Gonadotropin-Releasing Hormone Antagonists in Prostate Cancer

Androgen deprivation therapy (ADT) comes in several forms, such as surgical castration or medical castration using gonadotropin-releasing hormone (GnRH) agonist or GnRH antagonist therapy. ADT is a critical treatment for high-risk and metastatic prostate cancer. There are important differences between GnRH agonists and antagonists. Here we review the mechanism of action between GnRH agonists and antagonists and the studies that led to the approval of degarelix. We also comment on the potential risks and benefits of degarelix, particularly when it comes to cardiovascular health. Finally, we describe an oral GnRH antagonist, which is not currently used in prostate cancer, but is included for completeness.

Introduction

Prostate cancer is the third leading cause of cancer death in the United States and accounts for one-fifth of new cancer diagnoses.[1] Androgen deprivation therapy (ADT) is the backbone of treatment for patients with advanced prostate cancer, and it is indicated for use in multiple clinical settings of prostate cancer. Chemical castration consists of gonadotropin-releasing hormone (GnRH) agonists and antagonists administered intramuscularly, subcutaneously, or orally. Notably, the GnRH is sometimes called luteinizing hormone-releasing hormone (LHRH). A commonly used ADT is leuprolide acetate, a GnRH agonist that was approved for the treatment of advanced prostate cancer in 1985.[2] Goserelin, another GnRH agonist, was approved in 1996. One of the main concerns when using GnRH agonists is a surge in testosterone caused by the medication’s initial effect on the pituitary gland. This testosterone surge could lead to a tumor flare, a rapid expansion of the prostate cancer, leading to pain and potential debilitation in patients specifically with spinal metastases. This phenomenon has led prostate cancer experts to mandate the use of an anti-androgen, ie, bicalutamide, concurrently during the first month of treatment with a GnRH agonist, since anti-androgens have been found to abrogate the testosterone surge. This concern of tumor flare led to the development of the GnRH antagonists, which do not cause a testosterone surge, since there is no initial stimulation of the pituitary gland by the medication. The GnRH antagonist degarelix is currently approved by the US Food and Drug Administration (FDA) for the treatment of patients with advanced prostate cancer.[3] Abarelix, another GnRH antagonist, showed clinical promise, but was taken off the market due to adverse events. Relugolix is an oral GnRH antagonist that is currently being developed for the treatment of prostate cancer in clinical trials. Herein, we review degarelix and relugolix and their efficacy and safety in the treatment of prostate cancer.

Mechanism of Action

Degarelix and abarelix are both injectable GnRH antagonists and relugolix is taken orally. They all bind to the GnRH receptor on the anterior pituitary. They are analogs of GnRH, and act as a competitive inhibitor of GnRH.[4] GnRH mediates stimulation of gonadotropin (ie, follicle-stimulating hormone [FSH] and luteinizing hormone [LH]) secretion. Unlike GnRH agonists, the GnRH antagonists do not cause an initial surge of gonadotropins. They rapidly decrease the secretion of LH and FSH from the pituitary, thereby leading to an immediate decrease in testosterone secretion from the Leydig cells of the testicles.[5-7]

The FDA has approved degarelix given subcutaneously as a 240-mg initial dose, followed by 80 mg injected every 28 days. It has a half-life of 43 days for the starting dose, and 28 days for the maintenance dose.

