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 an antiandrogen for 4 weeks or longer if indicated in the opinion of the investigator)

37 Section B: What are the results?

7. How large was the treatment effect? 介入措施的效果有多大? 8. How precise was the estimate of the treatment effect? 介入措施的效果估計有多精確?

Relugolix v.s Leuprolide 95% CI (p<0.001) Primary endpoint Sustained castration rate 96.7% v.s 88.8% 94.9 to 97.9 / 84.6 to 91.8 Secondary endpoints Noninferiority and superiority of Relugolix 7.9% 4.1 to 11.8 to Leuprolide for sustained castration rate

HINT: Consider • what outcomes were measured? •測量那些結果? • Is the primary outcome clearly specified? •主要結果是否有清楚界定? • what results were found for each outcome? •每個研究結果有哪些發現? HINT: Consider • what are the confidence limits? 38 39 Section B: What are the results?

7. How large was the treatment effect? 介入措施的效果有多大? 8. How precise was the estimate of the treatment effect? 介入措施的效果估計有多精確? Relugolix v.s Leuprolide 95% CI (p<0.001) Secondary endpoints Cumulative probability of testosterone suppression to <50 ng/dl on day 4 56% v.s 0% p<0.001 Cumulative probability of testosterone suppression to <50 ng/dl on day 15 98.7% v.s 12.0% p<0.001

PSA response at day 15 followed by confirmation at day 29 79.4% v.s 19.8% p<0.001

Cumulative probability of profound testosterone suppression to 78.4% v.s 1.0% p<0.001 <20 ng/dl on day 15 Mean FSH level at end of wk 24 (IU/liter) 1.72 v.s 5.95 p<0.001

Cumulative Incidence of MACE 2.8% v.s 5.6% Section C: Will the results help locally?

9. Can the results be applied to the local population, or in your context? 研究結果是否可以應用在你的情境當中(或當地族群?)  Geographic region: • North and South America: 34.6% • North America: 28.9% • Europe: 39.7% • Asia–Pacific region: 25.7%  Gleason score: • Score of 2-4: 0.1% • Score of 5-6: 15.5% • Score of 7: 38.6% • Score of 8-10: 43.1% HINT: Consider whether • the patients covered by the trial are •你有理由相信你照顧的對象 similar enough to the patients to whom 跟研究的受試者不同嗎? you will apply this? •如果是的話,在哪些方面不同? • how they differ? 40 Section C: Will the results help locally?

10. Were all clinically important outcomes considered?

 Outcomes: • Sustained castration rate (<50 ng/dl) • Profound castration rate (<20 ng/dl) • Mean testosterone level for testosterone recovery • PSA response • Mean FSH level  Adverse event: • MACE

HINT: Consider whether • there is other information you would like to have seen?

• if not, does this affect the decision? 41 Section C: Will the results help locally?

11. Are the benefits worth the harms and costs?  Efficacy: • Sustained castration rate: the superiority of Relugolix over Leuprolide (p<0.001) • Other secondary outcomes all favor Relugolix (p<0.001) • Percentage of patients with testosterone recovery to 280 ng/dl at 90 days: 54% in Relugolix v.s 3% in Leuprolide (p=0.002)  Cost: not discussed in the study  Safety: • The overall incidence of adverse events was consistent across treatment groups • Cumulative incidence of MACE with 54% lower risk in Relugolix than in Leuprolide (HR: 0.46; 95% CI, 0.24 to 0.88)

HINT: Consider • even if this is not addressed by the trial, what do you think? 42 Conclusion

Efficacy Efficacy Rapid Delayed Sustained Sustained Safety Safety Castration Castration 54% reduction of Greater risk in men

MACE Relugolix v.s Leuprolide with a history of MACE Testosterone recovery Testosterone recovery Faster testosterone recovery Mean testosterone: 58.6 ng/dl at 90 days Mean testosterone: 288.4 ng/dl at 90 days

Adherence to oral therapy Castration-resistant advanced prostate cancer more than 99% unknown

43 在晚期攝護腺癌的治療選擇上，口服Relugolix是否優於Leuprolide?

同意 (綠牌) 不同意 (紅牌) 需更多文獻支持(黃牌) 1位 2位 23位 44 Thank you for your attention