HERO Trial Research Articles

The performance of a Bayesian value-based sequential clinical trial design in the presence of an equivocal cost-effectiveness signal: evidence from the HERO trial

BackgroundThere is increasing interest in the capacity of adaptive designs to improve the efficiency of clinical trials. However, relatively little work has investigated how economic considerations – including the costs of the trial – might inform the design and conduct of adaptive clinical trials.MethodsWe apply a recently published Bayesian model of a value-based sequential clinical trial to data from the ‘Hydroxychloroquine Effectiveness in Reducing symptoms of hand Osteoarthritis’ (HERO) trial. Using parameters estimated from the trial data, including the cost of running the trial, and using multiple imputation to estimate the accumulating cost-effectiveness signal in the presence of missing data, we assess when the trial would have stopped had the value-based model been used. We used re-sampling methods to compare the design’s operating characteristics with those of a conventional fixed length design.ResultsIn contrast to the findings of the only other published retrospective application of this model, the equivocal nature of the cost-effectiveness signal from the HERO trial means that the design would have stopped the trial close to, or at, its maximum planned sample size, with limited additional value delivered via savings in research expenditure.ConclusionEvidence from the two retrospective applications of this design suggests that, when the cost-effectiveness signal in a clinical trial is unambiguous, the Bayesian value-adaptive design can stop the trial before it reaches its maximum sample size, potentially saving research costs when compared with the alternative fixed sample size design. However, when the cost-effectiveness signal is equivocal, the design is expected to run to, or close to, the maximum sample size and deliver limited savings in research costs.

A phase III randomized trial of radiotherapy optimization for low-risk HER2-positive breast cancer (HERO): NRG-BR008.

TPS613 Background: Breast radiotherapy (RT) is the standard of care for patients with early-stage breast cancer (BC) who undergo breast-conserving surgery (BCS). However, the magnitude of benefit of RT is less clear in BCS patients with low-risk disease who receive effective systemic therapy. Among patients with early-stage HER2-positive (HER2+) BC, 10-year locoregional recurrence has been reported as low as 1.5% following BCS, adjuvant chemotherapy and HER2-targeted therapy, and RT. Given these exceedingly favorable outcomes, with the addition of HER2-directed therapy, we seek to evaluate the feasibility of omitting RT among patients with early-stage HER2+ BC following BCS and appropriate systemic therapy. Methods: This is a phase III randomized trial for patients ≥40 years with early-stage, node-negative, HER2+ (IHC/FISH) BC treated with BCS with negative margins and sentinel lymph node biopsy or axillary dissection. Patients undergoing primary surgery must have pathologic T1 (≤2 cm) N0 disease, while patients receiving neoadjuvant therapy must have clinical T1-2 (with radiographically T≤3.0 cm) N0 disease and exhibit a pathologic complete response (ypT0N0) at surgery. All patients must receive cytotoxic chemotherapy and HER2-targeted therapy, either in the adjuvant or neoadjuvant setting. Stratification is by age (<60; ≥60), tumor size (≤1 cm; >1 cm), estrogen-receptor status (positive; negative), and systemic therapy sequencing (adjuvant vneoadjuvant). Patients will be randomized to standard breast RT in addition to continuation of trastuzumab to complete one year of treatment (Arm 1), or trastuzumab alone (Arm 2). Endocrine therapy will be recommended for patients with hormone-receptor positive tumors. The primary endpoint is the recurrence-free interval (RFI). Secondary endpoints include time to ipsilateral breast recurrence, locoregional recurrence, disease-free survival, and overall survival, in addition to the 7-year ipsilateral breast recurrence rate among those not receiving RT. A health-related quality of life sub-study will assess differences in patient-reported breast pain and worry. We estimate a 7-year RFI of 97.5% with RT and allow for a clinically acceptable decrement of 3.63% without RT (7-year RFI of 93.87%; HR 2.5) to establish omission of RT as non-inferior. NRG-BR008 aims to enroll 1,300 patients over 4.5 years, yielding 80% power to detect the non-inferiority of RT omission with a one-sided α=0.05. We expect to observe the required 38 RFI events within 6 years of additional follow-up. The NRG-BR008/HERO trial opened to accrual in March 2023. Accrual is 13/1,300 as of 02-05-2024. Clinical trial information: NCT05705401 .

