Effect of renin-angiotensin system (RAS) inhibition on survival in advanced ductal adenocarcinoma (PDAC).

Abstract

464 Background: Advanced PDAC portends a poor survival due to several factors including development of resistance to therapies via tumor-stromal interactions. In preclinical studies, RAS inhibition has been implicated in PDAC development due to its anti-inflammatory effect by reducing pancreatic inflammation and fibrosis via suppressed activation of pancreatic stellate cells. Methods: A retrospective analysis was conducted at two institutions in North America of patients (pts) with advanced PDAC receiving palliative chemotherapy. Data collection included age, gender, ECOG, prescription for an angiotensin I-converting enzyme inhibitors (ACEIs) and/or angiotensin II type-1 receptor blockers (ARBs), and overall survival (OS). Statistical analysis included Kaplan Meier survival analysis along with the log-rank test to compare treatment strata. Additionally, multivariate analyses were performed using a Cox proportional hazard model. Results: The 403 pts included had a median age of 61 years (range: 25-86 yrs); 176(43%) were women and 329 (>80%) had an ECOG performance status of 0 or 1. A majority of patients received combination therapy that was either gemcitabine or 5-flurouracil based. 57 (14%) received ACEIs and 25(6.2%) received ARBs. There was no statistically significant difference in median OS between those prescribed ACEI or ARB and those who were not (13.7 vs. 14.2 months; p=0.432). Subgroup analysis of ACEI vs. no ACEI or ARBs vs. no ARBs was similar (ACEI =13.8 vs. 14.2 months (p=0.741) and ARB=13.7 vs. 14.2 months (p=0.405). In addition, ACEI vs. ARB showed similar results 13.8 months (ACEIs) vs. 13.7 months (ARBs) (p=0.687). Conclusions: Our study did not demonstrate a statistically significant difference in OS between advanced PDAC patients in North America that were prescribed ACEI, ARB, or to those who were not. Compliance with taking prescribed ACEI or ARB medications could not be determined. A prospective phase 2 study in a Japanese population using the combination of gemcitabine and candesartan (an ARB) did not demonstrate a survival benefit with the combination. Based on these clinical evaluations, use of ACEI or ARB to take advantage of blocking RAS in advanced PDAC cannot be supported.