Prolonged Treatment With Darolutamide Is Well Tolerated in Nonmetastic CRPC


February 12, 2021 - The androgen receptor inhibitor darolutamide continues to show favorable tolerability in patients with nonmetastatic castration-resistant prostate cancer, even when given for a prolonged period of time.

Matthew Raymond Smith, MD, PhD

Matthew Raymond Smith, MD, PhD

The androgen receptor inhibitor darolutamide continues to show favorable tolerability in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC), even when given for a prolonged period of time, according to a final analysis of the double-blind period of the phase 3 ARAMIS trial (NCT02200614) presented during the 2021 Genitourinary Cancers Symposium.1

In a presentation on darolutamide safety profile data lead author, Matthew Raymond Smith, MD, PhD, of the Massachusetts General Hospital Cancer Center, noted that no new safety signals were observed during the DB+ open-label (OL) period of treatment. “Darolutamide remained well-tolerated with longer exposure in patients with nmCRPC,” Smith said.

ARAMIS randomized 1509 patients with nmCRPC 2:1 to 600 mg darolutamide twice daily (n = 954) or matched placebo (n= 554), while also continuing androgen deprivation therapy. Primary analysis of the DB period data cut-off was September 3, 2018, and after study unblinding on November 30, 2018, 48.8% of patients in the darolutamide arm who were still receiving study treatment continued with OL darolutamide by the final cut-off date for analysis of the DB+OL period on November 15, 2019.

The median treatment duration in the darolutamide group was 18.5 months for the DB period and 25.8 months for the DB+OL period.

In ARAMIS, darolutamide was found to significantly reduce the risk of death by 31% (HR = 0.69; 95% CI: 0.53-0.88; p = 0.003) and prolonged median metastasis-free survival compared to placebo (40.4 months vs 18.4 months; HR = 0.41; 95% CI: 0.34-0.50; p < 0.001).

With ARI therapy, however, patient daily life can be impacted by AEs that typically include fatigue, falls, fractures, rash, mental impairment and hypertension, as well as drug interactions between ARIs and concomitantly administered drugs. This analysis examined the safety profile of the drug, and found it to be well-tolerated, with a ≤2% difference in most AEs of interest compared to placebo at the end of the DB period.

Additionally, at the data cut-off for final analysis of the DB+OL period, the incidence of permanent discontinuation due to AEs in the darolutamide arm increased slightly from 8.9% during the DB period to 10.5% during the DB+OL period, while discontinuation in the placebo group during the DB period was 8.7%. The only AE with a > 10% incidence with darolutamide was fatigue.

Researchers found the increase in the incidence of any-grade AEs (85.7% vs 89.8%) and serious AEs (26.1% vs 32.1%) to be small when comparing the DB and DB+OL periods.

When the incidences were adjusted for exposure, minimal differences between the DB and DB+OL period were found. In one example, researchers noted that the rate of bone fractures was 3.4 (DB) vs 4.0 (DB+OL) per 100 patient-years.

As Smith concluded, darolutamide was found to be well-tolerated, even with prolonged treatment. “For adverse events (AEs) of interest, the expected increases in incidence between the darolutamide DB and extended DB+OL periods largely disappeared when adjusted for longer exposure to darolutamide,” Smith said.

“These results confirm the favorable safety profile of darolutamide with prolonged treatment.”


  1. Smith M, Fizazi K, Tammela T, et al. Safety of darolutamide (DARO) for nonmetastatic castration-resistant prostate cancer (nmCRPC) from extended follow-up in the phase III ARAMIS trial. Presented at: 2021 ASCO Genitourinary Cancers Symposium. Abstract 239.
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