Background: Tumor Treating Fields (TTFields) therapy is a loco-regional antimitotic treatment approved for glioblastoma and malignant mesothelioma. TTFields (150 kHz), with/without chemotherapy, induced antiproliferative and anticlonogenic activity in pancreatic cancer cell lines invitro. The phase (ph) 2 PANOVA study (NCT01971281) demonstrated that TTFields therapy with gemcitabine and nab-paclitaxel (GnP; TTFields/GnP) is well-tolerated, with promising efficacy in metastatic and locally advanced pancreatic adenocarcinoma (LAPC). Despite advances in the treatment of LAPC, prognosis is poor and available therapies negatively impact quality of life (QoL); there is an unmet need for effective and tolerable treatments. Methods: PANOVA-3 (NCT03377491) is a prospective, randomized, ph 3 trial investigating the efficacy and safety of TTFields/GnP in patients (pts) with LAPC, with a planned enrollment of 556 pts. Pts with unresectable LAPC (per NCCN guidelines), ECOG PS of 0–2, and no prior treatment are eligible. Pts will be stratified by performance status and geographical region, and assigned 1:1 to TTFields/GnP or GnP alone. Standard doses of GnP will be administered on days 1, 8, and 15 of a 28-day cycle. TTFields (150 kHz) generated by the NovoTTF-200T System, will be delivered ≥ 18 h/day until local disease progression per RECIST v1.1. Pt usage is tracked by the device. Follow-up will be performed Q4W; CT scans of the chest and abdomen will be taken Q8W. After local disease progression, pts will be followed every month until death. The primary endpoint is overall survival. QoL, pain-free survival, and puncture-free survival will be compared between TTFields/GnP and GnP alone. Other secondary endpoints include progression-free survival (PFS), local PFS, objective response rate, 1-year survival rate, rate of resectability, and safety. Device Support Specialists (DSS) will provide technical and lifestyle integration training for pts and caregivers throughout TTFields therapy. The device manufacturer will also provide guidance on preventing and managing skin adverse events in line with published guidance, by means of DSS, field personnel, and various information resources. Usage information from the NovoTTF-200T System is provided to pts and physicians to facilitate discussions to optimize outcomes by maximizing time on therapy. Together, these novel support approaches help pts to confidently operate the NovoTTF-200T System with the knowledge that a multi-faceted support structure is available, ensuring TTFields therapy is seamlessly integrated into everyday life, increasing likelihood of high usage and ultimately optimizing pt outcomes. The trial is currently recruiting at 148 sites, globally. The DMC last reviewed the trial in September 2022, and suggested that the trial continue as planned. Clinical trial information: NCT01971281.