Abstract PO1-19-01: NRG-BR008: A Phase III Randomized Trial of Radiotherapy Optimization for Low-risk HER2-positive Breast Cancer (HERO)

Abstract Background: Breast radiotherapy (RT) is the standard of care for patients with early-stage breast cancer (BC) who undergo breast-conserving surgery (BCS). However, the magnitude of benefit of RT is less clear in BCS patients with low-risk disease who receive effective systemic therapy. Among patients with early-stage HER2-positive (HER2+) BC, 10-year locoregional recurrence has been reported as low as 1.5% following BCS, adjuvant chemotherapy and HER2-targeted therapy, and RT. Given these exceedingly favorable outcomes, with the addition of HER2-directed therapy, we seek to evaluate the feasibility of omitting RT among patients with early-stage HER2+ BC following BCS and appropriate systemic therapy. Methods: This is a phase III randomized trial for patients ≥40 years with early-stage, node-negative HER2+ (IHC/FISH) BC treated with BCS with negative margins and sentinel lymph node biopsy or axillary dissection. Patients undergoing primary surgery must have pathologic T1 (< 2 cm) N0 disease, while patients receiving neoadjuvant therapy must have clinical T1-2 (with radiographically T< 3.0 cm) N0 disease and exhibit a pathologic complete response (ypT0N0) at surgery. All patients must receive cytotoxic chemotherapy and HER2-targeted therapy, either in the adjuvant or neoadjuvant setting. Stratification is by age (< 60; ≥60), tumor size (≤1 cm; >1 cm), estrogen-receptor status (positive; negative), and systemic therapy sequencing (adjuvant vs neoadjuvant). Patients will be randomized to standard breast RT in addition to continuation of trastuzumab to complete a year of treatment (Arm 1), or trastuzumab alone (Arm 2). Endocrine therapy will be recommended for patients with hormone-receptor positive tumors. The primary endpoint is the recurrence-free interval (RFI). Secondary endpoints include the time to ipsilateral breast recurrence, locoregional recurrence, disease-free survival, and overall survival, in addition to the 7-year ipsilateral breast recurrence rate among those not receiving RT. A health-related quality of life sub-study will assess differences in patient-reported breast pain and worry. We estimate a 7-year RFI of 97.5% with RT and allow for a clinically acceptable decrement of 3.63% without RT (7-year RFI of 93.87%; HR 2.5) to establish omission of RT as non-inferior. NRG-BR008 aims to enroll 1,300 patients over 4.5 years, yielding 80% power to detect the non-inferiority of RT omission with a one-sided α=0.05. We expect to observe the required 38 RFI events within 6 years of additional follow-up. The NRG-BR008/HERO trial opened to accrual in March, 2023. NCT05705401. Support: U10CA180868, -180822, UG1CA189867, U24CA196067; Susan G. Komen Foundation (JR) Citation Format: Lior Braunstein, Melissa Mitchell, Hanna Bandos, William Sikov, Atif Khan, Peter Chen, Patricia Ganz, Reshma Jagsi, Julia White, Reena Cecchini, Hyejoo Kang, Shannon Puhalla, Kelly Bolton, Eileen Connolly, Erica Stringer-Reasor, Kimberly Gergelis, Thomas Julian, Eleftherios Mamounas, Norman Wolmark. NRG-BR008: A Phase III Randomized Trial of Radiotherapy Optimization for Low-risk HER2-positive Breast Cancer (HERO) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-19-01.

Efficacy and Safety of Radiotherapy Plus Relugolix in Men With Localized or Advanced Prostate Cancer

Combination androgen deprivation therapy (ADT) with radiotherapy is commonly used for patients with localized and advanced prostate cancer. To assess the efficacy and safety of the oral gonadotropin-releasing hormone antagonist relugolix with radiotherapy for treating prostate cancer. This multicenter post hoc analysis of patients with localized and advanced prostate cancer receiving radiotherapy in 2 randomized clinical trials (a phase 2 trial of relugolix vs degarelix, and a subset of the phase 3 HERO trial of relugolix vs leuprolide acetate) included men who were receiving radiotherapy and short-term (24 weeks) ADT (n = 103) from 2014 to 2015 and men receiving radiotherapy and longer-term (48 weeks) ADT (n = 157) from 2017 to 2019. The data were analyzed in November 2022. Patients receiving short-term ADT received relugolix, 120 mg, orally once daily (320-mg loading dose) or degarelix, 80 mg, 4-week depot (240-mg loading dose) for 24 weeks with 12 weeks of follow-up. Patients receiving longer-term ADT received relugolix, 120 mg, orally once daily (360-mg loading dose) or leuprolide acetate injections every 12 weeks for 48 weeks, with up to 90 days of follow-up. Castration rate (testosterone level <50 ng/dL [to convert to nmol/L, multiply by 0.0347) at all scheduled visits between weeks 5 and 25 for patients receiving short-term ADT and weeks 5 and 49 for patients receiving longer-term ADT. Of 260 patients (38 Asian [14.6%], 23 Black or African American [8.8%], 21 Hispanic [8.1%], and 188 White [72.3%] individuals), 164 (63.1%) received relugolix. Relugolix achieved castration rates of 95% (95% CI, 87.1%-99.0%) and 97% (95% CI, 90.6%-99.0%) among patients receiving short-term and longer-term ADT, respectively. Twelve weeks post-short-term relugolix, 34 (52%) achieved testosterone levels to baseline or more than 280 ng/dL. Ninety days post longer-term ADT, mean (SD) testosterone levels were 310.5 (122.4) (106.7) ng/dL (relugolix; n = 15) vs 53.0 ng/dL (leuprolide acetate; n = 8) among the subset assessed for testosterone recovery. Castration resistance-free survival was not statistically different between the relugolix and leuprolide acetate cohorts (hazard ratio, 0.97; 95% CI, 0.35-2.72; P = .62). Adverse events grade 3 or greater for short-term or longer-term relugolix (headache, hypertension, and atrial fibrillation) were uncommon (less than 5%). The results of these 2 randomized clinical trials suggest that relugolix rapidly achieves sustained castration in patients with localized and advanced prostate cancer receiving radiotherapy. No new safety concerns were identified when relugolix was used with radiotherapy.

