ARAMIS: Efficacy and safety of darolutamide in nonmetastatic castration-resistant prostate cancer (nmCRPC).

Abstract

140 Background: Delaying metastases for nmCRPC patients, while minimizing the risk of adverse events, is an important treatment goal. Darolutamide, a structurally unique androgen receptor (AR) antagonist, is being evaluated for the treatment of advanced prostate cancer. The ARAMIS trial studied the efficacy and safety of darolutamide in nmCRPC patients. Methods: This double-blind, placebo-controlled phase III trial randomized nmCRPC patients in a 2:1 ratio to receive darolutamide 600 mg (two 300 mg tablets) twice-daily or placebo, while continuing androgen deprivation therapy. Patients were stratified by prostate-specific antigen doubling time (≤6 months or >6 months) and use of osteoclast-targeted therapy. The primary endpoint was metastasis-free survival (MFS), with independent central review of radiographic imaging every 16 weeks. Secondary endpoints include overall survival (OS), times to pain progression (assessed by Brief Pain Inventory), first cytotoxic chemotherapy and first symptomatic skeletal event, as well as safety profile. Results: In total, 1,509 patients were randomized (955 to darolutamide, 554 to placebo). Median MFS was 40.4 months with darolutamide vs 18.4 months with placebo (hazard ratio [HR] 0.41; 95% confidence interval [CI] 0.34–0.50; 2-sided p<0.0001). OS showed a trend in favor of darolutamide (HR 0.71, 95% CI 0.50–0.99, 2-sided p=0.045), as did time to pain progression (HR 0.65; 95% CI 0.53–0.79; 2-sided p<0.0001). Other secondary and exploratory efficacy endpoints also favored darolutamide. Incidences of treatment-emergent adverse events (AEs) with ≥5% frequency or grade 3–5 were comparable between darolutamide and placebo arms; none except fatigue occurred in >10%. Discontinuation rates due to AEs were 8.9% with darolutamide and 8.7% with placebo. Grouped terms for AEs noted with other AR inhibitors (including fracture, falls, seizures, weight decrease, hypertension, and cognitive disorder) showed minimal or no difference in incidence between study arms. Conclusion: Among men with nmCRPC, MFS was significantly longer with darolutamide than with placebo with a low incidence of treatment-related AEs in this asymptomatic patient population. Clinical trial information: NCT02200614.

Evaluation of Cognitive Function in Trials Testing New-Generation Hormonal Therapy in Patients with Prostate Cancer: A Systematic Review

“…As shown in Table 5 , one RCT testing darolutamide (1509 patients, 955 assigned to apalutamide) was eligible for the analysis: ARAMIS [ 66 ].…”

“…In the double-blind, randomized, Phase 3 ARAMIS trial, patients with nonmetastatic CRPC, with a prostate-specific antigen doubling time of 10 months or less, were randomly assigned to receive darolutamide or placebo, in addition to ADT [ 66 ]. After a mFU of 17.9 months, 64% of patients were still receiving darolutamide.…”

“…In the description of investigator-assessed adverse events, no significant difference in the incidence of any grade cognitive disorders was described between darolutamide and placebo (0.4% vs. 0.2% respectively). However, given that QoL was evaluated by the means of FACT-P and EORTC PR25, no reliable measure of the impact of darolutamide on cognitive function is available [ 66 ]. Furthermore, no direct comparison is available between darolutamide and the other NGHTs.…”

Treatment of Advanced Prostate Cancer: Where Are We in 2019?

“…No Yes M0 immature (98) Darolutamide* CPEC -M0 Oral twice Daily No Yes M0 immature (112) * Not available in Brazil.…”

“…In addition, there was a trend favoring darolutamide in terms of OS (Median not reached for either arm, HR 0.71, 95% CI 0.50-0.99, p = 0.045). (112) Importantly, robust data on OS are lacking to define the real benefit of these three new agents.…”