ESMO 2017: ARASENS: A Phase 3 Trial of Darolutamide in Males with Metastatic Hormone-Sensitive Prostate Cancer

Madrid, Spain ( Dr. Tombal and colleagues presented their phase III trial design assessing darolutamide in males with metastatic hormone-sensitive prostate cancer (mHSPC). It is well established that androgen-deprivation therapy (ADT) demonstrates antitumor activity in mHSPC with prolonged disease control, albeit resistance ultimately occurs and patients die of castration resistant prostate cancer (CRPC) with up to half of patients developing CRPC in <5 years.

In the last few years, we have seen the advent of chemohormonal therapy [1-3] and abiraterone + hormonal therapy [4-5] as first-line treatment of metastatic, castration-naïve disease. Darolutamide (ODM-201) is a unique investigational oral androgen receptor (AR) antagonist that binds to the AR and AR mutants (eg, W742L and F877L) with high affinity and selectivity. This inhibits receptor function and dihydrotestosterone binding with negligible blood-brain barrier penetration. Importantly, in the phase 1/2 ARADES [6] and ARAFOR [7] trials, darolutamide had antitumor activity and was well tolerated in men with mCRPC. Based on these results, the objective of the ARASENS trial is to evaluate darolutamide plus standard ADT + docetaxel in men with mHSPC.

Trial design: This is an international, randomized, double-blind, placebo-controlled, phase III trial being conducted in 23 countries. This trial will target 1,300 men with newly diagnosed mHSPC, randomized 1:1 to either 600 mg (2 × 300 mg) darolutamide BID with food, equivalent to a total daily dose of 1200 mg or placebo, both with ADT + docetaxel (6 cycles after randomization). Stratification will include by extent of disease and alkaline phosphatase levels. Key inclusion criteria are confirmed prostate cancer with documented metastases, started ADT ± first generation androgen inhibition therapy ≤12 weeks before randomization, and ECOG performance status 0 or 1. The primary objective is to show superior overall survival with darolutamide vs placebo, both with ADT + docetaxel. Secondary end points include initiation of subsequent anticancer therapy, symptomatic skeletal event-free survival (SSE-FS), and time to: CRPC, first SSE, initiation of opioid use, pain progression, and worsening of physical symptoms. These measures will be assessed at 12-week intervals. This trial is currently open for enrollment, with the first patient, first visit in November 2016. There are currently >110 sites in 16 countries enrolling. Clinical trial identification: NCT02799602


1. Gravis G, Boher JM, Joly F, et al. Androgen Deprivation Therapy (ADT) Plus Docetaxel Versus ADT Alone in Metastatic Non castrate Prostate Cancer: Impact of Metastatic Burden and Long-term Survival Analysis of the Randomized Phase 3 GETUG-AFU15 Trial. Eur Urol. 2016;70(2):256-262.

2. Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N Engl J Med. 2015;373(8):737-746.

3. James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016;387(10024):1163-1177.

4. James ND, de Bono JS, Spears MR, et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. N Engl J Med. 2017;377(4):338-351.

5. Fizazi K, Tran N, Fein L, et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med. 2017;377(4):352-360.

6. Fizazi K, Massard C, Bono P, et al. Activity and safety of ODM-201 in patients with progressive metastatic castration-resistant prostate cancer (ARADES): an open-label phase 1 dose-escalation and randomized phase 2 dose expansion trial. Lancet Oncol. 2014;15(9):975-985.

7. Massard C, Penttinen HM, Vjaters E, et al. Pharmacokinetics, antitumor activity, and safety of ODM-201 in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer: An open-label phase 1 study. Eur Urol 2016;69(5):834-840.

Speaker: Bertrand Tombal, Service d’Urologie, Clinique Universitaires, Brussels, Belgium

Co-Authors: F. Saad (Montreal, Canada) M. Hussain (Chicago, United States of America) C. N. Sternberg (Rome, Italy) K. Fizazi (Villejuif, France) E. D. Crawford (Boston, United States of America) K. Yamada (Whippany, United States of America) C. Kappeler (Berlin, Germany) I. Kuss (Berlin, Germany) M. R. Smith (Boston, United States of America)

Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md at the European Society for Medical Oncology Annual Congress - September 8 - 12, 2017 - Madrid, Spain

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