Testosterone suppression and recovery in patients with advanced prostate cancer treated with intermittent androgen deprivation therapy (iADT) with relugolix.

70 Background: Many patients with advanced prostate cancer do not want to pursue continuous androgen deprivation therapy (cADT) because of concerns about side effects, and pursue iADT. However, even intermittent treatment with GNRH agonist therapy may not lead to rapid recovery of testosterone during the off-treatment period. In the pivotal HERO trial of relugolix (GNRH antagonist) the testosterone recovery time was in weeks [PMID 32469183]. The objective of the study was to measure the time to testosterone suppression to castrate level and time to recovery of serum testosterone to non-castrate level in real-world patients with advanced prostate cancer undergoing intermittent relugolix therapy. Methods: In this IRB-approved retrospective study, the eligibility was: patients with advanced prostate cancer undergoing iADT with relugolix. iADT with relugolix was defined as initiating relugolix at PSA ≥ 10 ng/ml and holding relugolix when PSA ≤ 4 ng/ml. The primary endpoints were: 1) time to serum castrate level of testosterone after relugolix initiation and 2) time to recovery to non-castrate level after discontinuation of relugolix. Castrate level of serum testosterone was defined as serum testosterone level ≤ 50 ng/dL. Results: Overall 25 consecutive patients with advanced prostate cancer treated with iADT with relugolix were eligible and included. The median age was 75 [range 68-88]. Patients with a Gleason score of ≥ 8 comprised 44% of the cohort. The median PSA at the start of therapy was 18.2 ng/ml [5.1 – 99.1 ng/ml]. Median time to testosterone ≤ 50 ng/dl after relugolix initiation was 1.13 months [0.67 – 2.5 months], and median time to testosterone recovery after relugolix discontinuation was 1.4 months [0.83 – 6.57 months]. The median PSA nadir achieved with relugolix was 2.02 ng/ml [0.1 – 4.8], and median time to PSA nadir was 1.35 months from initiation of therapy (0.67 – 4.8 months). Median time to PSA relapse ≥ 10 ng/dl after holding relugolix was 3.4 months (0.9 – 8.23 months). Conclusions: This is the first real-world study to show that iADT with relugolix is associated with a rapid time to testosterone suppression and recovery. These results may guide patients’ counseling, monitoring of serum testosterone and PSA levels in patients wishing to pursue iADT for advanced prostate cancer. These hypothesis-generating data need external validation.

A multi-center, prospective, observational study of patients with prostate cancer being treated with relugolix: OPTYX.

TPS398 Background: Androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) receptor agonists or antagonists are the foundation of advanced prostate cancer (aPC) treatment. Relugolix is an oral non-peptide GnRH receptor antagonist approved in the US for the treatment of aPC. In the phase 3 HERO trial, relugolix maintained suppression of testosterone to castration levels in 96.7% of men from Day 29 to 48 weeks, with superiority to leuprolide acetate. Relugolix was well tolerated and associated with a 54% lower risk of major adverse cardiovascular events relative to leuprolide acetate (Shore N, NEJM 2020;382;23). The goal of this current study (OPTYX) is to generate real-world evidence about the safety and effectiveness of relugolix in patients with prostate cancer during routine clinical care. Methods: This prospective observational cohort study (registry) is enrolling patients who have planned initiation with relugolix within 1 month prior to the time of study enrollment. The study is designed to prospectively understand the actual experience of patients with prostate cancer treated with relugolix through data collection on patients selected for treatment, treatment patterns, adherence, patient reported quality of life (QoL) and safety data. Additionally, a better understanding of the trajectory of patients with prostate cancer following cessation of relugolix therapy will be gained by observing the clinical course of the disease, health outcomes, and health-related quality-of-life (HRQoL) in these patients. Inclusion criteria include patients &gt; 18 years old with prostate cancer and planned total treatment with relugolix of at least 4 months. Estimated enrollment is 1000 patients, and patients will be followed for up to 5 years. In addition to assessing routine clinical care and disease progression, patient reported outcomes will be assessed with the Functional Assessment of Cancer Therapy-Prostate (FACT-P) for HRQoL and Simplified Medication Adherence Questionnaire (SMAQ) for adherence at 3 and 6 months then every 6 months. Clinical trial information: NCT05467176 .

Relugolix: A Review in Advanced Prostate Cancer.

