Results of a phase III trial show the benefit of darolutamide (Nubeqa) in reducing the risk of metastases or death compared with placebo in men with nonmetastatic castration-resistant prostate cancer.
Results of a phase III trial show the benefit of darolutamide (Nubeqa) in reducing the risk of metastases or death compared with placebo in men with nonmetastatic castration-resistant prostate cancer (nmCRPC). The FDA recently announced approval of the novel nonsteroidal androgen receptor (AR) antagonist for the treatment of this patient population.
Study data presented at the American Society of Clinical Oncology annual meeting in Chicgo show that men treated with darolutamide maintain quality of life and benefit with delays in worsening of pain and time to symptomatic skeletal events.
The research was presented by Karim Fizazi, MD, PhD, head of cancer medicine, Institut Gustave Roussy, and professor of oncology, University of Paris-Sud, Villejuif, France.
“Recently, two AR antagonists, namely apalutamide [Erleada] and enzalutamide [XTANDI], demonstrated improvements in metastasis-free survival (MFS) in men with nmCRPC. However, they are associated with side effects, including fatigue, falls, and mental impairment, which may be related to their ability to cross the blood-brain barrier. Because most men with nmCRPC are asymptomatic, a major therapeutic objective is to prevent cancer progression while avoiding side effects and preserving quality of life,” Dr. Fizazi said.
“The [current] results show that darolutamide significantly improves MFS, has a very favorable safety profile with apparently no side effects associated with other AR antagonists, and delays worsening of pain and disease-related symptoms compared with placebo. This efficacy and safety profile could make darolutamide an attractive treatment option for men with nmCRPC.”
Known as ARAMIS, the phase III study investigating darolutamide included 1,509 men with nmCRPC who had a rapidly rising PSA, defined as a doubling time ≤10 months, and ECOG status 0 or 1. They were randomized 2:1 to treatment with darolutamide, 600 mg twice daily, or placebo. All patients continued on androgen deprivation therapy. The two study groups were well balanced in their baseline characteristics.
Metastasis-free survival was analyzed as the primary endpoint, and the results showed a 59% risk reduction (p<.0001). Median MFS was 18 months for the darolutamide group versus 14 months for the controls.
In an immature interim analysis, the 3-year overall survival rate was 83% for darolutamide and 73% for the control group (29% risk reduction; p=.0452). Median time to PSA progression was also significantly delayed by darolutamide treatment compared to placebo (median, 33.2 vs. 7.3 months; p<.0001).
“I would like to emphasize how rising PSA can be associated with patients’ anxiety,” Dr. Fizazi said.
Next: Time to pain progression delayed by 15 monthsTime to pain progression delayed by 15 months
Median time to pain progression, defined as an increase of ≥2 from baseline on the Brief Pain Inventory-Short Form or start of opioids, was delayed by 15 months with darolutamide (p<.0001). Analysis of the impact of darolutamide on symptomatic skeletal events was still immature due to a low number of events, but the available data showed a 57% reduction with darolutamide (p=.011).
Data on quality of life collected with the FACT-P Prostate Cancer Subscale questionnaire showed mean scores were unchanged in both treatment groups throughout the available follow-up. Median time to deterioration, defined as a ≥3.0-point decline from baseline, was approximately 11 months in the darolutamide group and 8 months in the control group (p=.0005).
A post-hoc analysis of data from subscales of the EORTC Quality of Life-PR25 questionnaire showed darolutamide treatment was associated with significant delays in deterioration of bowel symptoms and urinary symptoms, and there was a trend for a benefit in delaying deterioration of sexual activity. There were no differences between study groups in time to deterioration of hormonal treatment-related symptoms or incontinence.
After adjustment for duration of treatment exposure, the incidence of all adverse events associated with AR antagonists was similar in the darolutamide and placebo groups.
Prior to Dr. Fizazi’s presentation, Neal D. Shore, MD, presented a separate paper also containing data from ARAMIS at the AUA annual meeting in Chicago. Among the findings Dr. Shore presented was that darolutamide delayed time to subsequent antineoplastic therapies compared with placebo.
“It would appear that this is a very attractive option for patients with nmCRPC,” said Dr. Shore, director of Carolina Urologic Research Center, Myrtle Beach, SC.
Dr. Fizazi is a consultant/adviser for Amgen, Astellas Pharma, AstraZeneca, Bayer, Clovis Oncology, Curevac, ESSA, Janssen Oncology, Orion Pharma GmbH, Roche/Genentech, and Sanofi. For full disclosures from the study Dr. Fizazi presented, see bit.ly/aramisdisclosures. Dr. Shore is a consultant/adviser for Amgen, AstraZeneca, Bayer, Dendreon, Ferring, Genentech/Roche, Janssen Scientific Affairs, Medivation/Astellas, Myovant Sciences, and Tolmar.