Japanese Approval Sought for Darolutamide in CRPC

An application has been submitted to Japan's Ministry of Health, Labor and Welfare for darolutamide for the treatment of patients with castration-resistant prostate cancer.

Scott Fields, MD

An application has been submitted to Japan's Ministry of Health, Labor and Welfare for darolutamide for the treatment of patients with castration-resistant prostate cancer (CRPC), according to Bayer, which codevelops the agent with Orion Corporation.1

The marketing authorization application is based on findings from the phase III ARAMIS study, which showed that darolutamide plus androgen deprivation therapy (ADT) had a significant improvement in metastasis-free survival (MFS) versus placebo plus ADT in patients with nonmetastatic CRPC.2,3 The companies also completed a rolling submission of a new drug application to the FDA in this setting in February 2019, and is in discussions with other regulatory agencies regarding submissions for darolutamide.

“In the early stage of prostate cancer, patients are typically asymptomatic. Thus, it is critically important for men to have treatment options that significantly delay the development of metastases while limiting burdensome side effects of therapy, which allow them to continue their day-to-day lives,” said Scott Z. Fields, MD, senior vice president and head of Oncology Development at Bayer's Pharmaceutical Division. “With this submission, we are one step closer to providing patients and physicians in Japan with a potential new treatment option for CRPC.”

In the multicenter, double-blind phase III ARAMIS trial, 1509 patients with nonmetastatic CRPC and a PSA doubling time <10 months were accrued who were being treated with ADT and determined to be at-risk for developing metastatic disease. All men had an ECOG performance status of 0 to 1. Patients were randomized in a 2:1 ratio to darolutamide at 600 mg twice daily while maintaining ADT or matching placebo plus ADT.

Results showed that, at a median follow-up of 17.9 months, median MFS was 40.4 months in the darolutamide arm versus 18.4 months in the placebo arm, corresponding to a 59% reduction in the risk of metastases or death in favor of darolutamide (HR, 0.41; 95% CI, 0.34-0.50; P <.0001).1 The MFS benefit occurred across patient subgroups, including those for baseline PSA doubling time, use of bone-targeting agents, Gleason score, age, and ECOG performance status.

At an interim analysis for overall survival (OS), the 3-year rates of OS were 83% in the darolutamide arm versus 73% with placebo, leading to a 29% reduction in the risk of death (HR, 0.71; 95% CI, 0.50-0.99, P = .0452). Median OS was not yet reached in either arm.

The findings also showed that the median time to pain progression, using the Brief Pain Inventory-Short Form or by opioid use, was superior with darolutamide, at a median of 40.3 months versus 25.4 months with placebo, which was consistent with a 35% risk reduction (HR, 0.65; 95% CI, 0.53-0.79; P <.0001).

Progression-free survival (PFS), which included local relapse, distant metastases, or death, was an exploratory endpoint. Median PFS was 36.8 months in the darolutamide arm versus 14.8 months in the placebo arm, for a 62% risk reduction with darolutamide (HR, 0.38; 95% CI, 0.32-0.45; P <.0001).

Moreover, time to cytotoxic chemotherapy (HR, 0.43; 95% CI, 0.31-0.60; P <.0001) and time to first symptomatic skeletal event (HR, 0.43; 95% CI, 0.22-0.84; P = .0113) also favored the androgen receptor antagonist.

At baseline, the median PSA doubling time was 4.4 months and 4.7 months in the darolutamide and placebo groups, respectively. Only 3% and 6%, respectively, were taking a bone-sparing agent. The median duration of treatment was 14.8 months for darolutamide and 11.0 months for placebo. At data cutoff of September 3, 2018, 64% of patients on darolutamide and 36% on placebo were still on treatment.

Regarding safety, there were rare incidences of grade 3/4 adverse events (AEs). Fatigue was the sole AE with an all-grade rate >10% in the darolutamide arm compared with placebo (12.1% vs 8.7%). However, the difference in the rate of fatigue between groups disappeared when adjusting for duration of exposure. Incidences of falls and fractures did not differ between arms, at approximately 4% each, as was the incidence of hypertension at 6.6% with darolutamide arm compared 5.2% with placebo.

Darolutamide is also being investigated in the phase III ARASENS trial (NCT02799602), which is evaluating the agent in patients with metastatic castration-sensitive prostate cancer.


  1. Bayer Submits Darolutamide for Marketing Authorization in Japan. Bayer. Published March 5, 2019. https://bit.ly/2tQEN0M. Accessed March 5, 2019.
  2. Fizazi K, Shore ND, Tammela T, et al. ARAMIS: efficacy and safety of darolutamide in nonmetastatic castration-resistant prostate cancer (nmCRPC). J Clin Oncol. 37(suppl 7s; abstr 140). meetinglibrary.asco.org/record/170190/abstract.
  3. Fizazi K, Shore N, Tammela T, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer [published online ahead of print February 14, 2019]. N Eng J Med. doi: 10.1056/NEJMoa1815671.