Treatment with the androgen receptor inhibitor darolutamide, in combination with androgen-deprivation therapy (ADT) and docetaxel, significantly improved overall survival (OS) compared with ADT and docetaxel alone in patients with metastatic hormone-sensitive prostate cancer (HSPC), according to recent results from the phase 3 ARASENS clinical trial, which were simultaneously published in the New England Journal of Medicine.1
Lead investigator Matthew R. Smith, MD, PhD, Director, Genitourinary Malignancies Program, Massachusetts General Hospital Cancer Center, Boston, presented the data at the 2022 ASCO GU Cancers Symposium. Darolutamide is approved by the FDA for the treatment of patients with nonmetastatic castration-resistant prostate cancer (CRPC) who are at high risk for metastatic disease.
ARASENS was a global, randomized, multicenter, double-blind, placebo-controlled clinical trial of 1306 newly diagnosed patients with metastatic HSPC who were randomized (1:1) to oral darolutamide (600 mg twice daily) in combination with ADT and 6 cycles of docetaxel or to placebo, ADT, and docetaxel.
The patients (median age, 67 years) had an ECOG performance score 0 or 1 and had adequate bone marrow, liver, and renal function. Approximately 78% of patients in both arms had a Gleason score of ≥8 at initial diagnosis, 79% had bone metastases, and 18% had visceral metastases with or without bone metastases.
Darolutamide plus ADT and docetaxel reduced the relative risk for death by 32.5% compared with ADT, docetaxel and placebo. The hazard ratio (HR) for death was 0.68 (P <.001) in favor of the darolutamide arm. The primary end point was overall survival (OS).
The 4-year OS was 62.7% in the darolutamide arm versus 50.4% in the placebo arm. The median OS was 48.9 months in the placebo arm and was not yet reached in the darolutamide arm.
“Darolutamide improved OS despite a high rate of subsequent life-prolonging therapies in the placebo group,” said Dr Smith. “More than 75% of patients in the placebo group received 1 or more subsequent life-prolonging therapies. The most commonly administered subsequent life-prolonging therapies [in the placebo arm] were abiraterone acetate [46.9%], enzalutamide [27.5%], cabazitaxel [18%], and docetaxel [15.0%].”
In addition, darolutamide significantly improved the key secondary end points, including the time to CRPC (HR, 0.36; P <.001), time to pain progression (HR, 0.79; P = .01), time to first symptomatic skeletal event (HR, 0.71; P = .02), and time to first subsequent antineoplastic therapy (HR, 0.39; P <.001).
“The treatment effect of darolutamide on OS was consistent across all of the prespecified groups, including extent of disease, by metastatic stage at study entry, baseline alkaline phosphatase, age, race, and Gleason grade,” he said. “The effect of darolutamide on OS was also consistent by metastatic stage at initial diagnosis.”
For patients with de novo metastatic disease, the HR for death was 0.71 (95% confidence interval [CI], 0.59-0.85) in favor of darolutamide, and for those with recurrent metastatic disease, the HR was 0.61 (95% CI, 0.35-1.05).
Consistent with previous experience, darolutamide had a favorable safety profile. The rates of any treatment-emergent adverse events, serious adverse events, and adverse events leading to the permanent treatment discontinuation were similar between the darolutamide and the placebo arms. After adjustment for drug exposure, there were no differences between the arms in the rates of adverse events of special interest.
“Based on the results of ARASENS, darolutamide in combination with ADT should become a new standard of care for the treatment of patients with [metastatic]HSPC,” Dr Smith concluded.
Commenting on the study results, Elisabeth I. Heath, MD, FACP, Hartmann Endowed Chair for Prostate Cancer Research, Karmanos Cancer Institute, Detroit, MI, said that the “time to CRPC is meaningful, because if you can keep this patient on treatment and delay that onset of resistance, that has a lot of value.”
“This time to CRPC with the triplet has not been reached in median compared with placebo and ADT and docetaxel, as are all of these other parameters” of the secondary end points, Dr Heath noted.
- Smith MR, Hussain M, Saad F, et al; for the ARASENS trial investigators. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med. 2022;386:1132-1142.