1. Fuerst, Mark L.

Article Content

Early treatment combining the oral androgen receptor inhibitor darolutamide with standard therapy significantly increases overall survival (OS) in patients with metastatic hormone-sensitive prostate cancer. At data cutoff, darolutamide plus androgen deprivation therapy (ADT) and chemotherapy with docetaxel significantly reduced the risk of death by 32.5 percent compared to ADT plus docetaxel, and more than doubled the median treatment duration.

doctor-patient conve... - Click to enlarge in new windowdoctor-patient conversation. doctor-patient conversation

First results from the international, double-blind, investigational Phase III ARASENS trial were presented at the 2022 ASCO Genitourinary Cancers Symposium (Abstract 13) and simultaneously published in the New England Journal of Medicine (2022; doi: 10.1056/NEJMoa2119115).


Darolutamide received FDA approval in July 2019 for the treatment of patients with non-metastatic castration-resistant prostate cancer based on the ARAMIS trial, a randomized, double-blind, placebo-controlled, multi-center Phase III study. That trial found a 31 percent lower risk of death and median metastasis-free survival about 2 years longer for patients who received darolutamide with ADT as compared to placebo plus ADT, with a low incidence of treatment-emergent adverse events (TEAEs).


Metastatic prostate cancer is a uniformly fatal disease and, despite progress in recent years, only 30 percent of these men will survive beyond 5 years.


"ARASENS demonstrated that the addition of darolutamide significantly increased OS for patients receiving standard ADT and docetaxel as initial treatment for metastatic hormone-sensitive prostate cancer. Darolutamide also improved time to castration-resistant prostate cancer and other key secondary endpoints," said lead author Matthew Smith, MD, PhD, Director of the Genitourinary Malignancies Program at Massachusetts General Hospital Cancer Center. "These results are an important step forward for the treatment of patients with metastatic hormone-sensitive prostate cancer."



In the ARASENS trial, a total of 1,306 newly diagnosed patients with metastatic hormone-sensitive prostate cancer, median age 67 years, were randomized to receive 600 mg of darolutamide twice a day (651 patients) or matching placebo (655 patients), plus ADT and docetaxel. The primary endpoint of this trial was OS. Secondary endpoints included time to castration-resistant prostate cancer (CRPC), time to pain progression, time to first symptomatic skeletal event, and time to initiation of subsequent anticancer therapy, all measured at 12-week intervals.


A significant improvement in OS was observed despite substantially higher use of subsequent systemic antineoplastic therapies (such as abiraterone, enzalutamide, cabazitaxel, docetaxel, radium-223 dichloride, sipuleucel-T, lutetium-177 PSMA, or apalutamide) among patients receiving ADT plus docetaxel who entered follow-up (75.6%) compared with the group who received darolutamide plus ADT and docetaxel (56.8%). The significant OS benefit was consistent across prespecified subgroups, Smith noted.


Darolutamide plus ADT and docetaxel also demonstrated statistically significant benefits across multiple secondary endpoints compared to ADT plus docetaxel, including delaying the time to CRPC, time to pain progression, time to first symptomatic skeletal event, and time to initiation of subsequent systemic antineoplastic therapy.


Median duration of treatment was longer in the darolutamide group (41 months) than in the placebo group (16.7 months), and a higher percentage of patients in the darolutamide group (45.9%) were still receiving the assigned trial treatment as compared to the placebo group (19.1%).


Adverse Events

After a median follow-up of 29 months in the overall trial population, darolutamide continued to have a favorable safety profile, similar to that described previously. TEAEs were similar between treatment arms, Smith said. The most common TEAEs (>=10%) were highest during the overlapping docetaxel treatment period for both arms and decreased progressively thereafter.


The most frequently reported adverse events in the treatment arms (darolutamide plus standard therapy vs. standard therapy) were alopecia (40.5% and 40.6%), neutropenia (39.3% and 38.8%), fatigue (33.1% and 32.9%), and anemia (27.8% and 25.1%).


Grade 3 or 4 adverse events reported in 66.1 percent versus 63.5 percent of patients were mainly due to neutropenia (33.7% vs. 34.2%, respectively). Serious adverse events occurred in 44.8 percent versus 42.3 percent of patients, and TEAEs leading to treatment discontinuation occurred in 13.5 percent versus 10.6 percent of patients.


Adverse events of special interest in patients treated with AR pathway inhibitors for prostate cancer such as fatigue, falls, fractures, mental impairment, and cardiovascular events were similar between the study arms.


"Based on the results of ARASENS, darolutamide in combination with ADT and docetaxel should become a new standard of care for treatment of patients with metastatic hormone-sensitive prostate cancer," Smith noted.


Darolutamide is also being investigated in further studies across various stages of prostate cancer, including another Phase III trial in metastatic hormone-sensitive prostate cancer (ARANOTE), as well as a Phase III trial evaluating darolutamide as an adjuvant treatment for localized prostate cancer with very high risk of recurrence.


Mark L. Fuerst is a contributing writer.