Relugolix (Orgovyx®), an orally active nonpeptide gonadotropin-releasing hormone (GnRH) receptor antagonist that provides rapid testosterone suppression, is indicated in the USA for the treatment of advanced prostate cancer and in the EU for advanced hormone-sensitive prostate cancer. In the pivotal phase III HERO trial in men with advanced prostate cancer, once-daily oral relugolix (with a loading dose on day 1) led to a sustained castration rate over 48weeks of treatment of > 90%, a rate that was non-inferior to that provided by intramuscular leuprolide depot every 3months (with an exploratory analysis further indicating the superiority of relugolix over leuprolide). Relugolix was generally well tolerated, having an adverse event profile that is consistent with testosterone suppression. Furthermore, there is evidence that relugolix may be associated with a lower risk of major adverse cardiac events compared with leuprolide. With the ability to provide the rapid testosterone suppression (with no initial surge in testosterone upon treatment initiation) combined with the benefits of oral administration and potentially improved cardiac safety, relugolix presents a valuable treatment option for men with advanced prostate cancer where androgen deprivation therapy is indicated.

Relugolix in the management of prostate cancer

ABSTRACT Introduction Relugolix is the first oral gonadotrophin-releasing hormone (GnRH) receptor antagonist. Based on the phase III HERO trial results, relugolix received Food and Drug Administration approval for adult patients with advanced prostate cancer (PCa). Areas covered We provide an overview of the preclinical and clinical development of relugolix and its role in the current treatment landscape of PCa. Expert opinion Relugolix leads to rapid inhibition of testicular production of testosterone and its rapid recovery upon discontinuation. In the HERO trial, relugolix was associated with a superior cardiovascular safety profile compared to GnRH agonists. These attributes make relugolix a promising therapy for patients with preexisting cardiovascular comorbidities, those pursuing intermittent androgen deprivation therapy, and those who desire rapid testosterone recovery during ‘off-treatment’ periods. In the HERO trial, very few patients received concomitant enzalutamide (n = 17, 2.7%) or docetaxel (n < 10, 1.3%). Safety of relugolix has not been established in combination with many androgen-receptor-axis targeted therapies (e.g. abiraterone, apalutamide), cabazitaxel, or lutetium Lu 177 vipivotide tetraxetan, which precludes its use in combination with these agents. In addition, being an oral drug, relugolix may also be associated with challenges of affordability, adherence, and compliance in this predominantly elderly population.

The adoption of relugolix for treatment of prostate cancer (PCa) in a large community medical oncology practice.

e13541 Background: Relugolix was approved by the FDA in late 2020 as an oral gonadotropin-releasing hormone (GnRH) receptor antagonist for the treatment of adults with advanced PCa. The approval was based on a large randomized trial (Shore et al NEJM) of patients with evidence of biochemical or clinical relapse after local primary intervention with curative intent (50%), newly diagnosed mCSPCa (23%), and advanced localized disease not suitable for primary surgical intervention with curative intent (28%). Our study aims to observe the adoption of relugolix in a large community-based medical oncology practice with affiliated urologists. Methods: A retrospective study using our EMR identified 39 males with PCa for whom relugolix was initiated between January 2021 and December 2021. The charts were analyzed for demographics, indications for treatment, barriers encountered to initiation of treatment, duration of therapy, previous therapies, specialty, primary insurance, and cardiovascular history. Results: Thirty-nine (39) patients with either localized PCa (40%) or with metastases to lymph nodes or distant sites (51%) were recommended initiation of relugolix by either urology (26%) or oncology (74%). Of these, 77% actually started the medication. 9 patients did not start therapy, of which 3 were due to insurance denial, 1 due to death, 2 changed their mind, and 3 did not start for unclear reasons. Medicare covered 56% of the patients. Cardiovascular disease was notable in 87%. 28% switched from another ADT due to intolerance, 10% started relugolix due to progressive disease, and 33% started as initial ADT. 13% discontinued within 6 months. Of these, 1 completed planned therapy, 3 were intolerant, 1 was switched to alternate therapy due to progression, and 1 had complications due to COVID. In comparison, 689 patients initiated ADT with leuprolide over the same time. Conclusions: ADT using GnRH agonists or antagonists form the backbone of PCa treatment, typically given as injections. The HERO trial showed that relugolix, a newer oral therapy, is associated with lower rates of cardiovascular events compared to leuprolide. While having at least one cardiovascular risk factor is a consideration for patients to either start with or switch to relugolix, the large majority of our patients still received first-line therapy with leuprolide. This study demonstrates limitations to initiating relugolix including financial constraints (e.g., insurance coverage), patient preference, and medication intolerance.[Table: see text]

Treatment for hepatitis C virus with direct acting antiviral agents: Perspectives and treatment experiences of people who inject drugs

