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Darolutamide plus ADT explored in phase 3 mHSPC trial


Darolutamide is currently approved by the FDA for the treatment of men with nonmetastatic castration-resistant prostate cancer.

The phase 3 ARANOTE trial is launching to explore darolutamide (Nubeqa) in men with metastatic hormone-sensitive prostate cancer (mHSPC), according to Bayer and Orion Corporation, the developers of the androgen receptor antagonist.1

The randomized, double-blind trial is comparing darolutamide plus androgen-deprivation therapy (ADT) with placebo plus ADT. The primary end point is radiological progression-free survival and the target enrollment is 555 patients. Patient enrollment on the trial is planned to start by the end of March 2021.

“Darolutamide has already shown in men with nonmetastatic castration-resistant prostate cancer (nmCRPC) that it extends life with a favorable safety profile allowing men to continue their lifestyle with only minimal disruption” Scott Z. Fields, MD, senior vice president and head of Oncology Development, Bayer, stated in a press release.

“Given the encouraging results that we have seen with the compound so far, it is important that we also evaluate the potential of darolutamide in other stages of the disease to offer men with mHSPC a new treatment option that is effective and addresses the challenge of bothersome side effects,” added Fields.

FDA approval

The FDA approved darolutamide in July 2019 for the treatment of patients with nmCRPC, based on findings from the phase 3 ARAMIS trial.

The double-blind ARAMIS trial included 1509 patients with nonmetastatic CRPC. Patients were randomized in a 2:1 ratio to receive oral darolutamide at 600 mg twice daily plus androgen deprivation therapy (ADT; n = 955) or placebo plus ADT (n = 554). Patients had an ECOG performance status of 0 to 1. The primary end point of the trial was metastasis-free survival (MFS), with overall survival (OS) as the key secondary end point.

In the study, adding darolutamide to ADT reduced the risk of death by 31% compared with ADT plus placebo in men with nonmetastatic CRPC (HR, 0.69; P = .003).2 At a median follow-up of 29 months, the 3-year OS rates were 83% and 77% in the darolutamide and placebo arms, respectively.

This OS benefit was reached even though over half (55%) of the patients on the control arm received darolutamide (n = 170) or other subsequent treatments (docetaxel, abiraterone acetate [Zytiga], enzalutamide [Xtandi], sipuleucel-T [Provenge], and cabazitaxel [Jevtana]) after the study was unblinded.

In addition to improving OS, the darolutamide regimen also led to statistically significant delays in the time to first symptomatic skeletal event (HR, 0.48; P = .005), time to pain progression (HR, 0.65; P <.0001), and time to initiation of cytotoxic chemotherapy (HR, 0.58; P <.0001).

Further, MFS was 40.4 months in the darolutamide cohort and 18.4 months in the placebo cohort, translating to a 59% reduction in the risk of metastases or death (HR, 0.41; P <.001).

Other pivotal research

Another key ongoing study of darolutamide, the phase 3 ARASENS trial (NCT02799602), is examining the triplet of darolutamide, ADT, and docetaxel versus docetaxel plus ADT alone in men with mHSPC.3

This randomized, double-blind, placebo-controlled, multicenter trial has a target enrollment of 1300 patients. The estimated primary completion date of the study is June 1, 2021.

The trial’s primary end point is OS. Key secondary end point include time to castration resistant prostate cancer, time to initiation of subsequent antineoplastic therapy, and symptomatic skeletal event free survival.


1. Bayer and Orion expand development program for darolutamide in prostate cancer. Published online February 8, 2021. Accessed February 8, 2021. https://bit.ly/39XpYzi.

2. Fizazi K, Shore N, Tammela TL, et al. Nonmetastatic, castration-resistant prostate cancer and survival with darolutamide. N Engl J Med. 2020;383(11):1040-1049. doi: 10.1056/NEJMoa2001342

3. NIH ClinicalTrials.gov. ODM-201 in Addition to Standard ADT and Docetaxel in Metastatic Castration Sensitive Prostate Cancer (ARASENS). Last update January 22, 2021. Accessed February 8, 2021. https://clinicaltrials.gov/ct2/show/NCT02799602

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