Degarelix: Efficacy

The pivotal trial that ultimately led to the approval of degarelix was published by Klotz et al in 2008. This trial, herein referred to as “CS21,” was a phase III randomized non-inferiority trial comparing standard-of-care leuprolide acetate vs degarelix. Patients with all stages of prostate cancer were randomized in a 1:1:1 fashion to receive degarelix 240 mg, followed by monthly maintenance dosing of 80 mg or 160 mg, or to receive leuprolide acetate 7.5 mg per month. The primary endpoint was defined as suppression of testosterone level to < 50 ng/dL between 28 and 364 days, which was achieved in > 96% of patients in all groups. As a secondary endpoint, the clinical trial also showed that degarelix was superior to leuprolide at decreasing testosterone levels to < 50 ng/dL within 3 days of initial treatment in > 90% of patients. Injection site reactions were more common in the group that received degarelix, but urinary tract infections were decreased in the degarelix arm; rates of all other adverse events were not significantly different. Interestingly, 22 of 202 patients (11%) receiving leuprolide acetate also received bicalutamide during the initial administration for tumor flare protection. In a subgroup analysis, the patients who had concomitant bicalutamide with leuprolide had rapid reductions in their prostate-specific antigen (PSA) level, similar to those patients receiving degarelix.[8] As the primary endpoint of non-inferiority was met, this clinical trial ultimately led to the approval of degarelix, at a dose of 240 mg/80 mg, for the treatment of patients with prostate cancer as an alternative to leuprolide acetate.

CS21 led to further subset analyses, each attempting to evaluate the efficacy of degarelix when compared with leuprolide acetate. Based on these analyses, it appears that degarelix is superior to leuprolide in PSA recurrence or death at 1 year, is faster at decreasing testosterone to castrate levels, and is more effective at decreasing alkaline phosphatase in those patients with metastatic disease to the bone.[9-11] Only PSA progression–free survival was a preplanned analysis. One such subset analysis attempted to study the concept of a “testosterone microsurge,” a testosterone surge occurring after prolonged GnRH agonist therapy. They examined testosterone levels on day 252, day 255, and day 259, attempting to see if there was a rise in testosterone after having been on treatment for 252 days. They found that after receiving the ninth dose of leuprolide acetate or degarelix on day 252 that there was an increase in testosterone for patients receiving leuprolide acetate (P < .001). An increase in mean change in testosterone of 0.018, 0.040, and 0.054 ng/mL was seen for baseline testosterone levels of < 3.5, 3.5–5.0, and > 5.0 ng/mL, respectively, in those patients receiving leuprolide, whereas for degarelix the mean change was negative.[10] This suggests that even after the first month of therapy, a testosterone surge occurs upon subsequent dosing of leuprolide acetate. However, it is not known if this increase is clinically significant.

Safety, tolerability, and long-term efficacy were explored in an extension trial that continued with the same patient population as CS21. Patients who completed 1 year of therapy on CS21 were either continued on degarelix at the same maintenance dose they were randomized to, or if they were on leuprolide acetate, they were randomized to receive degarelix at a dose of 240 mg followed by either 160-mg or 80-mg maintenance for a total of 5 years. After a median follow-up of 27.5 months, the patients who had switched from leuprolide acetate to degarelix had a statistically significant decrease in the rate of PSA progression–free survival at year 1 compared with every year thereafter. Incidence of treatment-related adverse events were similar in the 3 groups.[12] At the 5-year analysis of the trial, the most common adverse event was once again injection site reactions at the initial injection vs subsequent injections (31% and 2.5%, respectively). Forty-two percent of patients completed the 5-year study; discontinuations were not thought to be related to study treatment, but the authors did not elaborate.[13]

Degarelix: Lower Urinary Tract Symptoms and the International Prostate Symptom Score

The clinically meaningful outcome of lower urinary tract symptoms (LUTS) was first evaluated in a randomized trial comparing degarelix vs goserelin plus bicalutamide in patients receiving ADT, with an endpoint of total prostate volume (TPV) reduction. They randomized 182 patients in a 1:1 fashion to degarelix vs goserelin for 12 weeks. Patients who received goserelin also received bicalutamide for the first 28 days to prevent a testosterone flare. They found that degarelix was non-inferior to goserelin plus bicalutamide for decreasing TPV (−37.2% vs −39.0%). They also found that patients receiving degarelix had more relief of their LUTS, as defined by the International Prostate Symptom Score (IPSS). There was also a trend towards improved quality of life for those patients receiving degarelix, but this trend was not significant.[14]