IntroductionIncreasingly, people who inject drugs (PWID) infected with hepatitis C virus (HCV) are gaining access to highly effective direct-acting antiviral agents (DAAs). Although past studies examined patient experiences with interferon-based treatments, few have explored patient experiences with these new generation therapeutics. Research and real world experience indicate that many PWID can be successfully treated with the new DAAs. Yet a substantial minority fail to complete treatment or achieve only suboptimal adherence. This qualitative study examines experiences with treatment among participants in Project HERO, a large multisite trial designed to compare treatment delivery methods for DAAs. We explored treatment experiences among HERO participants, with the goal of understanding potential barriers to treatment engagement and completion. MethodsWe conducted qualitative interviews with a sample of 21 participants, including 14 who completed HCV treatment and 7 participants who discontinued treatment before the end of the 12-week medication course. The first phase of the analysis was descriptive, examining participants' life experiences, histories of disease and treatment seeking, experiences with the program, and barriers to treatment completion. The second phase of the analysis examined differences between completers and noncompleters. ResultsParticipants offered a variety of reasons for seeking treatment. Both groups of participants reported highly positive experiences of the HERO trial. Participants described research staff as caring, respectful, and nonjudgmental. Substance use was reported by both groups, yet completers described “manageable” substance use, while noncompleters described substance use that sapped their energy and motivation. Shame over drug use was a barrier to treatment completion. Homelessness and a reported lack of social support were much more common in the noncompleter group. ConclusionsReasons for noncompletion were not related to features of the clinical trial or treatment program. Our results indicate the importance of: 1) recognizing and addressing severe social and economic challenges such as homelessness; and 2) building a program culture of respect and compassion in treatment programs for PWID infected with HCV.

Impact of concomitant cardiovascular therapies on efficacy and safety of relugolix verus leuprolide in men with advanced prostate cancer: Subgroup analysis from the phase 3 HERO study.

101 Background: Cardiovascular (CV) events are the leading cause of death in prostate cancer. Men with prostate cancer are likely to have CV risk factors and CV-related concomitant medications. In the phase 3 HERO study, a 54% lower incidence of major adverse cardiac events was reported in men treated with the oral GnRH receptor antagonist relugolix vs leuprolide. Herein, we characterize the impact of concomitant CV therapies on efficacy and safety in the HERO study. Methods: In HERO, 930 men with advanced prostate cancer were randomized 2:1 and treated with relugolix (120 mg orally once daily [after single 360 mg loading dose] or leuprolide (injections every 3 months) for 48 weeks. Subgroups analyzed included men who received antihypertensives, antithrombotics, or lipid-modifying therapies, as well as the most common drug classes (&gt;10%) and single most common agent within each class. Assessments included sustained testosterone suppression to castrate levels (&lt;50 ng/dL) through 48 weeks and safety parameters (adverse events). Results: Antihypertensives, antithrombotics, and lipid modifying agents were utilized by 52.7%, 39.1%, and 39.6% of men in the HERO trial, respectively (table). In the main subgroups, point estimates for sustained castration rates were consistent with the overall estimates of relugolix and leuprolide observed in the overall population (table). Sustained castration rates were also consistent for men taking the most common drug classes (table) and individual agents in each class (losartan [n=103]: relugolix, 95.4% vs. leuprolide, 80.6%; amlodipine [n=229]: 97.2% vs. 85.5%; metoprolol [n=88]: 95.7% vs. 86.9%; acetylsalicylic acid [n=259]: 97.0% vs. 92.1%; clopidogrel [n=43]: 96.4% vs. 86.7%; simvastatin [n=78]: 98.0% vs. 87.3%). Incidence and types of adverse events were similar among men who received antihypertensives, antithrombotics, and lipid modifying agents during the trial. Conclusions: In the HERO trial, relugolix suppressed testosterone and was generally well tolerated when given with concomitant CV agents, with results consistent with those of the overall population. Clinical trial information: NCT03085095. [Table: see text]

Real-world experience with relugolix.

57 Background: Gonadotropin-releasing hormone (GnRH) antagonists were developed in part to avoid testosterone flare to achieve faster and more consistent testosterone suppression. Relugolix (Rel) was given FDA approval for use in prostate cancer (PCa) based on the phase 3 HERO trial but some real-world concerns include compliance, affordability, and performance in patients transitioning from another GnRH agent or in combination with other therapeutic agents. The aim of our study was to evaluate the real-world implications of prescribing and/or switching to Rel. Methods: A single institution retrospective study was conducted on patients prescribed Rel. Treatment data including concomitant therapeutic agents were collected. Compliance data was measured via chart review and pharmacy dispensary records. Patients were classified as either newly castrated or transitioning from another agent. PSA and testosterone levels were tabulated. Reported adverse effects (AE), and reasons for discontinuation if applicable including financial toxicity were noted. Results: 50 patients were reviewed; 15 (30%) treated for adjuvant, 18 (36%) for biochemical recurrence, and 17 (34%) for metastatic PCa. 12% were on concomitant therapy with abiraterone, 4% with enzalutamide, and 2% with apalutamide. 80% reported compliance to Rel. 5 (10%) never filled the prescription. 30 (60%) were newly castrated (castration restart or naïve) while 16 (36%) were transitioned from another GnRH. No changes in PSA or testosterone were noted in patients switched form injected GnRH to Rel. The most common documented AE effects included hot flashes 24%, fatigue, 29%, and weight gain 9%. No unexpected toxicity was reported in combination with abiraterone. Of 11 patients who discontinued therapy, 45% did so due to cost, 36% due to AE, and 27% due to therapy completion. 4 of 16 (25%) of those who transitioned from injection GnRH felt symptoms were worse on Rel. Conclusions: In our early experience with Rel, patients did comply to therapy based on self-reporting, pharmacy fill dates, and laboratory evidence of castration. However, financial toxicity was and remains a significant barrier both accessing Rel and remaining on Rel therapy. While a differential toxicity was reported by those who switched from injection GnRH, sometimes leading to discontinuation, there were no new safety signals reported, especially in combination with abiraterone.

