Current and emerging gonadotropin-releasing hormone (GnRH) antagonists for the treatment of prostate cancer

ABSTRACT

Introduction:Androgen deprivation therapy (ADT) is currently the backbone treatment of metastatic prostate cancer and is also used in combination with external beam radiotherapy (EBRT). Castration may be achieved either by bilateral orchiectomy or by administration of LHRH agonists or GnRH antagonists.

Areas covered: In this article, the authors assess the current and emerging role of GnRH antagonists for the treatment of prostate cancer focusing on oncological results and safety (i.e. cardiovascular risk). In addition, updated data regarding the first orally administered GnRH antagonist, relugolix, is presented.

Expert opinion: Studies demonstrate that GnRH antagonists are at least equal with LHRH agonists in terms of testosterone suppression and PSA progression free survival with a major advantage being rapid testosterone suppression. Thus, the optimal group of patients included symptomatic metastatic prostate cancer patients especially if cardiovascular comorbidities or LUTS are also present. Emerging data regarding benefit of the use of GnRH antagonists in patients with concomitant cardiovascular disease are of great interest. Relugolix has emerged as the first orally administered GnRH antagonist able to achieve and maintain testosterone castration levels and it is associated with a profound reduction of major cardiovascular events.

KEYWORDS:

• Prostate cancer
• GnRH antagonist
• lhrh agonist
• abarelix
• degarelix
• relugolix

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One reviewer is a shareholder of Myovant Sciences who manufacture relugolix and an advisor to them on a periodic basis. Furthermore, they previously acted as an industry developer of abarelix; both compounds are mentioned in the article. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Article highlights

• ADT is the cornerstone metastatic prostate cancer treatment and is the backbone therapy in castration resistant prostate cancer regardless the presence of metastatis.

• LHRH agonists are most widely used in order to achieve testosterone suppression but are associated with potentially suboptimal testosterone control as well as flare effects.

• GnRH antagonists suppress testosterone to castration levels more rapid than LHRH agonists with the benefit of avoiding flare phenomenon, thus co-administration of antiandrogens is not required.

• Degarelix is the most widely used GnRH antagonist as abarelix use was halted due to histamine mediated reactions. Relugolix is the first orally administered FDA approved GnRH antagonist but clinical experience is at the present time limited.

• The optimal group of patients suitable for treatment with GnRH antagonists are patients with symptomatic metastatic prostate cancer or any advanced/metastatic prostate cancer patients with concomitant cardiovascular comorbidities.

Additional information

Funding

This manuscript was not funded.