Balsam01 & others have posted on the study, but not many responded. The study is re-posted below [2]. Neal Shore was the author & he speaks in [1].
Note that Relugolix [Relumina] is an oral gonadotropin-releasing hormone (GnRH) antagonist, whereas Leuprorelin [Lupron] is a GnRH analogue acting as an agonist at pituitary GnRH receptors.
. 2020 Jun 4;382(23):2187-2196. doi: 10.1056/NEJMoa2004325. Epub 2020 May 29.
Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer
Neal D Shore 1 , Fred Saad 1 , Michael S Cookson 1 , Daniel J George 1 , Daniel R Saltzstein 1 , Ronald Tutrone 1 , Hideyuki Akaza 1 , Alberto Bossi 1 , David F van Veenhuyzen 1 , Bryan Selby 1 , Xiaolin Fan 1 , Vicky Kang 1 , Jackie Walling 1 , Bertrand Tombal 1 , HERO Study Investigators
Collaborators, Affiliations expand
PMID: 32469183 DOI: 10.1056/NEJMoa2004325
Abstract
Background: Injectable luteinizing hormone-releasing hormone agonists (e.g., leuprolide) are the standard agents for achieving androgen deprivation for prostate cancer despite the initial testosterone surge and delay in therapeutic effect. The efficacy and safety of relugolix, an oral gonadotropin-releasing hormone antagonist, as compared with those of leuprolide are not known.
Methods: In this phase 3 trial, we randomly assigned patients with advanced prostate cancer, in a 2:1 ratio, to receive relugolix (120 mg orally once daily) or leuprolide (injections every 3 months) for 48 weeks. The primary end point was sustained testosterone suppression to castrate levels (<50 ng per deciliter) through 48 weeks. Secondary end points included noninferiority with respect to the primary end point, castrate levels of testosterone on day 4, and profound castrate levels (<20 ng per deciliter) on day 15. Testosterone recovery was evaluated in a subgroup of patients.
Results: A total of 622 patients received relugolix and 308 received leuprolide. Of men who received relugolix, 96.7% (95% confidence interval [CI], 94.9 to 97.9) maintained castration through 48 weeks, as compared with 88.8% (95% CI, 84.6 to 91.8) of men receiving leuprolide. The difference of 7.9 percentage points (95% CI, 4.1 to 11.8) showed noninferiority and superiority of relugolix (P<0.001 for superiority). All other key secondary end points showed superiority of relugolix over leuprolide (P<0.001). The percentage of patients with castrate levels of testosterone on day 4 was 56.0% with relugolix and 0% with leuprolide. In the subgroup of 184 patients followed for testosterone recovery, the mean testosterone levels 90 days after treatment discontinuation were 288.4 ng per deciliter in the relugolix group and 58.6 ng per deciliter in the leuprolide group. Among all the patients, the incidence of major adverse cardiovascular events was 2.9% in the relugolix group and 6.2% in the leuprolide group (hazard ratio, 0.46; 95% CI, 0.24 to 0.88).
Conclusions: In this trial involving men with advanced prostate cancer, relugolix achieved rapid, sustained suppression of testosterone levels that was superior to that with leuprolide, with a 54% lower risk of major adverse cardiovascular events. (Funded by Myovant Sciences; HERO ClinicalTrials.gov number, NCT03085095.).
One question that arises is why Degarelix [Firmagon], another GnRH antagonist, hasn't become the standard ADT drug. It was approved in 2008 (it might become generic as early as next May):
"Unlike GnRH agonists, which cause an initial stimulation of the hypothalamic-pituitary-gonadal axis (HPGA), leading to a surge in testosterone levels, and under certain circumstances, a flare-up of the tumour, GnRH antagonists do not cause a surge in testosterone or clinical flare. Clinical flare is a phenomenon that occurs in patients with advanced disease, which can precipitate a range of clinical symptoms such as bone pain, urethral obstruction, and spinal cord compression." [1] (Wikipedia)
I have read of a number of men who started on Firmagon (for obvious reasons), but were switched to Lupron. Was that because of the convenience of a 3-monthly shot (versus monthly)? Cost? Injection site reaction?
From a recent meta-analysis [2]:
"Existing data indicate that GnRH antagonist use is associated with significantly lower overall mortality and cardiovascular events as compared with agonists."
"Patient summary: Gonadotropin-releasing hormone (GnRH) antagonist is associated with lower death rates and cardiovascular events than GnRH agonists, based on the data from trials with short follow-up duration. GnRH agonists are associated with lower adverse events, such as decreased libido, hot flushes, erectile dysfunction, back pain, weight gain, constipation, and injection site reactions. There were no significant differences in prostate-specific antigen progression or fatigue."
It seems clear that anyone with a CVD history or risk factor should seriously consider a GnRH antagonist. & given that men with PCa (even before ADT) are noted for being at increased risk for cardiovascular-related mortality, that might include a high percentage of men. But it doesn't seem to have happened.
In the new trial, men with major adverse cardiovascular events within the past 6 months were excluded. However, over 90% of patients had at least one cardiovascular risk factor. e.g. tobacco use, obesity, diabetes, hypertension or a major adverse cardiovascular event.
So in this population, one might perhaps expect a CVD event even in a short-term (48 week) trial.
For men without CVD risk (but recognizing that ADT is itself a risk factor), Lupron might be preferred because of the "lower adverse events" mentioned in [2]
Even so, the fact that Relugolix is an oral drug will be attractive to men (although not to doctors who will lose office visit revenue). And the peace of mind that Relugolix has greater castration-level efficacy. Not to mention that testosterone recovery is faster.
IMO Covid 19 changes everything. This is a threat that will not suddenly go away. Men in our age group will want to eliminate avoidable visits to doctors. The developers of oral Relugolix must be congratulating themselves.
One statistic mentioned in the full text:. Now that we have drugs like Abiraterone & Enzalutamide, men are surviving (from PCa) longer, but CVD mortality is now 27-34%. That's a chilling number (to me.) Gives one pause for thought. I want to lower PCa mortality risk AND CVD mortality risk. The case for Relugolix appears to be very strong.
" Was that because of the convenience of a 3-monthly shot (versus monthly)? Cost? Injection site reaction?" I think all three of them, but mainly injection site reactions (pain, swelling) each month. The doctor or nurse needs quite some time and experience to prepare the injection and do that properly to minimize the reaction.
I heard a discussion of urologists and one said: "I was part of the trial to get Degarelix approved but I would not use it in my practice now." The reason was the injection site reactions he observed.
So Relugolix could have more success than Degarelix.
Does the study detail what percentage of Lupron men got the full dose and what percentage got half of the normal dose?
Trial details say "Relugolix 120 mg orally once daily or leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in some Asian countries)" It mentions 138 Chinese men, so it sounds possible that at LEAST around 15% of Lupron men were only receiving the 11.25 dose every three months.
I don't know significance that has. Does anybody have a problem with this?
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Relugolix/Orgovyx with pelvic radiation?
Revised Plot of PSA vs Testosterone: Estrogen vs Lupron ADT
Overwhelming hot flashes. Orgovyx/Relugolix
Oral Relumina better that leuprolide in HERO trial 
Relugolix. Could It Be A Game-changing Drug for Advance Prostate Cancer
