Final data from the pivotal phase 3 ARAMIS trial with darolutamide and androgen deprivation therapy showed that the combination continued to demonstrate a statistically significant improvement in overall survival versus ADT alone in patients with nonmetastatic, castration-resistant prostate cancer.
Karim Fizazi, MD, PhD
Final data from the pivotal phase 3 ARAMIS trial (NCT02200614) with darolutamide and androgen deprivation therapy (ADT) showed that the combination continued to demonstrate a statistically significant improvement in overall survival (OS) versus ADT alone in patients with nonmetastatic, castration-resistant prostate cancer (CRPC).1
Results showed that darolutamide plus ADT resulted in a 31% reduction in the risk of death compared with ADT alone in this patient population (HR, 0.69; 95% CI, 0.53-0.88; P =.003). This statistically significant improvement was observed despite more than half of patients, or 55% (n = 307/554), who were taking placebo receiving subsequent darolutamide or other life-prolonging treatment after the trial was unblinded at the November 15, 2019 data cutoff for the final analysis.
“Through ongoing research, we have established the importance of focusing treatments on extending lives and limiting [adverse] effects for men living with nonmetastatic CRPC,” Karim Fizazi, MD, PhD, professor of medicine at the Institut Gustave Roussy, stated in a press release.2 “With these encouraging darolutamide results, physicians are further armed to treat based on the multiple needs of this patient population, including efficacy, delaying morbidity, and treatment tolerability.”
In the double-blind, placebo-controlled, multicenter phase 3 trial, investigators set out to evaluate the safety and efficacy of darolutamide in combination with ADT in a total of 1509 patients with nonmetastatic CRPC who were receiving a concomitant gonadotropin-releasing hormone analog or had a bilateral orchiectomy. Patients were randomized in a 2:1 fashion to receive either oral darolutamide at a dose of 600 mg twice daily plus ADT (n = 955) or placebo plus ADT (n = 554). Participants continued treatment until disease progression, discontinuation of treatment due to toxicities, the start of another anticancer treatment, or withdrawn consent.
The demographic and clinical characteristics of the 2 treatment arms were noted to be well balanced at baseline. All participants had an ECOG performance status of 0 or 1 and a prostate-specific antigen (PSA) doubling time of 10 months or less. Participants were stratified by PSA doubling time (6 months or less vs greater than 6 months) and whether they had received osteoclast targeted therapy.
During the double-blind treatment period, data were collected at 16-week intervals. Data were also collected at the start of the open-label treatment period and every 16 weeks thereafter until the end of the trial. Trial treatment was discontinued upon metastatic progression. At that time, treatment outside of the trial protocol could be given at the discretion of the treating physician.
The primary end point of the trial was metastasis-free survival (MFS), and key secondary end points were comprised of OS, time to pain progression, time to initiation of first cytotoxic chemotherapy, time to first symptomatic skeletal event, as well as safety and tolerability of darolutamide.
At the time of the primary analysis of ARAMIS, the MFS with darolutamide was 40.4 months compared with 18.4 months with placebo; this translated to a 59% reduction in the risk of metastasis or death (HR, 0.41; 95% CI, 0.34-0.50; P <.001).3,4 Additionally, for those who experienced metastatic progression, the distribution of sites of metastases were comparable between the treatment arms. The data cutoff date was September 3, 2018 for the primary analysis.
The unblinding of the treatment assignments was completed on November 30, 2018. At this time, all 170 patients who had still been receiving placebo crossed over to the darolutamide arm.
The data cutoff for the final analysis was November 15, 2019. The median follow-up time was 29.0 months for the study population. At this time, just under half, or 49%, of those who were originally randomized to the experimental arm were still receiving darolutamide; 86% of those in the crossover cohort were also still receiving the study drug.
Moreover, the median duration of treatment with darolutamide was 25.8 months during the double-blind and open-label portions of the trial combined. The median duration of treatment with placebo was 11.6 months during the double-blind period of the trial. Those in the crossover cohort had a median duration of treatment with darolutamide of 11.0 months.
Fifty-five percent of patients (n = 307/554) were given subsequent treatment with darolutamide or life-preserving therapy. Additionally, 137 of 384 patients who had been randomized to the placebo arm, who had discontinued treatment before the unblinding occurred, received subsequent life-prolonging treatment that was not darolutamide. These treatments included docetaxel, abiraterone acetate (Zytiga), and enzalutamide (Xtandi). Fifteen percent (n = 141/955) of those in the darolutamide arm received subsequent life-prolonging treatment beyond darolutamide.
The final OS analysis was conducted after 254 and 106 deaths had been reported in the darolutamide and placebo arms, respectively. Eighty-three percent (95% CI, 80-86) of patients on the experimental arm were alive at 3 years versus 77% (95% CI, 72-81) of those on the placebo arm. Moreover, the risk of death was substantially lower with the androgen receptor therapy versus ADT alone (HR, 0.69; 95% CI, 0.53-0.88; P =.003).
Across both arms, the number of prostate cancer–related deaths was higher than the number of deaths that occurred from other causes, although the trial was not powered to evaluate the impact of darolutamide on deaths due to disease.
Notably, the impact of treatment on OS was found to favor darolutamide compared with placebo across the following subgroups analyzed: baseline PSA doubling time of 6 months or less or more than 6 months, geographic region, presence or absence of lymph node involvement at baseline, and ECOG performance status of 0 or 1 at baseline.
Time to pain progression, time to first use of cytotoxic chemotherapy, and time to first symptomatic skeletal event were analyzed hierarchically. Data from the primary analysis demonstrated a longer time to pain progression with the androgen receptor compared with ADT alone, at a median of 40.3 months versus 25.4 months, respectively (HR, 0.65; 95% CI, 0.53-0.79; P <.001).
More patients in the investigational arm compared with the placebo arm had not yet received their first cytotoxic chemotherapy at 3 years, at 83% versus 75%, respectively. Those who received darolutamide/ADT experienced a substantially longer time to first use of cytotoxic chemotherapy compared with those who were given placebo (HR, 0.58; 95% CI, 0.44-0.76; P <.001). Moreover, the androgen receptor therapy plus ADT was also linked with a significantly longer time to first symptomatic skeletal event versus ADT alone (HR, 0.48; 95% CI, 0.29-0.82; P =.005).
With regard to safety, 85.7% of participants who received darolutamide/ADT experienced adverse effects (AEs) versus 79.2% of those who received ADT alone in the double-blind portion of the trial and 70.0% of those in the crossover cohort. The percentage of patients who experienced toxicities that resulted in treatment discontinuation were comparable between the arms, at 8.9% in the experimental arm and 8.7% in the control arm.
Results from the final analysis of the safety of the androgen receptor proved to be consistent with the data that had been reported at the time of the primary analysis. At this time, 13.2% of patients on the experimental arm experienced fatigue; this toxicity was reported in over 10% of the patients on that arm during the double-blind period of the trial. Toxicities reported in more than 5% of patients on either arm proved to be comparable.
“MFS and OS were significantly longer with darolutamide than with placebo among men with nonmetastatic CRPC and a PSA doubling time of 10 months or less,” the study authors concluded. “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.”
In July 2019, the FDA approved darolutamide for the treatment of patients with nonmetastatic CRPC based on earlier data from ARAMIS.