aPDT). The three PDT enzymes were expressed and capable of inducing cytotoxicity to the cells when exposed to the FdAdo prodrug. However, in the context of the armed adenoviruses, only AdNuPAR-wtPDT, AdNuPAR-iPDT were able to successfully combine the cytotoxic activity of the GDEPT, and the lytic effect of viral replication in a panel of cancer cell lines. This demonstrates that a concerted optimization of transgene expression and viral replication is needed for effective therapies. The multimodal system was also capable to generate a bystander cytotoxic effect, inducing the death of non-infected cells and further enhancing the anticancer effect.  Altogether, our work shows that optimal codon usage PDT armed AdNuPAR oncolytic virus can be an efficacious therapy against pancreatic tumours.