The median MFS for patients receiving darolutamide was 40.4 months, compared with 18.4 months in the placebo group. Darolutamide is the third drug in a short time to show a benefit in MFS when compared with placebo in the nmCRPC setting, joining enzalutamide (PROSPER) and apalutamide (SPARTAN). In this population of patients, it is critical to evaluate the quality of life, as patients may be receiving the drug for many years which has yet to show definitive benefit in overall survival (median OS not yet reached in ARAMIS), although many experts suggest that MFS may be a reasonable surrogate to OS. Darolutamide is unique when compared with enzalutamide and apalutamide in that its molecular structure lends itself for lower penetration of the blood-brain barrier, potentially decreasing neuro-related side effects such as fatigue.2 This is reflected in the lower rates of fatigue with darolutamide (12.1%), compared with 30.4% with apalutamide, and enzalutamide (33%).2-4 At ASCO 2019, Karim Fizazi, MD, PhD, reported on the impact of darolutamide on the quality of life of patients with nmCRPC.
This abstract describes the pain progression and quality of life outcomes for 1509 patients who were randomly assigned to darolutamide or placebo in a 2:1 ratio. Darolutamide significantly delayed pain progression (40.3 vs 25.4 mo; HR 0.65; 95% CI 0.53–0.79; P < 0.001) and delayed urinary symptoms (25.8 vs 14.8 mo; HR 0.64; 95% CI 0.54–0.76; P < 0.01). Given the additional androgen blockade, hormone treatment-related symptoms were also analyzed and there was no difference in symptoms between patients on darolutamide or placebo (18.9 vs 18.4 mo; HR 1.06; 95% CI 0.88–1.27; P = 0.52). In terms of adverse events of interest, there was no significant difference in fatigue, hypertension, hot flushes, fractures, falls, cognitive disorders, or seizures.
In summary, for patients with non-metastatic castration-resistant prostate cancer with a PSA doubling time of 10 months or less, darolutamide not only improves metastases-free survival but also improves the quality of life and pain progression when compared with placebo. This may be especially helpful for men with pre-existing urinary or bowel symptoms, as these two measures were significantly delayed in this study. It is unlikely that a randomized trial will study darolutamide vs apalutamide vs enzalutamide for patients with nmCRPC – thus, we must use this data to help us decide which therapy may be best for our patients given their side effect profile.
Presented by: Karim Fizazi, MD, Ph.D, Medical Oncologist, Head of the Department of Cancer Medicine, Institut Gustave Roussy, Villejuif, France, Professor of Oncology, University of Paris, Paris, France
Written by: Jason Zhu, MD, Fellow, Division of Hematology and Oncology, Duke University Twitter: @TheRealJasonZhu at the 2019 ASCO Annual Meeting #ASCO19, May 31-June 4, 2019, Chicago, IL USA
- Fizazi K, Smith MR, Tombal B Clinical Development of Darolutamide: A Novel Androgen Receptor Antagonist for the Treatment of Prostate Cancer. Clin Genitourin Cancer. 2018 Oct;16(5):332-340. doi: 10.1016/j.clgc.2018.07.017. Epub 2018 Jul 24,
- Fizazi K, Shore N, Tammela TL, et al. Darolutamide in Nonmetastatic, castration-resistant prostate cancer. New England Journal of Medicine 2019.
- Hussain M, Fizazi K, Saad F, et al. PROSPER: A phase 3, randomized, double-blind, placebo (PBO)-controlled study of enzalutamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (M0 CRPC). American Society of Clinical Oncology; 2018.
- Small EJ, Saad F, Chowdhury S, et al. SPARTAN, a phase 3 double-blind, randomized study of apalutamide (APA) versus placebo (PBO) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC). American Society of Clinical Oncology; 2018.