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21st February 2023
An international team of researchers have found that combining darolutamide with androgen-deprivation therapy and docetaxel improved overall survival in men with metastatic hormone sensitive prostate cancer.
Darolutamide is a potent androgen-receptor inhibitor which has been shown to improve survival in men with non-metastatic, castration-resistant prostate cancer when used alongside androgen-deprivation therapy. Furthermore, the ARASENS trial published in 2022 in the New England Journal of Medicine, found that in men with metastatic, hormone-sensitive prostate cancer, use of oral darolutamide (600 mg twice daily), androgen-deprivation therapy (ADT) and docetaxel (DOC) significantly improved overall survival compared to a placebo group without the drug but with both ADT and DOC.
In the current analysis, researchers undertook a post hoc analysis of ARASENS and focused on the effect of darolutamide in various subgroups. Participants were categorised into those with high-volume disease (defined by visceral metastases and or > 4 bone metastases with ≥ 1 beyond the vertebral column/pelvis) or high-risk disease, which was a Gleason score > 8 and > 3 bone lesions and the presence of visceral metastases. The team also investigated those with both low risk and low volume disease, i.e., not meeting the high volume/risk criteria. For their analysis the primary endpoint was set as overall survival.
Darolutamide and overall survival in subgroups
A total of 1,305 participants of whom 1,005 (77%) had high-volume disease and 912 (70%) high-risk disease were included in the analysis.
Treatment with darolutamide improved overall survival compared to placebo in those with high volume disease by 31% (hazard ratio, HR = 0.69, 95% CI 0.57 – 0.82) and by a similar amount in those with high-risk disease (HR – 0.71, 95% CI 0.58 – 0.86). There were also broadly similar improvements in overall survival among those with low volume and low risk disease.
In terms of safety, grade 3 or 4 adverse events occurred in a similar proportion of patients (64.9% vs 64.2% darolutamide vs placebo group) in the high volume subgroup and the incidence was similar across all subgroups.
The authors concluded that in men with hormone sensitive metastatic prostate cancer, treatment intensification with darolutamide, androgen-deprivation therapy, and docetaxel led to an increased OS and with a similar adverse effect profile in the subgroups.
Hussain M et al. Darolutamide Plus Androgen-Deprivation Therapy and Docetaxel in Metastatic Hormone-Sensitive Prostate Cancer by Disease Volume and Risk Subgroups in the Phase III ARASENS Trial. J Clin Oncol 2023
28th February 2022
Darolutamide combined with androgen-deprivation therapy and docetaxel, provides a better overall survival in men with metastatic, hormone-sensitive prostate cancer compared not using the drug. This was the findings of a randomised trial by researchers from the Genitourinary Malignancies Program, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, US.
Among men with metastatic, hormone-naive, prostate cancer the addition of an androgen-receptor pathway inhibitor such as abiraterone, apalutamide, enzalutamide or docetaxel improves overall survival compared to androgen-deprivation therapy alone.
Darolutamide is an androgen-receptor inhibitor and in the Phase III ARAMIS study, it was found that for men with non-metastatic, castration-resistant prostate cancer, darolutamide treatment, metastasis-free survival was significantly longer with darolutamide than with placebo.
However, whether combining darolutamide, androgen-deprivation therapy and docetaxel, would increase survival among patients with metastatic, hormone-sensitive prostate cancer is currently unclear and was the rational for the current study by the US team.
The researchers included adults (> 18 years of age) with an Eastern Cooperative Oncology Group performance status (ECOG) of 0 or 1 (where higher scores, reflect a greater disability). All received androgen-deprivation therapy, in the form of a luteinising hormone-releasing hormone or analogue) or underwent orchiectomy within 12 weeks before randomisation.
Participants were randomised 1:1 to darolutamide 600 mg twice daily or matching placebo and received six cycles of docetaxel with prednisolone within 6 weeks after randomisation. The primary endpoint of the trial was overall survival, defined as the time from randomisation until any cause of death. Secondary outcomes included time to castration-resistant prostate cancer and time to pain progression and participants were assessed every 12 weeks.
Darolutamide and overall survival
A total of 1305 men with metastatic disease and a median age of 67 years were included in the final dataset, with most (71.1%) having an ECOG score of 0.
The risk of death was 32.5% lower in the darolutamide group (hazard ratio, HR = 0.68, 95% CI 0.57 – 0.80, p < 0.001). After 4 years, the overall survival was 62.7% in the darolutamide group compared to 50.4% in the placebo arm.
With respect to the secondary outcomes, the time to castration-resistant prostate cancer was significantly lower in the darolutamide group (HR = 0.36, 95% CI 0.30 – 0.42, p < 0.001) as was the time to pain progression (HR = 0.79, 95% CI 0.66 – 0.95, p = 0.01).
In terms of safety, the incidence of adverse effects was similar in both groups (99.5 vs 98.9, darolutamide vs placebo) as was the incidence of a serious adverse event (44.8% vs 42.3%).
Based on these findings, the authors concluded that darolutamide combined with androgen-deprivation therapy and docetaxel in men with metastatic, hormone-sensitive prostate cancer, led to a significantly longer overall survival.
Smith MR et al. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer New Engl J Med 2022