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Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer

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Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer N E n g l J Med published on June 4, 2020 Presenter: 萬芳醫院藥劑部 林杪蓁 藥師 ; 指導藥師: 郭俊男 藥師 Date: 2020/08/04 Journal club Outline Background PICO Critical appraisal CASP系統性文獻回顧檢核表 2 Background Background Androgen deprivation therapy (ADT) GnRH agonist/antagonist Brief history of ADT 4 Androgen deprivation therapy (ADT) • Prostate cancer needs testosterone to grow. Reducing how much testosterone the body makes may slow the cancer’s growth or shrink the cancer temporarily. Testosterone is an androgen (male sex hormone), so this treatment is called androgen deprivation therapy (ADT). 5 Androgen deprivation therapy (ADT) The critical role of androgens in stimulating prostate cancer growth was established in 1941 by Charles Huggins These findings led to the development of androgen deprivation therapy (ADT) as the treatment for patients with advanced prostate cancer. Ref: Studies on prostatic cancer: I. The effects of castration, of estrogen, and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate; Cancer Res. 1941; 1:293 6 Androgen deprivation therapy (ADT) • Androgen deprivation therapy (ADT): 1. Surgical castration (手術去勢): orchiectomy 2. Medical castration (藥物去勢): GnRH agonist or antagonist • Goal serum testosterone <50 ng/dl after 1 month of therapy 7 GnRH: Gonadotropin-Releasing Hormone FSH: Follicle-Stimulating Hormone LH: Luteinizing hormone GnRH agonist/antagonist 8 Ref: International Journal of Clinical Practice, Volume: 74, Issue: 1, First published: 01 October 2019, DOI: (10.1111/ijcp.13429) Brief history of ADT 1941 1960s 1970s 1980s 2000 2020 Surgical Medical castration Antiandrogens GnRH agonist GnRH antagonist GnRH antagonist castration Diethylstilbestrol Steroid: Goserelin Abarelix Relugolix Orchiectomy Cyproterone acetate Leuprolide Degarelix Non-steroid: Buserelin Flutamide Triptorelin Nilutamide Bicalutamide Ref: Hormonal Therapy in Prostate Cancer: Historical Approaches; Rev Urol 2004; 6(Suppl 7): S3–S11 9 PICO PICO 臨床問題 在晚期攝護腺癌的治療選擇上， 口服Relugolix是否優於Leuprolide? 11 PICO 12 Critical appraisal Critical appraisal Methods Results Discussion 14 Study design ≥ 18 yrs male Dx of prostate cancer Candidate for ≥ 1 yr ADT N=622 testosterone ≥ 150 ng/dL Oral Relugolix N=624 N=137 Single loading dose: 360 mg PSA > 2.0 ng/mL Relugolix Relugolix 120 mg once daily N=1327 2:1 Assessed N=934 for Randomized Eligibility N=308 N=310 SC or IM Leuprolide N=47 Leuprolide 22.5 mg Q3M Leuprolide (11.25 mg in Japan and Taiwan) Screening period Randomized Treatment period Follow up period 28 days 48 weeks 12 weeks (Testosterone and PSA assessed monthly) 15 Study design HERO, a multinational, open-label, phase 3, randomized trial From April 2017 through October 2018 Exclusion criteria (1) Patients likely to require chemotherapy or surgical therapy for symptomatic disease management within 2 months of initiating ADT (2) Previously received ADT > 12 months duration (3) Previously received ADT < 12 months duration, needs to be off the therapy at least 12 months (4) Brain metastasis (5) Scheduled for major surgery (6) History of surgical castration (7) Patients with major adverse cardiovascular events (MACE) within 6 months before trial initiation 16 Outcome Primary Sustained castration rate: cumulative probability of testosterone suppression endpoint < 50 ng/dL from day 29 through 48 weeks Secondary (1) Noninferiority of Relugolix to Leuprolide for sustained castration rate endpoints (margin -10%) (2) Superiority of Relugolix to Leuprolide for sustained castration rate (3) Cumulative probability of testosterone suppression < 50 ng/dL on day 4 and day 15 (4) Percentage of patients with a PSA response (>50% decrease) on day 15 (5) Profound castration rate to < 20 ng/dL on day 15 (6) FSH level at the end of week 24 (7) Castration resistance–free survival is ongoing and not yet reported 17 Statistical analysis • Sample size required for the primary endpoint: Sustained testosterone suppression at the end of week 48 were assumed to be 94% for Relugolix and 96% for Leuprolide, with a dropout rate of 15% • Noninferiority analysis: 915 patients yield 99% power • Ineffective castration: serum testosterone ≥ 50 ng/dL at day 29 or any subsequent visit 18 Non-inferiority (NI) analysis To demonstrate that the effect of test drug is close to the effect of an active control. There is no placebo arm in the study. The goal of the study is to show that the effect of the test drug (T) is not inferior to the effect of the active control (C) by a specified amount, called the NI margin, or M. Ref: U.S. Department of Health and Human Services Food and Drug Administration; November 2016 19 Baseline characteristics 20 