The addition of the androgen receptor inhibitor darolutamide to androgen-deprivation therapy and docetaxel reduced the risk of death by 30% compared with androgen-deprivation therapy plus docetaxel in patients with metastatic hormone-sensitive prostate cancer, according to a post hoc analysis of data from the phase III ARASENS trial. This benefit was observed regardless of disease volume or risk status.1 Lead author Maha Hussain, MD, FACP, FASCO, presented these results at the 2023 ASCO Genitourinary (GU) Cancers Symposium in San Francisco. Dr. Hussain is the Genevieve Teuton Professor of Medicine and Deputy Director of the Genitourinary Oncology Program at the Robert H. Lurie Comprehensive Cancer Center at the Northwestern University Feinberg School of Medicine.
Maha Hussain, MD, FACP, FASCO
In addition, for those with high-volume disease, the median overall survival was not reached in the darolutamide plus androgen-deprivation therapy and docetaxel arm vs 42.4 months in the placebo plus androgen-deprivation therapy plus docetaxel arm. For patients with low-volume disease, the median overall survival was not reached in the darolutamide arm or the placebo arm.
Among patients with high-risk disease, median overall survival was not reached in the darolutamide arm vs 43.2 months with placebo, androgen-deprivation therapy, and docetaxel. Among those with low-risk disease, the median overall survival was not reached in either arm.
The authors of the abstract consider the combination of darolutamide, androgen-deprivation therapy, and docetaxel the new standard of care for metastatic hormone-sensitive prostate cancer. The results of the post hoc analysis of the ARASENS trial were published in the Journal of Clinical Oncology to coincide with the presentation at the meeting.2
“The hazard ratio for both the low-volume and high-volume subgroups favored the triplet therapy,” said Dr. Hussain. “I want to point out that the median overall survival is not reached in both categories [with darolutamide]. One of the issues is with low-volume disease; the upper confidence interval (CI) on the hazard ratio (HR) slightly crosses 1 (HR = 0.68; 95% CI = 0.41–1.13). However, this is a generally favorable group of patients, [and] the medians have not been reached yet, but there is some separation in the curves later.”
“We conclude that darolutamide with androgen-deprivation therapy and docetaxel should be considered a new standard of care for patients with metastatic hormone-sensitive prostate cancer,” she stated.
Overall survival from ARASENS was reported previously.3 The triplet combination improved survival by 32.5% compared with androgen-deprivation therapy plus docetaxel (P < .001). The post hoc analysis presented at the 2023 ASCO GU meeting focused on subgroups of patients by disease volume and risk, important prognostic factors.
Study Details
The analysis presented at the GU meeting included 1,305 patients: 1,005 (77%) with high-volume disease, 300 (23%) with low-volume disease, 912 (70%) with high-risk disease, and 393 (30%) with low-risk disease.
High-volume disease was defined according to the CHAARTED criteria, which included visceral metastases and/or at least four bone metastases with at least one beyond the vertebral column or pelvis. High-risk disease was defined using the LATITUDE criteria with at least two of the following risk factors: Gleason score of 8 or higher, at least three bone lesions, and presence of measurable visceral metastasis. More than 80% of patients in the high-volume subgroup and more than 90% in the high-risk subgroup had de novo metastatic disease, another poor prognosis feature.
Patients were randomly assigned 1:1 to receive 600 mg of darolutamide twice daily or placebo, in combination with androgen-deprivation therapy. Docetaxel was administered for six cycles in both arms.
Key Secondary Outcomes
Time to castration-resistant disease was longer with the darolutamide triplet arm for all subgroups compared with the control arm. Other secondary efficacy endpoints also demonstrated improved outcomes with triplet treatment across disease volume and risk subgroups, including time to pain progression, time to first symptomatic skeletal event, and time to initiation of subsequent systemic antineoplastic therapy, which were generally consistent with the overall ARASENS population.
“All of these secondary endpoints are important,” Dr. Hussain said. “And what you see here, irrespective of the risk criteria or the volume of disease, the triplet had a better outcome, [with] the hazard ratios favoring the triplet therapy.”
Adverse events in the high/low volume and risk subgroups were similar between treatment groups and to those reported in the overall study.
Clinical Implications
The triplet of darolutamide, androgen-deprivation therapy, and docetaxel is a guideline-preferred regimen for patients with metastatic hormone-sensitive prostate cancer. Dr. Hussain related that this analysis may help to provide individualized treatment selection.
“You’re going to have to tailor the treatment to the patient,” Dr. Hussain responded during a discussion of an audience question after her presentation. “For high-volume disease, no question about it in my mind, the triplet right now is the way to go. For patients with low-volume disease, it’s one of those shared-decision discussions…. If somebody is young with aggressive disease, de novo metastatic disease, I am on the side of the triplet.”
DISCLOSURE: Dr. Hussain has received honoraria from Astellas Pharma, AstraZeneca, Clinical Care Options, Great Debates and Updates in GU Oncology, Medscape Zero, Merck, Precisca, Targeted Oncology, and UroToday; has served as a consultant or advisor to AstraZeneca, Bayer, Convergent Therapeutics, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, and Tempus; and has received institutional research funding from Arvinas, AstraZeneca, Bayer, Genentech, and Pfizer.
REFERENCES
1. Hussain MHA, Tombal BF, Saad F, et al: Efficacy and safety of darolutamide in combination with androgen-deprivation therapy and docetaxel by disease volume and disease risk in the phase 3 ARASENS study. 2023 ASCO GU Cancers Symposium. Abstract 15. Presented February 18, 2023.
2. Hussain M, Tombal B, Saad F, 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. February 16, 2023 (early release online).
3. Smith MR, Hussain M, Saad F, et al: Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med 386:1132-1142, 2022.
