The results from the prespecified final analysis of overall survival (OS), all other secondary endpoints and long-term safety in the ARAMIS study indicate that metastasis-free survival (MFS) and OS were significantly longer with darolutamide than with placebo among men with non-metastatic, castration-resistant prostate cancer (CRPC) and a PSA doubling time of 10 months or less. An OS benefit was observed even though more than half the patients in the placebo group received subsequent treatment with darolutamide or another life-prolonging therapy. The time to first use of cytotoxic chemotherapy, the time to first symptomatic skeletal event, and the time to pain progression were significantly longer with darolutamide than with placebo. The incidence of side effects was similar in the darolutamide group and the placebo group. The findings are published by Prof. Karim Fizazi of the Department of Cancer Medicine, Institut Gustave Roussy in Villejuif, France and colleagues on 10 September 2020 in The New England Journal of Medicine.
In the ARAMIS study, addition of darolutamide to androgen-deprivation therapy (ADT) significantly prolonged median MFS by 22 months. However, the OS data were immature at the time of the primary analysis for MFS, with the occurrence of only 136 deaths. The final OS analysis was planned to be performed after the occurrence of approximately 240 deaths.
The interim OS analysis favoured darolutamide over placebo (hazard ratio [HR] for death 0.71; 95% confidence interval [CI], 0.50 to 0.99; p = 0.045), although the prespecified significance level of 0.0002 was not reached. Darolutamide was not associated with a higher incidence of side effects that are known to be associated with other androgen-receptor inhibitors than placebo. Quality of life was maintained for the duration of treatment.
In this double-blind, placebo-controlled trial, the study investigators randomly assigned 1509 men, in a 2:1 ratio, 955 to receive a structurally distinct androgen-receptor inhibitor darolutamide or 554 placebo while they continued to receive ADT. After the results of the primary endpoint analysis were found to be positive, unblinding of the treatment assignments occurred, and patients in the placebo group were permitted to crossover to receive open-label darolutamide treatment.
The median follow-up time was 29.0 months. At the time of unblinding of the data, all 170 patients who were still receiving placebo crossedover to receive darolutamide; 137 patients who had discontinued placebo before unblinding had occurred received at least one other life-prolonging therapy.
In their article published on 10 September 2020 in the NEJM, the ARAMIS investigators reported the results from the prespecified final analysis of OS, all other secondary endpoints, and long-term safety in the study.
The OS at 3 years was 83% (95% CI 80 to 86) in the darolutamide group and 77% (95% CI 72 to 81) in the placebo group. The risk of death was significantly lower, by 31%, in the darolutamide group than in the placebo group (HR for death, 0.69; 95% CI 0.53 to 0.88; p = 0.003).
Darolutamide was also associated with a significant benefit with respect to all other secondary endpoints, including the time to first symptomatic skeletal event and the time to first use of cytotoxic chemotherapy.
The results of the final analysis of the safety profile of darolutamide are consistent with those of the primary analysis reported previously. Fatigue was reported in 13.2% of the patients in the darolutamide group. The incidence of all other side effects that occurred in more than 5% of the patients in either group was generally similar.
The results of the analysis of key side effects that are known to be associated with ADT continued to show small or no differences. After adjustment for treatment exposure, the incidences of most of the side effects, including falls, seizures, hypertension, mental-impairment disorders, and depressed-mood disorders, showed little or no difference between the darolutamide and the placebo group.
The authors commented that a major strength of their study is the large size, which enabled a robust statistical analysis, particularly for the reported OS analysis with extended follow-up. However, a limitation is the low numbers of events in the subgroups and the low numbers of patients of particular races or ethnic groups.
The authors concluded that among men with non-metastatic CRPC, the percentage of patients who were alive at 3 years was significantly higher among those who received darolutamide than among those who received placebo. The incidence of side effects was similar in the two groups.
The study was funded by Bayer HealthCare and Orion Pharma.
Fizazi K, Shore N, Tammela TL, et al. Nonmetastatic, Castration-Resistant Prostate Cancer and Survival with Darolutamide. N Engl J Med 2020;383:1040-9. DOI: 10.1056/NEJMoa2001342.