Cost-effectiveness of hydroxychloroquine versus placebo for hand osteoarthritis: economic evaluation of the HERO trial

Background: An economic evaluation alongside the Hydroxychloroquine Effectiveness in Reducing symptoms of hand Osteoarthritis (HERO) trial was undertaken to assess the cost-effectiveness of hydroxychloroquine compared with placebo for symptomatic treatment of hand osteoarthritis for patients with at least moderate hand pain and inadequate response to current therapies. Methods: A trial-based cost–utility analysis was undertaken from the perspective of the UK National Health Service and Personal Social Services over a 12-month time horizon, using evidence from 248 participants included in the HERO trial, conducted in England. Patient-level data were collected prospectively over a 12-month period, using participant-completed questionnaires and investigator forms, to collect healthcare utilisation, costs and quality-adjusted life years (QALYs) using the EQ-5D-5L. The base-case analysis was conducted on an intention-to-treat basis and used multiple imputation methods to deal with missing data. Results were presented in terms of incremental cost-effectiveness ratios (incremental cost per QALY) and net health benefit, with uncertainty surrounding the findings explored using cost-effectiveness acceptability curves. Results: The base-case analysis estimated slightly lower costs on average (−£11.80; 95% confidence interval (CI) −£15.60 to −£8.00) and marginally fewer QALYs (−0.0052; 95% CI −0.0057 to −0.0047) for participants in the hydroxychloroquine group versus placebo group at 12 months. The resulting incremental cost-effectiveness ratio of £2,267 per QALY lost indicated that although costs were saved, health-related quality of life was lost. Even assuming symmetrical preferences regarding losses and gains for health benefits, the findings do not fall within the cost-effective region. Similar findings arose for analyses conducted from the societal perspective and using complete cases only. Conclusions: This economic evaluation indicates that hydroxychloroquine is unlikely to provide a cost-effective pain relief option for improving health-related quality of life in adult patients with moderate-to-severe hand osteoarthritis.

Cost-effectiveness of hydroxychloroquine versus placebo for hand osteoarthritis: economic evaluation of the HERO trial.

Background: An economic evaluation alongside the Hydroxychloroquine Effectiveness in Reducing symptoms of hand Osteoarthritis (HERO) trial was undertaken to assess the cost-effectiveness of hydroxychloroquine compared with placebo for symptomatic treatment of hand osteoarthritis for patients with at least moderate hand pain and inadequate response to current therapies. Methods: A trial-based cost-utility analysis was undertaken from the perspective of the UK National Health Service and Personal Social Services over a 12-month time horizon, using evidence from 248 participants included in the HERO trial, conducted in England. Patient-level data were collected prospectively over a 12-month period, using participant-completed questionnaires and investigator forms, to collect healthcare utilisation, costs and quality-adjusted life years (QALYs) using the EQ-5D-5L. The base-case analysis was conducted on an intention-to-treat basis and used multiple imputation methods to deal with missing data. Results were presented in terms of incremental cost-effectiveness ratios (incremental cost per QALY) and net health benefit, with uncertainty surrounding the findings explored using cost-effectiveness acceptability curves. Results: The base-case analysis estimated slightly lower costs on average (-£11.80; 95% confidence interval (CI) -£15.60 to -£8.00) and marginally fewer QALYs (-0.0052; 95% CI -0.0057 to -0.0047) for participants in the hydroxychloroquine group versus placebo group at 12 months. The resulting incremental cost-effectiveness ratio of £2,267 per QALY lost indicated that although costs were saved, health-related quality of life was lost. Even assuming symmetrical preferences regarding losses and gains for health benefits, the findings do not fall within the cost-effective region. Similar findings arose for analyses conducted from the societal perspective and using complete cases only. Conclusions: This economic evaluation indicates that hydroxychloroquine is unlikely to provide a cost-effective pain relief option for improving health-related quality of life in adult patients with moderate-to-severe hand osteoarthritis.

HERO trial: A rescue from injectable androgen deprivation therapy.

HERO trial: A rescue from injectable androgen deprivation therapy.