TPV was studied in the neoadjuvant setting as well, and degarelix was found to be non-inferior to goserelin plus bicalutamide in decreasing TPV prior to radical radiotherapy for localized disease. It is important to note that neoadjuvant ADT is not standard of care. In this study, degarelix was again found to be more efficacious at decreasing IPSS scores. Furthermore, this is one of the only clinical trials to prospectively evaluate the efficacy of a GnRH antagonist vs a GnRH agonist plus an anti-androgen in terms of lowering testosterone levels. Although this wasn’t a prespecified endpoint, the researchers noted there was no difference in median levels of testosterone at weeks 4, 8, and 12 in both groups.[15] Combining three phase III randomized trials,[14-16] a pooled analysis published in 2015 showed that degarelix was significantly better at decreasing IPSS scores when compared with goserelin at 12 weeks. Once again, no difference was seen in TPV reduction or urinary tract infection–related adverse events.[17]

Degarelix: Pooled and Meta-Analyses

Two large hypothesis-generating meta- and pooled analyses have since been performed. One pooled analysis looked at five phase III clinical trials comparing degarelix vs leuprolide acetate or goserelin after 3 or 12 months of treatment. From the 1,925 patients analyzed, the researchers reported that patients treated with degarelix had a statistically significant improvement in PSA progression–free survival at 1 year, overall survival (OS), joint-related symptoms, urinary tract infection events at 12 months, and musculoskeletal events at 12 months. It is thought that the difference in OS may have been driven by cardiovascular disease (CVD), since 51% of the 37 deaths occurred in the 29% of patients with baseline CVD. Patients with baseline CVD had a trend towards a decrease in death when treated with degarelix. One interesting correlation that was observed was that death at 1 year was predicted by testosterone level > 2 ng/mL and age > 70, and not disease stage or PSA level.[18]

Hosseini et al performed a systematic review and meta-analysis comparing six randomized controlled trials evaluating degarelix vs GnRH agonists. A total of 2,296 patients were evaluated. They discovered that there was a statistically significant difference between the groups, with the patients treated with degarelix demonstrating increased injection site reactions, decreased general mortality rate, IPSS reduction at week 12, and testosterone level reduction from days 1–28. Testosterone reduction after 28 days and TPV reduction did not have a statistically different result, but favored degarelix usage. The authors concluded that although testosterone and PSA levels were both reduced to a greater extent in the first 28 days of treatment with degarelix vs a GnRH agonist, ultimately after this time period these numbers were not significant.[19]

Degarelix: Recent Advances

One of the biggest barriers to the use of degarelix is inconvenience, since it must be given every 4 weeks. Leuprolide can be given every 1–6 months. In a recently published phase II study, researchers presented data to support a depot version of degarelix given at 3-month intervals. In 155 patients for whom ADT was indicated, degarelix depot was given at an initial dose of 240 mg, and then every 3 months at a dose of 360 mg or 480 mg for 12 months, with a primary endpoint of cumulative testosterone castration from days 28–364. The 480-mg dosage was found to be superior to the 360-mg dose, with a cumulative suppression of testosterone of 97.2% vs 88.3%. Fifty percent of patients in the 360-mg group and 60% of patients in the 480-mg group had injection site reactions, but no one discontinued treatment because of this. Thus, the 480-mg dose was chosen as the dose to continue on to phase III trials.[20]

Degarelix and Cardiovascular Risk

There is controversy surrounding whether ADT in and of itself is an independent risk factor for CVD. The leading hypothesis is that ADT causes a distinct metabolic syndrome, caused by low testosterone levels and highlighted by increased insulin resistance, body weight, and dyslipidemia, leading to an increase in cardiovascular deaths.[22,23] There are large studies that both support and weaken this theory. However, it must be noted that CVD is the most common cause of death in men with early-stage prostate cancer, and thus this theory needs to be clarified more extensively.[24,25] Furthermore, there is a retrospective analysis that suggests that this risk may be confined to patients with pre-existing CVD.[26] This controversy ultimately led the FDA, along with the American Heart Association, the American Cancer Society, the American Urological Association, and the American Society for Radiation Oncology, to issue warnings about the potential risk of increased cardiovascular events for patients receiving ADT.[22]

