ESMO 2021: Time Course Profile of Adverse Events of Interest and Serious Adverse Events with Darolutamide in the ARAMIS Trial

( The European Society of Medical Oncology (ESMO) 2021 annual meeting’s prostate cancer session included a presentation by Dr. Christian Gratzke discussing the time course profile of adverse events with darolutamide in the ARAMIS phase 3 trial.

Darolutamide is a structurally distinct and highly potent androgen-receptor inhibitor that improved metastasis-free survival by almost 2 years and reduced the risk of death by 31% versus placebo in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) in the ARAMIS trial.1 Men with nmCRPC are generally asymptomatic and may receive prolonged treatment with androgen receptor inhibitors. Understanding the burden and time course of adverse events commonly associated with androgen receptor inhibitors that may impact patients’ daily life will help inform optimal treatment selection for men with nmCRPC.

At the 2021 ESMO annual meeting, Dr. Gratzke and colleagues presented results of their analysis of time to adverse events of interest associated with some androgen receptor inhibitors (fatigue, falls, fracture, hypertension, mental impairment, and rash) and the cumulative incidence of these adverse events, grade 3/4 adverse events, and serious adverse events from ARAMIS.

ARAMIS was a global, multicenter, double-blind, randomized, phase 3 trial of men with nmCRPC randomized 2:1 to darolutamide (n=955) or placebo (n=554) while continuing androgen deprivation therapy. The cumulative incidence of adverse events was analyzed using Kaplan-Meier estimates for the first 24 months of the double-blind period to ensure >10% of the population in each treatment cohort. Time interval–specific analysis determined new event rates at each scheduled study visit.

During the first 24 months of the double-blind period, the incidence of adverse events of interest in the darolutamide group was low and ≤2% different from that in the placebo group, except for fatigue.


During the first month of darolutamide and placebo treatment, new event rates were very low and similar for falls (0.2%, 0.7%), fractures (0.4%, 0.5%), mental impairment (0%, 0.4%), hypertension (1.7%, 1.1%), and rash (0.7%, 0.2%). In men who had fatigue during the first 24 months (darolutamide, 12.6% and placebo, 8.3%), almost half of the men experienced fatigue onset during the first month in both arms (darolutamide, 5.9% vs placebo, 4.0%).


The cumulative incidence of rash was 2.9% (placebo 1.1%) at 24 months, with half of the events occurring in the first 4 months and almost all being grade 1 or 2.


The rate of initial onset and cumulative incidence of grade 3/4 adverse events and serious adverse events were similar for darolutamide and placebo groups over 24 months.


Dr. Gratzke concluded his presentation assessing the timing of adverse events among patients in the ARAMIS trial with the following conclusions:

  • The time course profile of most adverse events of interest, grade 3/4 adverse events, and serious adverse events confirms the safety profile of darolutamide, showing a similar onset and cumulative incidence versus placebo
  • Most events of fatigue were reported early in treatment, and the incidence of rash was very low, with almost all being grade 1 or 2 events


Presented by: Christian J. Gratzke, MD, Urology, University Hospital Freiburg, Freiburg, Germany

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2021 European Society for Medical Oncology (ESMO) Annual Congress 2021, Thursday, Sep 16, 2021 – Tuesday, Sep 21, 2021.


  1. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in nonmetastatic castration-resistant prostate cancer. N Engl J Med. 2019;380(13):1235-1246.