• David P Dearnaley, Daniel R Saltzstein, John E Sylvester, Lawrence Karsh, Bryan A Mehlhaff, Christopher Pieczonka, James L Bailen, Hongliang Shi, Zhan Ye, Hélène M Faessel, Huamao Lin, Yanyan Zhu, Fred Saad, David B MacLean, and Neal D Shore.
• The Institute of Cancer Research and Royal Marsden Hospital, London, UK. Electronic address: david.dearnaley@icr.ac.uk.
• Eur. Urol. 2020 Aug 1; 78 (2): 184-192.

BackgroundExternal beam radiotherapy (EBRT) with neoadjuvant/adjuvant androgen deprivation therapy (ADT) is an established treatment option to prolong survival for patients with intermediate- and high-risk prostate cancer (PCa). Relugolix, an oral gonadotropin-releasing hormone (GnRH) receptor antagonist, was evaluated in this clinical setting in comparison with degarelix, an injectable GnRH antagonist.ObjectiveTo evaluate the safety and efficacy of relugolix to achieve and maintain castration.Design, Setting, And ParticipantsA phase 2 open-label study was conducted in 103 intermediate-risk PCa patients undergoing primary EBRT and neoadjuvant/adjuvant ADT between June 2014 and December 2015.InterventionPatients randomly assigned (3:2) to 24-wk treatment with either daily oral relugolix or 4-wk subcutaneous depot degarelix (reference control).Outcome Measurements And Statistical AnalysisThe primary endpoint was the rate of effective castration (testosterone <1.73nmol/l) in relugolix patients between 4 and 24 wk of treatment. Secondary endpoints included rate of profound castration (testosterone <0.7nmol/l), prostate-specific antigen (PSA) levels, prostate volume, quality of life (QoL) assessed using the Aging Males' Symptoms scale, and the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (30-item EORTC core questionnaire [EORTC QLQ-C30] and 25-item EORTC prostate cancer module [EORTC QLQ-PR25]) questionnaires, and safety. No formal statistical comparisons with degarelix were planned.Results And LimitationsCastration rates during treatment were 95% and 82% with relugolix and 89% and 68% with degarelix for 1.73 and 0.7nmol/l thresholds, respectively. Median time to castration in the relugolix arm was 4 d. During treatment, PSA levels and prostate volumes were reduced in both groups. Three months after discontinuing treatment, 52% of men on relugolix and 16% on degarelix experienced testosterone recovery (statistical significance of differences not tested). Mean and median QoL scores improved following treatment discontinuation. The most common adverse event was hot flush (relugolix 57%; degarelix 61%). Lack of blinding was a potential limitation.ConclusionsRelugolix achieved testosterone suppression to castrate levels within days and maintained it over 24 wk with a safety profile consistent with its mechanism of action.Patient SummaryOral once-daily relugolix may be a novel oral alternative to injectable androgen deprivation therapies.Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.

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