Background: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of death by cancer worldwide. Mostly diagnosed with locally advanced or metastatic disease, patients lack for treatment options. Gene alterations (GAs) are frequently observed in PDAC, some of them considered as actionable with molecular targeted therapies (MTTs), with potential clinical benefits and improved outcomes. Methods: We conducted a retrospective analysis of all patients, aged ≥18 years, with histologically confirmed PDAC, who underwent tumor molecular profiling between 2010 and 2020 in our institution as part of personalized medicine trials. Overall survival was the primary study endpoint (minimal follow-up after molecular profiling, 6 months). Results: Of 115 eligible patients, molecular profiling was successful in 102 patients (89%). KRAS mutations were the most frequent GAs, mostly G12D. Actionable GAs were found in 29 patients (28%), involving mainly BRCA1/2 (5 [18%]), HER2 (5 [18%]), MTAP (5 [18%]), and FGFR (3 [11%]). Only 12 of these 29 patients (41%, or 10% of the whole population) could receive MTTs accordingly, with a median progression-free survival of 1.6 months. Median OS was 17 months in patients with actionable GAs treated with MTTs (n = 12 [11.8%]), 14 months in patients with actionable GAs not treated with MTTs (n = 17 [16.7%]), and 19 months in patients without actionable GAs treated with standard therapies (n = 73 [71.5%]; p = 0.26). The absence of liver metastases was associated with better OS (HR = 0.471, p = 0.01). The longest duration of response with MTTs was observed in patients with BRCA mutations treated with olaparib. Conclusions: Actionable GAs are found in more than the quarter of patients with advanced PDAC. Overall, targeting actionable GAs with MTTs was not associated with improved OS in this retrospective study. However, selected GA/MTT duets (e.g., BRCA mutations/olaparib) were associated with better outcome.