Genitourinary cancers—best of ASCO 2020

SummaryThe aim of this short review is to summarize “clinical practice changing” abstracts about genitourinary cancers from this year’s ASCO Annual Meeting. The phase 3 JAVELIN Bladder 100 trial showed astonishing overall survival (OS) data up to 22 months in metastatic urothelial carcinoma (mUC), using a novel gold standard in the first-line setting of mUC—immunotherapy maintenance with avelumab after response to platinum-based chemotherapy. In the first-line treatment of metastatic RCC (mRCC), two phase 2 trials (OMNIVORE and HCRN GU16-260) evaluated the efficacy of a novel sequential strategy, nivolumab monotherapy followed by ipilimumab rescue if nonresponse to nivolumab, confirming that this therapeutic concept is less effective as upfront combination treatment. Finally, updated 24-month progression-free survival (PFS) and OS rates of the KEYNOTE-426 are presented, showing efficacy most in intermediate- and poor-risk patients for the combination pembrolizumab plus axitinib compared with sunitinib. According to the impressive data from the HERO trial, the US Food and Drug Administration granted relugolix priority review as the first oral GNRH receptor antagonist in advanced prostate cancer. Moreover, 18F‑DCFPyL-PET/CT is a promising diagnostic tool for biochemical recurrence as the CONDOR trial confirmed diagnostic superiority of PyL-PET/CT compared with conventional imaging in detecting occult metastasis even in low PSA values. In nonmetastatic castration-resistant prostate cancer (nmCRPC), final OS data of ARAMIS, PROSPER and SPARTAN evaluating efficacy and safety of second-generation antiandrogens versus placebo were presented. In patients with mCRPC progressing after docetaxel, 177Lu-PSMA-617 demonstrated improved rates of 50% reduction in PSA relative to cabazitaxel (TheraP study).

HERO phase III trial: Results comparing relugolix, an oral GnRH receptor antagonist, versus leuprolide acetate for advanced prostate cancer.

5602 Background: LHRH agonists are the mainstay for medical castration in advanced prostate cancer; however, they cause an initial testosterone (T) surge with a delayed onset of castration and require depot injection. Relugolix is the first oral GnRH receptor antagonist, which was previously shown to rapidly suppress T levels. The HERO trial compared the safety and efficacy of relugolix with leuprolide acetate in advanced prostate cancer patients. Methods: HERO is a 48-week, global, pivotal phase III trial that randomized 934 patients with androgen-sensitive advanced prostate cancer in a 2:1 ratio to receive relugolix 120 mg orally QD after a single l or leuprolide acetate 3-month depot injection. The primary endpoint was to achieve and maintain serum T suppression to castrate levels (&lt; 50 ng/dL) through 48 weeks. Key secondary endpoints included castration rates at Day 4, profound castration (&lt; 20 ng/dL) rates at Days 4 and 15, PSA response rate at Day 15 and FSH levels at Week 25. Testosterone recovery was evaluated in a subset of 184 patients. Results: A total of 96.7% (95% CI: 94.9%, 97.9%) of men on relugolix achieved and maintained castration through 48 weeks compared to 88.8% on leuprolide. The difference of 7.9% (95% CI: 4.1%, 11.8%) demonstrated non-inferiority (margin -10%) and superiority (P &lt; 0.0001) of relugolix to leuprolide. All key secondary efficacy endpoints tested demonstrated superiority over leuprolide (P &lt; 0.0001) (Table). In the testosterone recovery subset, median T levels were 270.76 ng/dL in the relugolix compared to 12.26 ng/dL in the leuprolide group 90 days after discontinuation of therapy. In a prespecified analysis, the incidence of major adverse cardiovascular events (MACE) was lower in the relugolix group than in the leuprolide group (2.9% vs. 6.2%, respectively); otherwise the safety and tolerability profiles were generally similar. Conclusion: Relugolix achieved castration as early as Day 4 and demonstrated superiority over leuprolide in sustained T suppression through 48 weeks, faster T recovery after discontinuation and a 50% reduction in MACE. Relugolix has the potential to become a new standard for T suppression for patients with advanced prostate cancer. Clinical trial information: NCT03085095 . [Table: see text]

LBA02-07 HERO PHASE 3 TRIAL: RESULTS COMPARING RELUGOLIX, AN ORAL GNRH RECEPTOR ANTAGONIST, VS LEUPROLIDE ACETATE FOR ADVANCED PROSTATE CANCER