As the efficacy of GnRH antagonists was being elucidated, interest rose around the idea that GnRH antagonists could lead to fewer cardiovascular events than GnRH agonists. In 2010 and 2011, two articles were published addressing this hypothesis. They first analyzed the CS21 trial, focusing on the effect of degarelix vs leuprolide acetate on QT intervals and serious adverse events suggesting arrhythmia. They found no significant increase in QT interval for either treatment arm, nor did they find a significant difference in the change of QT measurements between the two groups. Furthermore, they found no significant difference in rates of new ischemic heart disease or arrhythmia between the two groups. They concluded that the cardiovascular safety profile was similar for both degarelix and leuprolide acetate. Interestingly, ischemic heart disease was lower in patients receiving the FDA-approved dose of degarelix compared with those patients receiving leuprolide acetate (8% vs 21%).[27]

Oliver Sartor, MD

GnRH Antagonists, GnRH Agonists, or None of the Above?

Gonadotropin-releasing hormone (GnRH) antagonists in prostate cancer treatment were initially considered to be a substantial advance because there is no initial surge of gonadotropin; testosterone falls rapidly to castrate levels, and no testosterone “flare” is detected. At the time that GnRH antagonists were conceived, most patients had marked metastasis, and advanced disease was rampant. Today, most patients treated with GnRH analogs have much lower-volume disease and may not have metastases at all. Consequently, the implications of testosterone flare are much less significant in today’s patient.

Pooled analyses have suggested a lower risk of cardiovascular disease for patients treated with GnRH antagonists; however, prospective randomized trials have yet to be concluded. GnRH antagonists are more expensive and must be given more frequently than GnRH agonists. As such, in my mind, there should be clear evidence supporting their use. Currently, that clear evidence is lacking.

Prospective randomized trials should demonstrate unequivocal improvement in outcomes in order to justify their expense and inconvenience. Assuming that cost will be higher than conventional alternatives, oral GnRH antagonists should be held to the same standard; higher cost and greater effectiveness should go hand in hand.

Ultimately, men will prefer to avoid castration. The side effects of castration are similar for GnRH antagonists and agonists. Researchers need to continue the search for non-castrating alternatives in order for real advances to occur. Can prostate-specific membrane antigen–
targeted radiopharmaceuticals serve that purpose?

Financial Disclosure: Dr. Sartor has served an advisory role for Advanced Accelerator Applications, Astellas, Bavarian-Nordic, Bellicum, Blue Earth Diagnostics, Inc, Celgene, EMD Serono, Myovant, Pfizer, and Teva. He has been both consultant for, and a grant/research support recipient of, AstraZeneca, Bayer, BMS, Constellation, Dendreon, Endocyte Innocrin, Invitae, Johnson & Johnson, Merck, Progenics, Sanofi, and SOTIO. He has provided expert testimony for Sanofi.

Dr. Sartor is C.E. & Bernadine Laborde Professor of Cancer Research and Medical Director of Tulane Cancer Center, and Assistant Dean for Oncology at Tulane Medical School in New Orleans, Louisiana.

A larger analysis of nine clinical trials was then performed, examining changes in cardiovascular events before and after patients received degarelix, with a focus on delineating effect of pre-existing CVD. For all patients, they found that CVD events were no different before and after degarelix treatment. However, they did note two interesting findings. For men with no CVD history, cardiovascular events decreased when started on degarelix, though these results were not statistically significant. In comparison, for men with pre-existing CVD at baseline, cardiovascular events increased after degarelix was given, from 5.3 to 10.5 events per 100 person-years, respectively (P = .0013).[28] Although both of these articles are retrospective analyses, they suggest that, like GnRH agonists, GnRH antagonists might cause an increase in cardiovascular events in patients with CVD history, and that GnRH antagonists may be safer than GnRH agonists when it comes to cardiovascular events in those without a cardiac history.

