AGITG SPAR: A randomized, placebo-controlled, phase II trial of simvastatin in addition to neoadjuvant chemotherapy and radiation for rectal cancer.

141 Background: Retrospective clinical studies and preclinical studies demonstrated that statin use during preoperative (chemo)radiation (pCRT) for rectal cancer is associated with improved survival, response, and toxicity. Tumor regression following pCRT has strong prognostic significance and can be assessed using MRI-based tumor regression grading (mrTRG), including with non-operative management. SPAR was designed to prospectively evaluate the benefits of adding simvastatin (SIM) to pCRT on tumor regression and gastrointestinal (GI) adverse events (AE). Methods: SPAR is a double-blind randomized phase 2 trial investigating SIM/placebo (PBO) in addition to long-course fluoropyrimidine-based pCRT for rectal adenocarcinoma. Stratification included trial site, clinical T stage (<4 vs 4), clinical N stage (<2 vs 2), either mesorectal fascia involvement (MRFI) or extramural venous invasion (EMVI) on MRI (yes vs no), and total neoadjuvant therapy (TNT): induction vs consolidation chemotherapy vs none. Study treatment was SIM 40mg/PBO daily for 90 days, starting 1 week prior to pCRT; recent statin use was excluded. Pelvic MRI was repeated 6-8 weeks after pCRT to determine mrTRG. An amendment in January 2022 allowed TNT with either induction or consolidation chemotherapy; the timing of post-pCRT MRI remained unchanged. The design was amended to open-label due to PBO supply issues. Primary objective: rate of centrally assessed grade 1-2 mrTRG. Secondary objectives include centrally assessed favorable pathologic TRG (pathTRG), safety and cancer outcomes. Analysis was by intention-to-treat. Results: Between April 2018 - November 2023, 135 of 222 planned participants from 17 sites in Australia and New Zealand were randomized (68 SIM; 67 no SIM). Recruitment was hampered by the COVID-19 pandemic and adoption of TNT as standard care before the protocol amendment. Participant characteristics: median age 59 years; 85 (63%) males; 118 (87%) T2-3 disease, 80 (59%) N0-1 disease; 55 (41%) MRFI or EMVI; 25 (19%) had TNT. Rates of grades 1-2 mrTRG with SIM vs no SIM were 38.5% and 29.7% (X 2 = 1.09, p = 0.30), respectively. There was no significant difference in rates of > grade 2 GI and non-GI AE. Four serious AE were recorded, none related to study treatment. Median follow-up was 3.2 years. 3-year local recurrence rates (LRR) were low: 1 (2.2%) and 3 (5.5%) with SIM vs no SIM, respectively (HR: 0.29, 95% CI: 0.03 to 2.67, p = 0.26). 3-year disease-free survival (DFS) with SIM vs no SIM was 84% and 72%, respectively (HR 0.48; 95% CI: 0.21–1.08, p = 0.07). Conclusions: The rates of favorable mrTRG, 3-year LRR and DFS were numerically better with the addition of SIM to pCRT, though the differences were not statistically significant. SIM was well tolerated. Interpretation is limited by reduced sample size and statistical power. PathTRG and other key outcomes will be presented at the meeting. Clinical trial information: ACTRN12617001087347 .