You have accessJournal of UrologyLate-Breaking Abstracts (LBA2)1 Apr 2020LBA02-07 HERO PHASE 3 TRIAL: RESULTS COMPARING RELUGOLIX, AN ORAL GNRH RECEPTOR ANTAGONIST, VS LEUPROLIDE ACETATE FOR ADVANCED PROSTATE CANCER Neal Shore*, Fred Saad, Michael Cookson, David J. George, Daniel R. Saltzstein, Ronald Tutrone, Hideyuki Akaza, Alberto Bossi, David van Veenhuyzen, Bryan Selby, Xiaolin Fan, Vicky Kang, Jackie Walling, and Bertrand Tombal Neal Shore*Neal Shore* More articles by this author , Fred SaadFred Saad More articles by this author , Michael CooksonMichael Cookson More articles by this author , David J. GeorgeDavid J. George More articles by this author , Daniel R. SaltzsteinDaniel R. Saltzstein More articles by this author , Ronald TutroneRonald Tutrone More articles by this author , Hideyuki AkazaHideyuki Akaza More articles by this author , Alberto BossiAlberto Bossi More articles by this author , David van VeenhuyzenDavid van Veenhuyzen More articles by this author , Bryan SelbyBryan Selby More articles by this author , Xiaolin FanXiaolin Fan More articles by this author , Vicky KangVicky Kang More articles by this author , Jackie WallingJackie Walling More articles by this author , and Bertrand TombalBertrand Tombal More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000958.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Introduction: LHRH agonists are the mainstay for medical castration in advanced prostate cancer, however, they cause an initial testosterone (T) surge with a delayed onset of castration and require depot injection. Relugolix is the first oral GnRH receptor antagonist, which was previously shown to rapidly suppress T levels. The HERO trial compared the safety and efficacy of relugolix with leuprolide acetate in advanced prostate cancer patients. Methods: HERO is a 48-week, global, pivotal phase 3 trial that randomized 934 patients with androgen-sensitive advanced prostate cancer in a 2:1 ratio to receive relugolix 120 mg orally QD after a single loading dose of 360 mg or leuprolide acetate 3-month depot injection. The primary endpoint was to achieve and maintain serum T suppression to castrate levels (< 50 ng/dL) through 48 weeks. Key secondary endpoints included castration rates at Day 4, profound castration (< 20 ng/dL) rates at Days 4 and 15, PSA response rate at Day 15 and FSH levels at Week 25. Testosterone recovery was evaluated in a subset of 184 patients. Results: A total of 96.7% (95% CI: 94.9%, 97.9%) of men on relugolix achieved and maintained castration through 48 weeks compared to 88.8% on leuprolide. The difference of 7.9% (95% CI: 4.1%, 11.8%) demonstrated non-inferiority (margin -10%) and superiority (P < 0.0001) of relugolix to leuprolide. All key secondary efficacy endpoints tested demonstrated superiority over leuprolide (P < 0.0001). In the testosterone recovery subset, median T levels were 270.76 ng/dL in the relugolix compared to 12.26 ng/dL in the leuprolide group 90 days after discontinuation of therapy. In a prespecified analysis, the incidence of major adverse cardiovascular events (MACE) was lower in the relugolix group than in the leuprolide group (2.9% vs. 6.2%, respectively); otherwise the safety and tolerability profiles were generally similar. Conclusions: Relugolix achieved castration as early as Day 4 and demonstrated superiority over leuprolide in sustained T suppression through 48 weeks, faster T recovery after discontinuation and a 50% reduction in MACE. Relugolix has the potential to become a new standard for T suppression for patients with advanced prostate cancer. Source Of Funding: Myovant Sciences Inc. © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e1117-e1117 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Neal Shore* More articles by this author Fred Saad More articles by this author Michael Cookson More articles by this author David J. George More articles by this author Daniel R. Saltzstein More articles by this author Ronald Tutrone More articles by this author Hideyuki Akaza More articles by this author Alberto Bossi More articles by this author David van Veenhuyzen More articles by this author Bryan Selby More articles by this author Xiaolin Fan More articles by this author Vicky Kang More articles by this author Jackie Walling More articles by this author Bertrand Tombal More articles by this author Expand All Advertisement PDF downloadLoading ...

Meningitis, urinary tract, and bloodstream infections in very low birth weight infants enrolled in a heart rate characteristics monitoring trial.

Background:Displaying heart rate characteristics (HRC) scores was associated with lower sepsis-associated mortality in very low birth weight (VLBW) infants in a multicenter randomized controlled trial (HeRO trial).Objective:To test whether HRC indices rise before diagnosis of urinary tract infection (UTI) or meningitis, with and without concomitant BSI.Design/Methods:Blood, urine and cerebrospinal fluid (CSF) culture data after 3 days of age and within 120 days of study enrollment were analyzed from 2,989 VLBW infants. The HRC index was analyzed 12h prior to positive cultures compared to 36h prior, using paired signed rank tests.Results:UTI, meningitis, and BSI was diagnosed in 10%, 2%, and 24% of infants respectively. The mean hourly HRC index was significantly higher 12h prior to diagnosis of UTI and BSI compared to 36h prior (UTI 2.07 versus 1.81; BSI 2.62 versus 2.25, both p<0.0001). The baseline HRC index was higher for meningitis, compared to UTI or BSI, but without a statistically significant rise in the day prior to meningitis diagnosis.Conclusions:In a large cohort of VLBW infants enrolled in the HeRO trial, the HRC index increased in the 24h period prior to diagnosis of UTI and BSI, but not meningitis.

Corrigendum to “Hydroxychloroquine in hand OA; results of the UK HERO trial” [Osteoarthr Cartil 25 (2017) S3–S4

Corrigendum to “Hydroxychloroquine in hand OA; results of the UK HERO trial” [Osteoarthr Cartil 25 (2017) S3–S4