ASCO 2020: Results from the HERO Phase III Trial Comparing Relugolix, an Oral GnRH Receptor Antagonist, versus Leuprolide Acetate for Advanced Prostate Cancer

( Androgen deprivation is the backbone of treatment for men with metastatic prostate cancer. The current standard of care is leuprolide or degarelix, both given as subcutaneous injections. While degarelix is only available as a one-month formulation, leuprolide is available in 1, 3, or 6-month depo injections, which offers significant convenience for patients. These injections are fairly well tolerated by patients although there may sometimes be irritation and pain at the injection site. There is evidence that ADT increases the risk of adverse cardiovascular events such as myocardial infarction, stroke, and cardiovascular mortality, possibly by exacerbating cardiovascular risk factors.1 In addition, in men with prostate cancer, Dr. Shore provides data that shows that cardiovascular disease is now the leading cause of mortality in men with prostate cancer.


This study evaluates a Relugolix, the first oral GnRH receptor antagonist in men with advanced prostate cancer.


This study included 934 patients with hormone-sensitive prostate cancer, randomized in a 2:1 ratio to receive Relugolix 120 mg daily or leuprolide 3-month depot.  The study schema is shown below. The majority of men completed treatment with about 10% in both arms terminating early.


In terms of baseline characteristics, the majority of men were White, 20% were Asian, and 5% were African American. This was an international study, with 40% of patients from Europe, 30% from North America, and about 25% from Asia.


In terms of clinical characteristics, about half the patients enrolled were being treated for biochemical relapse, 22% with newly diagnosed metastatic hormone-sensitive disease, and 27% with advanced localized disease.  In terms of notable cardiovascular risk factors, about 14% of patients in each arm had a history of a major adverse cardiovascular event (MACE), defined as a myocardial infarction, stroke, or other cerebrovascular condition. Almost all patients had some form of cardiovascular risk factor, including current or former smokers, heavy alcohol use, or BMI>30.


The primary endpoint of this study was achieving and maintaining castrate levels of testosterone at 48 weeks. 97% of patients on Relugolix and 88.8% of patients on leuprolide had sustained castration from day 29 to day 337. Relugolix very rapidly suppressed testosterone compared with leuprolide – 56% of patients had testosterone suppression by day 4 with Relugolix compared with 0% of patients on Leuprolide. 79% of patients had a confirmed PSA response at Day 29 compared with 20% of patients on leuprolide.


In terms of major adverse cardiovascular events, patients on Relugolix had a lower rate of adverse events (2.9%) compared to patients on leuprolide (6.2%). There was a 54% reduction in risk of MACE for all patients. For patients who had a history of MACE, 17% of patients on leuprolide had another MACE event compared with 3.6% of patients on relugolix (OR 5.8).


One other interesting data of note was the testosterone recovery. Patients on relugolix recovered testosterone rapidly, and mean testosterone was almost over 280 by day 60, whereas patients on Lupron continued to have castrate levels of testosterone by day 90.


Relugolix is an effective oral GnRH receptor antagonist which rapidly drops testosterone to castrate levels for the majority of patients within 1 week (56%) and almost all patients by 2 weeks (98%). The efficacy and safety Relugolix holds up well in this randomized phase III study. There is no doubt that relugolix is effective at suppressing testosterone based on this data, but I think the most exciting part of this data is the difference in MACE in patients with pre-existing MACE (17.8% with leuprolide vs 3.6% with relugolix). I think the main barrier for patients and physicians will use a pill that has to be taken every day over an injection that could be every 6 months, especially for patients who have a heavy pill burden at baseline. I think relugolix should be considered for patients with a strong history of MACE, or for patients who may be only receiving a short treatment course of ADT with radiation, as they may be able to recover testosterone faster for better quality of life.

Presented by: Neal Shore, MD, FACS, Medical Director for the Carolina Urologic Research Center, Myrtle Beach, South Carolina, USA

Written by: Jason Zhu, MD. Medical Oncologist, Division of Genitourinary Cancers, Levine Cancer Institute, Twitter: @TheRealJasonZhu, at the 2020 ASCO Annual Meeting, Virtual Scientific Program #ASCO20, May 29-31, 2020.


  1. Hu J-R, Duncan MS, Morgans AK, et al. Cardiovascular Effects of Androgen Deprivation Therapy in Prostate Cancer: Contemporary Meta-Analyses. Arteriosclerosis, thrombosis, and vascular biology 2020;40:e55-e64.
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
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