Darolutamide Improves MFS in Phase III Nonmetastatic CRPC Trial

Darolutamide significantly improved metastasis-free survival versus placebo in patients with nonmetastatic castration-resistant prostate cancer enrolled in the phase III ARAMIS trial.

Scott Fields, MD

Darolutamide (ODM-201) significantly improved metastasis-free survival (MFS) versus placebo in patients with nonmetastatic castration-resistant prostate cancer (CRPC) enrolled in the phase III ARAMIS trial, according to Bayer and Orion Corporation, the co-developers of the oral androgen receptor antagonist.1

The companies did not share any specific data from the trial, but noted in a press release that safety and tolerability outcomes with darolutamide were similar to those previously published. Based on the results, the companies plan to communicate with health authorities about a regulatory filing.

"Despite recent advances in nonmetastatic CRPC, there remains a high unmet need for additional treatment options that delay the time to metastases," Scott Fields, MD, senior vice president and head of Oncology Development at Bayer's Pharmaceutical Division, said in a statement. "We are encouraged by the results of the ARAMIS trial and look forward to presenting the full data at an upcoming scientific meeting."

The multicenter, double-blind phase III ARAMIS trial accrued over 1500 patients with nonmetastatic CRPC who were being treated with androgen deprivation therapy (ADT) and determined to be at-risk for developing metastatic disease. Patients were randomized in a 2:1 ratio to darolutamide at 600 mg twice daily or matching placebo. Beyond the primary endpoint of MFS, secondary outcome measures included overall survival, time to first symptomatic skeletal event, time to initiation of first cytotoxic chemotherapy, time to pain progression, safety/tolerability.

Darolutamide is now the third agent to recently succeed in a phase III trial in the nonmetastatic CRPC setting. The two previous agents, apalutamide (Erleada) and enzalutamide (Xtandi), now have approved FDA indications in this setting.

In February 2018, apalutamide became the first FDA-approved treatment for patients with nonmetastatic CRPC, based on the phase III SPARTAN trial.2 In the study, apalutamide reduced the risk of metastasis or death by 72% in patients with nonmetastatic CRPC. The median MFS was 40.5 months in the apalutamide arm versus 16.2 months in the placebo arm (HR, 0.28; 95% CI, 0.23-0.35; P <.0001).

In July 2018, the FDA approved enzalutamide for nonmetastatic CRPC, based on the phase III PROSPER trial, in which the combination of enzalutamide and ADT reduced the risk of metastases or death by 71% compared with ADT alone for patients with nonmetastatic CRPC.3 In the double-blind study, the median MFS was 36.6 months with enzalutamide plus ADT versus 14.7 months with ADT alone (HR, 0.29; 95% CI, 0.24-0.35; P <.0001).

In an OncLive Insights segment earlier this year, Judd W. Moul, MD, Duke Cancer Institute, discussed the potential that darolutamide could have a better safety profile than apalutamide and enzalutamide.

“The other interesting thing is that [darolutamide] has a novel chemical structure, novel configuration, such that the drug does not cross the blood-brain barrier to any significant degree. So, people in the field feel that because it doesn’t cross the blood-brain barrier, it might have less toxicity than apalutamide or enzalutamide. Specifically, less fatigue and less falls, and certainly less risk of a seizure. Now, that is theoretical and needs to be borne out in the phase III trials. The drug was developed a little bit later. It’s a newer drug, so we don’t have the robust phase III data yet that we do for apalutamide or enzalutamide.”

The ongoing phase III ARASENS trial (NCT02799602) is examining darolutamide in combination with standard ADT and docetaxel versus standard ADT and docetaxel alone in patients with metastatic hormone-sensitive prostate cancer.


  1. Phase III Trial of Darolutamide in Patients with Non-metastatic Castration-resistant Prostate Cancer Meets Primary Endpoint. Published October 24, 2018. Accessed October 24, 2018. https://prn.to/2RatWbS.
  2. Small EJ, Saad F, Chowdhury S et al. SPARTAN, a phase 3 double-blind, randomized study of apalutamide (APA) versus placebo (PBO) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC). J Clin Oncol 36, 2018 (suppl 6s; abstract 161).
  3. Hussain M, Fizazi K, Saad F, et al. PROSPER: A phase 3, randomized, double-blind, placebo (PBO)-controlled study of enzalutamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (M0 CRPC). J Clin Oncol. 2018;36 (suppl 6S; abstr 3).