Results from an international phase 3 trial show that combining the androgen receptor inhibitor darolutamide (Nubeqa) with androgen-deprivation therapy (ADT) and docetaxel (Taxotere) chemotherapy improves overall survival (OS) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) compared to ADT and docetaxel alone. The findings from the ARASENS study (Abstract 13) were presented at the 2022 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium taking place this weekend in San Francisco, California, and published in The New England Journal of Medicine.
“Based on the results of ARASENS, we can conclude that darolutamide in combination with ADT and docetaxel should become a new standard of care for the treatment of patients with mHSPC,” said Matthew Raymond Smith MD, PhD, director of the Genitourinary Malignancies Program at Massachusetts General Hospital in Boston and lead author of the study.
While mHSPC has spread from the prostate to other parts of the body, it can be treated with hormone therapy. The standard treatment is adding either docetaxel or an androgen-receptor pathway inhibitor like darolutamide to ADT. Darolutamide, which slows down or stops the growth of cancer cells, is currently approved by the U.S. Food and Drug Administration for treating non-metastatic castration-resistant prostate cancer.
“Darolutamide is a structurally distinct and highly potent androgen-receptor inhibitor with low blood-brain barrier penetration and limited potential for clinically relevant drug-drug interactions,” said Dr. Smith.
In the ARASENS trial, researchers in 23 countries, including the United States, Canada, and China, randomized 651 patients to receive darolutamide, ADT, and docetaxel between November 2016 and June 2018. Another 654 were given a placebo, ADT, and docetaxel. The median age was 67 in both arms with the primary endpoint being overall survival (OS) defined as the time from randomization until death from any cause.
At the time of primary analysis, 229 patients in the darolutamide group had died, compared to 304 in the placebo arm. This meant the risk of death was 32.5% lower in patients who were given darolutamide than in the placebo group. Only 13.5% of the patients who received darolutamide discontinued treatment because of adverse events, along with 10.6% who were given the placebo.
On the data cutoff date for the primary analysis of October 25, 2021, the median treatment duration was 41 months for patients receiving darolutamide and 16.7 for patients who received a placebo. Median follow-up for OS was 43.7 months in the darolutamide arm and 42.4 months in the placebo cohort.
Elisabeth Heath, MD, director of prostate cancer research at Wayne State University’s Karmanos Cancer Institute in Detroit, was the discussant at the ASCO session and agreed with Dr. Smith that this combination therapy could be a new standard of care. However, she also said determining which patients with mHSPC will benefit the most from this therapy will be critical.
“We actually have a triplet therapy to now consider. Maybe it’s on us to figure out who is fit for this combination therapy and who with their metastatic disease would warrant this,” she said.
The study was funded by Bayer and Orion Pharma. Dr. Smith reported relationships with several companies, including Bayer, Lilly, and Novartis. Dr. Heath reported relationships with many companies, including AstraZeneca, Bayer, and Sanofi.
It is clear from this trial, as well as the previously presented PEACE-1 trial, that patients who receive ADT and docetaxel benefit from the addition of a next generation hormonal therapy agent.
Whether the triplet should be broadly used for all patients with newly diagnosed metastatic prostate cancer is not quite as clear. The data favor this approach for the highest risk patients.
More details from the ARASENS trial are needed to consider lower risk patients. Today the standard of care for newly diagnosed metastatic disease is either a hormonal doublet or a chemo-hormonal triplet.