HERO is a 48-week, global, pivotal phase 3 trial that randomized 934 patients with androgen-sensitive advanced prostate cancer ina 2:1 ratio to receive relugolix 120 mg orally QD after a single one (n=624) or leuprolide acetate 3-month depot injection (n=310). The primary endpoint was to achieve and maintain serum testosterone suppression to castrate levels (< 50 ng/dL) through 48 weeks.
Key secondary endpoints included castration rates at Day 4 and day 15, profound castration (< 20 ng/dL) rates at day 15, PSA response rate at day 15, and FSH levels at week 25. Testosterone recovery was evaluated in a subset of 184 patients. Key inclusion criteria included confirmed advanced prostate cancer (biochemical or clinical relapse, metastatic disease, or advanced localized disease), requiring >= 1 year of ADT, serum testosterone >= 150 ng/dL, serum PSA > 2.0 ng/mL, and ECOG score of 0-1.
The patient demographics were well balanced between the two groups, with 71% of men <= 75 years of age, >2/3 of men were Caucasian, and ~40% of men were from European countries. The median PSA for those on relugolix was 11.7 ng/mL (range 0.02-5517), compared to 9.4 ng/mL (range 0.20-2874) for those receiving leuprolide. Total cardiovascular risk factors included 91.6% of those receiving relugolix compared to 94.2% for those receiving leuprolide.
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 the superiority of relugolix over leuprolide (p < 0.0001), including:
- The proportion of patients with PSA response at Day 15 followed with confirmation at Day 29: 79.4% for relugolix vs 19.8% for leuprolide
- Cumulative probability of testosterone suppression to <50 ng/dL on Day 15: 98.71% for relugolix vs 12.05% for leuprolide
- Cumulative probability of profound testosterone suppression to <20 ng/dL on Day 15: 78.38% for relugolix vs 0.98% for leuprolide
- Cumulative probability of testosterone suppression to <50 ng/dL on Day 4: 56.04% for relugolix vs 0% for leuprolide
- Mean FSH level at the end of Week 24: 1.72 IU/L for relugolix vs 5.95 IU/L for leuprolide
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. Among a subset of patients with a history of MACE, a MACE event occurred in 3.6% of patients on relugolix compared to 17.8% of patients on leuprolide. Taken together, patients receiving relugolix had a 54% reduction in risk of MACE:
The most common adverse event reported for >10% of patients in any treatment group was hot flush (54.3% for relugolix vs 51.6% for leuprolide). Following the conclusion of Dr. Shore’s presentation, this important phase 3 trial was published in the New England Journal of Medicine.1
Dr. Shore concluded his presentation of the HERO trial with several take-home points:
- Relugolix achieved castration as early as Day 4 and demonstrated superiority over leuprolide in sustained testosterone suppression through 48 weeks
- Relugolix also had faster testosterone recovery after discontinuation and a 54% reduction in MACE
- Relugolix has the potential to become a new standard for testosterone suppression for patients with advanced prostate cancer
Presented by: Neal D. Shore, MD, FACS, Medical Director for the Carolina Urologic Research Center., Atlantic Urology Clinics in Myrtle Beach, South Carolina
Co-Authors: Daniel J. George, Fred Saad, Michael Cookson, Daniel R. Saltzstein, Ronald F. Tutrone, Hideyuki Akaza, Alberto Bossi, David van Veenhuyzen, Bryan Selby, Xiaolin Fan, Vicky Kang, Jacqueline M. Walling, Bertrand F. Tombal, Test Abstract Group; Duke University School of Medicine, Durham, NC; Centre Hospitalier de l’Université de Montréal (CHUM), Montréal, QC, Canada; University of Oklahoma Health Sciences Center, Oklahoma City, OK; Urology San Antonio, San Antonio, TX; Chesapeake Urology, Towson, MD; Strategic Investigation on Comprehensive Cancer Network, University of Tokyo, Tokyo, Japan; Institut Gustave Roussy, Villejuif, Villejuif, France; Myovant, Brisbane, CA; Myovant Sciences, Inc., Brisbane, CA; Abbvie Inc., Redwood City, CA; Myovant Sciences, Inc, Hillsborough, CA; Institut d Recherche Clinique, Université Catholique de Louvain, Brussels, Belgium
- Shore ND, Saad F, Cookson MS, et al. Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer. N Engl J Med 2020 May 29 [Epub ahead of print].
Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md at the 2020 ASCO Annual Meeting, Virtual Scientific Program #ASCO20, May 29- 31, 2020
Clinical Trial Information: NCT03085095 - HERO: A Multinational Phase 3 Randomized, Open-label, Parallel Group Study to Evaluate the Safety and Efficacy of Relugolix in Men With Advanced Prostate Cancer