ESPEYB16 14. Year in Science and Medicine 2019 (1) (18 abstracts)
14.18. Darolutamide in nonmetastatic, castration-resistant prostate cancer
Fizazi K , Shore N , Tammela TL , Ulys A , Vjaters E , Polyakov S , Jievaltas M , Luz M , Alekseev B , Kuss I , Kappeler C , Snapir A , Sarapohja T , Smith MR & Investigators A
To read the full abstract: N Engl J Med 2019;380:1235–1246
This paper reports a randomized, double-blind, placebo-controlled, phase 3 trial of darolutamide, a novel oral androgen-receptor antagonist, in 1509 men with non-metastatic, castration-resistant prostate cancer. Median metastasis-free survival was significantly longer with darolutamide (40.4 months) than placebo (18.4 months; hazard ratio for metastasis or death: 0.41; 95% CI, 0.34 to 0.50; P<0.001).
It is well established that androgens drive prostate cancer growth and metastasis. Hence, chemical castration using GnRH agonist therapy is first line treatment. However, full suppression of the hypothalamic-pituitary axis does not completely suppress androgen levels and most hormone dependent cancers become resistant to treatment after only a few years, presumably due to increased sensitivity to androgens. Darolutamide is a structurally unique non-steroidal androgen-receptor selective antagonist that can be taken orally. Unlike other selective androgen-receptor antagonists, it does not cross the blood-brain barrier and does not induce cytochrome P450, hence its apparent good side-effect profile.
Highly selective and effective novel sex hormone antagonists have been developed and are showing highly promising results for treatment of hormone sensitive cancers – see also recent results for fulvestrant, an oestrogen receptor anatagonist in metastatic breast cancer (1). Currently their costs are too high, even for acceptance onto some national cancer guidelines. However, in time, with reducing costs, future genetic versions and hopefully ongoing good safety profiles, we hope that these agents will open up new effective options for the management of various disorders of growth, puberty, and DSD.
Reference: 1. Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, Tirumali NR, Lew DL, Hayes DF, Gralow JR, Linden HH, Livingston RB, Hortobagyi GN. Overall Survival with Fulvestrant plus Anastrozole in Metastatic Breast Cancer. N Engl J Med. 2019 Mar 28;380(13):1226–1234.
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ESPE Yearbook of Paediatric Endocrinology
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