Real-world darolutamide safety and effectiveness in nonmetastatic castration-resistant prostate cancer (nmCRPC) by lipid-modifying agent use: Post hoc analyses of DAROL interim analysis 4 (IA4).

99 Background: Darolutamide is approved for nmCRPC based on significant metastasis-free survival (MFS) and overall survival (OS) benefits vs placebo and favorable safety in the phase 3 ARAMIS study. DAROL is assessing real-world outcomes with darolutamide in patients with nmCRPC. In this elderly population, many patients are receiving lipid-modifying agent (LMA) therapy. We assess the impact of the darolutamide + LMA combination on safety and effectiveness of darolutamide. Methods: DAROL is an ongoing, international, multicenter, prospective, open-label, single-arm, noninterventional study in patients with nmCRPC treated with darolutamide according to local practice. The primary endpoint is safety. OS and MFS are secondary endpoints. Concomitant LMA use was defined as LMA starting before darolutamide and continuing during darolutamide therapy. Using inverse probability of treatment weighting adjusting for baseline factors, the LMA subgroup was compared with all other patients (No LMA). Results: IA4 was conducted when 799 patients had received ≥12 months of treatment. Of these, 258 (32%) were receiving LMAs at baseline: statin n=251, non-statin n=35 (some patients received >1 LMA). Prostate cancer characteristics were similar between LMA and No LMA subgroups; however, there were important differences in medical history, including more metabolic (91% vs 39%), vascular (84% vs 66%), and cardiac (46% vs 21%) disorders in the LMA vs No LMA subgroup; fatigue incidence was 4% vs 2% at baseline; 7% in each subgroup had a medical history of hepatic disorders. Darolutamide maintained OS in patients with concomitant LMA with no difference vs the No LMA subgroup (adjusted HR 1.01, 95% CI 0.73–1.39); MFS slightly favored the No LMA subgroup (adjusted HR 1.39, 95% CI 1.09–1.77). The LMA vs No LMA subgroup had more treatment-emergent adverse events (TEAEs; 74% vs 55%) and grade 3/4 TEAEs (28% vs 12%), but fewer discontinuations due to TEAEs (7% vs 10%); darolutamide discontinuations due to disease progression were similar in the LMA and No LMA subgroups (17% each). The most frequent TEAEs showed <5% difference between the LMA and No LMA subgroups except for fatigue (16% difference: 27% vs 11% incidence), which may be related to comorbidity burden. Cardiac TEAEs occurred in 8% and 4%, respectively. TEAEs associated with LMAs, including liver abnormalities (LMA 3%, No LMA 2%), did not appear to be increased with concomitant darolutamide. Further effectiveness analyses and data comparing the LMA subgroup with other patients with cardiovascular disease but no LMA therapy will be reported. Conclusions: Darolutamide was well tolerated, with no new safety signals observed in the LMA vs no LMA subgroup. Darolutamide is a standard of care option for nmCRPC in patients irrespective of concomitant LMA use. Clinical trial information: NCT04122976 .