Baseline characteristics 21 Baseline characteristics 22 Result: Primary endpoint (cumulative probability of testosterone suppression < 50 ng/dL) (96.7-88.8) 23 Subgroup analysis in sustained castration rate 24 Result: Secondary endpoints 25 Mean testosterone level • Mean testosterone level on day 4 Relugolix: 38 ng/dl Leuprolide: 625 ng/dl 26 Testosterone recovery • Mean testosterone level at 90 days Relugolix: 288.4 ng/dl Leuprolide: 58.6 ng/dl • Percentage of patients with testosterone recovery to 280 ng/dl at 90 days Relugolix: 54% Leuprolide: 3% 27 * MACE: Major Adverse Cardiovascular Events Adverse events 28 Cumulative incidence of MACE • 54% reduction in MACE with Relugolix 29 Discussion-MACE • A large meta-analysis that pooled data from six phase 3, prospective, randomized studies for which 2328 men were recruited between 2005 and 2012. • Men with preexisting cardiovascular disease, the risk of cardiac events within 1 year after initiation of therapy: Lower in GnRH antagonist group than in LHRH agonists group (hazard ratio: 0.44; 95% CI: 0.26 to 0.74; P=0.002) • FSH receptors: on the luminal endothelial surface of proliferating tissue and may also play a role in endothelial cell function, lipid metabolism, and fat accumulation that may increase the risk of CV disease in men receiving GnRH agonist therapy. • GnRH agonists may promote destabilization of atherosclerotic plaques Ref: Cardiovascular Morbidity Associated with Gonadotropin Releasing Hormone Agonists and an Antagonist; European Urology 65 (2014) 565-573 30 Limitations • Open-label trial without blinded outcome assessment • Adherence to oral therapies: treatment adherence was more than 99% in both groups • The role of Relugolix in castration-resistant advanced prostate cancer is unknown. • In subgroup analysis, the superiority of Relugolix was not shown in PSA ≥ 20 ng/ml. 31 CASP系統性文獻回顧檢核表 Section A: Are the results of the trial valid? 1. Did the trial address a clearly focused issue? 研究問題是否清楚且聚焦? 臨床問題 在晚期攝護腺癌的治療選擇上，口服Relugolix是否優於Leuprolide? 問題/研究族群 Castration-sensitive advanced prostate cancer Problem/Patient 給予的措施 Relugolix 120 mg once daily after a single oral loading dose of 360 mg Intervention 對照組 Leuprolide 22.5 mg or 11.25 mg in Japan and Taiwan by injection Comparison every 3 months 結果 Primary outcome: sustained castration rate Outcome Secondary outcomes: noninferiority and superiority of Relugolix to Leuprolide for sustained castration rate HINT: An issue can be ‘focused’ In terms of • the population studied • the intervention given • the comparator given • the outcomes considered 33 Section A: Are the results of the trial valid? 2. Was the assignment of patients to treatments randomised? 受試者是否確實被隨機分派到不同組別? Patients are assigned to one of 2 treatment arms in accordance with the randomization schedule using an integrated randomization system (IWRS). Patients enrolled in this study will be randomized 2:1 to receive oral relugolix or leuprolide acetate 3-M depot subcutaneous or intramuscular injection. Randomization will be stratified by geographic region, presence of metastatic disease, and age. The HERO study is a phase 3 multinational randomized, open-label, parallel-group study HINT: Consider • how this was carried out? •如何進行隨機分派? • was the allocation sequence concealed •研究者是否被隱匿分組訊息? from researchers and patients? 34 Section A: Are the results of the trial valid? 3. Were all of the patients who entered the trial properly accounted for at its conclusion? 是否所有進入試驗的受試者在研究結論當中均被適當的考量過? The efficacy analyses will be conducted using an Intent-to-Treat (ITT) population defined as all randomized patients who have taken at least one dose of study treatment. HINT: Consider •試驗有提早結束嗎? •was the trial stopped early? •受試者是否一經隨機分派, •were patients analysed in the groups to 均納入最後的分析? which they were randomized? 35 Section A: Are the results of the trial valid? 4. Were patients, health workers and study personnel ‘blind’ to treatment? 受試者、健康相關工作人員及研究人員是否盲化? The HERO study is a phase 3 multinational randomized, open-label, parallel-group study 5. Were the groups similar at the start of the trial? 各組研究對象在一開始進入試驗時的基本特性是否相似? Patients were randomly assigned in a 2:1 ratio to receive either Relugolix or Leuprolide acetate The characteristics of the patients at baseline were well balanced between the treatment groups HINT: Consider • other factors that might affect the outcome, such as; age, sex, social class 36 Section A: Are the results of the trial valid? 6. Aside from the experimental intervention, were the groups treated equally? 除了實驗的介入措施之外,各組的所有對待是否相同? Relugolix: 120 mg will be administered once daily following an oral loading dose of 360 mg Leuprolide: 22.5 mg (or 11.25 mg in some Asian countries) 3-M depot subcutaneous or intramuscular injection will be administered (with
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