Darolutamide reduces CRPC metastasis risk
medwireNews: Addition of the androgen receptor antagonist darolutamide to androgen deprivation therapy (ADT) improves metastasis-free survival in patients with castration-resistant prostate cancer (CRPC), indicate ARAMIS trial results.
Darolutamide was also associated with improvements in all other endpoints and there was “no clinically relevant difference” between the drug and placebo comparator in terms of the incidence of adverse events, say the study investigators.
The phase IIII findings were simultaneously published in The New England Journal of Medicine, and presented at the 2019 ASCO Genitourinary Cancers Symposium, held in San Francisco, California, USA.
Among the trial participants, all of whom had nonmetastatic disease and a prostate-specific antigen doubling time of 10 months or less, metastasis-free survival was a median of 40.4 months for the 955 patients who were randomly assigned to receive darolutamide 600 mg twice daily alongside ADT with a luteinizing hormone-releasing hormone agonist or antagonist.
This was significantly greater than the median of 18.4 months achieved by the 554 patients given placebo plus ADT, and equated to a 59% reduced risk for metastasis or death in favor of darolutamide.
Overall survival was also better with darolutamide than placebo, at a 39% reduced risk for death, although the median durations were not reached for either arm in this analysis conducted at a median follow-up of 17.9 months.
And participants in the darolutamide group derived a significant benefit over their counterparts in the placebo group with regard to time to pain progression (hazard ratio [HR]=0.65), time to cytotoxic chemotherapy (HR=0.43), and time to first symptomatic skeletal event (HR=0.43).
The incidence of adverse events of grade 3 or 4 was 24.7% among darolutamide-treated patients and 19.5% among those given placebo, and grade 5 events occurred in a comparable 3.9% and 3.2%, respectively. The deaths of one man in the darolutamide arm and two in the placebo arm were deemed related to the study drugs.
A similar proportion of patients in the darolutamide and placebo groups discontinued treatment due to adverse events, at 8.9% and 8.7%, respectively, and the incidence of individual adverse events was also generally comparable between treatment arms, report Karim Fizazi, from Institut Gustave Roussy in Villejuif, France, and fellow authors.
They note that in the PROSPER and SPARTAN trials assessing enzalutamide and apalutamide, respectively, in similar patient populations, “hypertension and [central nervous system]-related adverse effects, such as mental-impairment disorders and dizziness were more common” in the experimental than placebo groups.
Darolutamide treatment, however, did not lead to a higher incidence of such adverse events over placebo, which the researchers speculate “may be linked to the low penetration of the blood–brain barrier that has been found in preclinical studies of the drug.”
Speaking to medwireNews, Fizazi noted that he expects darolutamide, if approved by regulatory authorities, to have a similar role in the treatment paradigm of patients with high-risk nonmetastatic CRPC as enzalutamide and apalutamide.
He added that phase III trials of the agent in other settings are also ongoing, such as the ARASENS study of men with metastatic castration-sensitive prostate cancer, which has already completed accrual.
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