Tom Keane: Hello, everybody. This is Tom Keane coming to you from Charleston, South Carolina, and the Medical University of South Carolina. But today I'm going to talk about a paper that was recently published in European Urology. It's entitled, "The Oral Gonadotropin-releasing Hormone Receptor Antagonist Relugolix as Neoadjuvant or Adjuvant Androgen Deprivation Therapy to External Beam Radiotherapy in Patients with Localized Intermediate-risk Prostate Cancer". This is a randomized, open-label, parallel-group, Phase II trial. Now the background to this is that there has up till now only been one LHRH agonist or antagonist, I should say. Relugolix represents the second such agent to have been developed. Degarelix was the original, which the one that got approval in 2008. Before that, in the early 2000s, there was abarelix.

Now, this is, as I mentioned, a Phase II trial and on the background, external beam radiotherapy with neoadjuvant or adjuvant androgen deprivation therapy is an established treatment option to prolong survival for patients with intermediate and high-risk prostate cancer. However, most of these trials have been done with an LHRH agonist. Relugolix is an oral gonadotropin-releasing hormone, receptor antagonist, and was evaluated in this clinical setting in comparison with degarelix, which is an injectable GnRH antagonist. So, both these drugs have the same mechanism of action, but one is an oral formulation, the other is a subcutaneous injection formulation. The objective was to evaluate the safety and efficacy of relugolix to achieve and maintain castration. Now, the design was a Phase II open-label study which was conducted in 103 intermediate-risk prostate cancer patients who were undergoing primary external beam radiation therapy and neoadjuvant or adjuvant androgen deprivation therapy. The trial was conducted between the time of June 2014 and December 2015. Patients were randomly assigned on a three to two basis to 24-week treatment with either daily oral relugolix or four weeks subcutaneous depot degarelix, which was the reference control.

The outcome measurements and the statistical analysis were as follows. The primary endpoint was the rate of effect of castration, which was defined in European terms as 1.73 nanograms per mole per liter. And in the US we would call this 50 nanograms per deciliter. And that was used in both the relugolix patients between four and 24 weeks of treatment and also in the degarelix treatment. The secondary endpoints included the rate of profound castration, which in Europe is less than 0.7 nanomoles per liter, and in the US it's a testosterone level of 20 or less. PSA levels were also monitored. Prostate volume, quality of life was assessed using two different tools. The first was the EORTC Aging Males' Symptoms scale and also there was an EORTC prostate cancer module which was a 25 item module. No formal statistical comparisons with degarelix were planned.

So castration rates during treatment were 95 and 82% with relugolix and 89 and 68% with degarelix. That's looking at the castration achieved level and the profound castration level achieved. The median time to castration in the relugolix arm was four days. The median time for castration with degarelix is generally two to three days. During treatment, PSA levels and prostate volumes were reduced in both groups. Three months after discontinuing treatment, 52% of men on relugolix and 16% on degarelix experienced testosterone recovery. The statistical significance of the differences were not tested. The mean and median quality of life scores improved following treatment discontinuation, which is what we would expect to see. The most common adverse event was hot flashes at relugolix at 57%, degarelix at 61%.

Lack of blinding is a potential limitation of this study. But the conclusions were that relugolix achieve testosterone suppression to castrate level left within days and maintained at over the 24-week period with a safety profile which is consistent with its mechanism of action. The patient's summary was that oral once-daily relugolix may be a novel oral alternative to injectable androgen deprivation therapy.

Now there's a couple of points about this paper. Again, it is not disturbing but it's frustrating to see that we are still using the 50 nanograms per deciliter are in Europe, the 1.73 nanomoles per liter level as a level of castration. If we look at the guidelines, the idea of testosterone levels to be achieved during androgen deprivation therapy in 2012 that passed the US consensus, recommended a level of 29 milligrams per deciliter for serum testosterone during ADT in patients with advanced prostate cancer as levels between 20 to 50 have had a poor clinical outcome. EAU guidelines define testosterone during ADT as reaching less than 20 nanograms per deciliter or the equivalent European value.

In 2018, the Canadian Urological Association consensus recommended the adoption of a value of 20 or less as the castrate level to be achieved, and regular monitoring of testosterone and PSA levels should be undertaken every three to six months during ADT. However, European Union Regulatory Authorities and the FDA continue to define castrate levels for testosterone at 50 nanograms per deciliter. Again, there is good data both in non-randomized trials and in the Canadian data, which was a randomized trial, that getting down to a level of 20 is significantly better than reaching a level of 50. And this paper is very interesting because for the first time, it gives us an alternative to the injectable form of an LHRH antagonist.

Having an oral form may have its benefits, may also have its drawbacks, but it's a very interesting study. It certainly, there is a Phase III study called the HERO trial, which has been presented but as that data is currently at the FDA, I think you should watch this space clearly. I do think that there will hopefully be an option between the injectable form as compared to the oral form, and we will await the results of the Phase III trials once they're published and we will be happy to bring them to you on UroToday.

This is Tom Keane signing off. Stay safe and I look forward to coming to you again. Thank you.