FDA approves label update for darolutamide in nonmetastatic CRPC

In the ARAMIS trial, darolutamide reduced the risk of death by 31% compared with placebo in men with nonmetastatic castration-resistant prostate cancer.

The FDA has approved a supplemental New Drug Application updating the label for darolutamide (Nubeqa) in nonmetastatic castration-resistant prostate cancer (CRPC) to include overall survival (OS) data from the pivotal phase 3 ARAMIS trial.1

In the ARAMIS trial, adding darolutamide to androgen-deprivation therapy (ADT) reduced the risk of death by 31% compared with ADT plus placebo in men with nonmetastatic CRPC (HR, 0.69; 95% CI, 0.53-0.88; 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).

"A key goal of cancer treatment is to ensure that patients can live longer while minimizing side effects," Scott Z. Fields, MD, senior vice president and head of Oncology Development at Bayer's Pharmaceutical Division, stated in a press release. “Nubeqa has a proven efficacy and safety profile in men with nonmetastatic CRPC and delayed the effects of disease progression in men who are otherwise generally asymptomatic. This update also gives physicians added certainty that Nubeqa should be prescribed to appropriate patients at nonmetastatic CRPC diagnosis to help ensure optimal outcomes for these men.”

Darolutamide was approved by the FDA in July 2019 based on primary data from ARAMIS, which showed that in the overall population the median metastasis-free survival (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; 95% CI, 0.34-0.50; P <.001).

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 MFS, with OS as the key secondary end point.

Regarding safety, the final analysis found that treatment-related adverse events (TRAEs) occurred in 85.7% and 79.2% of the darolutamide and control arms, respectively. Grade 3/4 TRAEs occurred in 26.3% versus 21.7%, respectively.

Serious TRAEs were experienced by 26.1% and 21.8% of the darolutamide and control arms, respectively. TRAEs led to treatment discontinuation in 9% of both study arms. The mortality rate was 4% with darolutamide and 3.4% with ADT alone.

Of note, a separate subgroup analysis of the ARAMIS trial showed that darolutamide is effective for the treatment of high-risk patients with nonmetastatic CRPC who have a rapid PSA doubling time (PSADT).3 Among patients with a PSADT ≤6 months, darolutamide plus ADT reduced the risk of metastases or death by 59% versus ADT alone (HR, 0.41). This benefit was similar to that observed in patients with a PSADT >6 months, in whom there was a 62% reduction in the risk of metastases or death (HR, 0.38).


1. U.S. FDA Approves Addition of Overall Survival and Other Secondary Endpoint Data to NUBEQA® (darolutamide) Prescribing Information. Posted online January 8, 2021. https://bit.ly/2L60YfW. Accessed January 8, 2021.

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. Bögemann MWH, Shore ND, Tammela TLJ, et al. Efficacy and safety of darolutamide (DARO) in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and a prostate-specific antigen doubling time (PSADT) >6 months. 2020 European Association of Urology Virtual Congress. July 17-26, 2020. Abstract 919.

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