A new era in anti-RAS therapy: Unique challenges and opportunities for radiotherapy clinical trials

The development of effective allele-specific and RAS-ON multiselective direct RAS inhibitors for pancreatic ductal adenocarcinoma (PDAC) represents unprecedented progress in systemic therapy for a devastating disease. These drugs are already changing the standard of care in PDAC, and their development raises important questions about how ongoing and future trials of local therapies such as radiotherapy (RT) may be affected. Although RT remains part of the therapeutic armamentarium for pancreatic ductal adenocarcinoma (PDAC), particularly in locally advanced disease and the adjuvant setting, decades of clinical trials have raised more questions than they have answered. One major challenge has been the concurrent evolution of systemic therapies, complicating the design, interpretation, and clinical relevance of RT trials. Here, we review how changes in systemic therapy have influenced seminal trials of RT for PDAC and will consider implications for ongoing and future trials in this space. These considerations, already relevant when options were more limited, are even more critical with the emergence of novel RAS-targeted therapies.