It is unclear why GnRH antagonists may lead to a decrease in cardiovascular events as opposed to agonists. One theory is that GnRH receptors are located on T cells and may increase T-cell activation and differentiation into the T helper 1 phenotype, destabilizing atherosclerotic plaques.[29-31] Also, FSH may play a role in endothelial cell function, and the GnRH antagonists’ ability to decrease both LH and FSH may be favorable in the setting of CVD.[32,33] Regardless of the reason, it is not entirely clear if GnRH antagonists should be used in lieu of GnRH agonists in the setting of CVD, and more research is needed to help clarify these hypotheses.

Degarelix: Criticisms, and Cost

While degarelix is currently approved for the treatment of advanced prostate cancer, its niche is still not well defined, even after an abundance of clinical evidence of efficacy. Furthermore, clinicians have an alternative to degarelix in leuprolide, which is superior in its ease of injections (ie, there is a 6-month formulation of leuprolide), as well as fewer injection site reactions. Aside from an improvement in LUTS, a clinically meaningful outcome that proves the greater efficacy of degarelix compared with GnRH agonists is yet to be proven. There have been some hints at benefit in terms of improved OS at 1 year and improved PSA progression–free survival, but these outcomes have not been shown in a randomized phase III clinical trial. Furthermore, it has been argued that the clinical trials that have been done with degarelix are fraught with bias. The pivotal trial CS21 that led to the approval of degarelix did not have a great comparator arm. Only 11% of patients received an anti-androgen along with leuprolide acetate. Moreover, there was large patient heterogeneity in CS21. Clinical stage ranged from localized disease with PSA recurrence to metastatic disease. These biases extend through every subsequent subset, pooled, and meta-analysis on the efficacy of degarelix.[34]

There have been some endpoints that have shown clear benefit from the use of degarelix. The clinical trials that evaluated TPV clearly show a benefit in favor of degarelix at improving IPSS scores at 4, 6, and 12 weeks, as opposed to GnRH agonists. This clinically makes sense, in that degarelix has been shown to decrease testosterone levels with greater rapidity, and efficacy in the first 28 days, than GnRH agonists. This clinical effect could be translated to use in the setting of vertebral metastatic disease. The avoidance of a testosterone flare is of utmost importance in this particular setting where cord compression is possible. A related endpoint, decreasing testosterone microsurges, has frequently been evaluated. Some authors have suggested that increases in testosterone from a nadir to > 50 ng/dL might be clinically relevant.[35] The clinical implications of testosterone breakthroughs with GnRH agonists were investigated in a study of patients with nonmetastatic prostate cancer that looked at androgen-independent progression. Patients with testosterone increases > 0.32 ng/mL had significantly shorter survival free of androgen-independent progression compared with those without these events.[36] However, when anti-androgens were used to abrogate testosterone flare, correlations to a clinical outcome (ie, spinal cord compression, fractures, bladder outlet obstruction) were not significant.[37]

One factor to consider is the cost of GnRH agonists. Per Lexicomp, the 3-month formulation of leuprolide acetate 22.5 mg is $5,252.86, calculating to a yearly cost of $21,011.44. Degarelix 120 mg costs $914.51, and $586.14 for the 80-mg dose, calculating to a yearly cost of $8,276.54. In 2016, a summary of the ERG report determined that the incremental cost-effectiveness for degarelix compared with triptorelin (every 3 months), goserelin (every 3 months), and leuprorelin (monthly) was at least 35,600, 28,000, and 26,200 pounds, respectively, per quality-adjusted life-year gained. Ultimately, the National Institute for Health and Care Excellence recommended the use of degarelix as an option for treating advanced hormone-dependent prostate cancer in patients with spinal metastases.[38]

Relugolix: An Orally Available GnRH Antagonist

The oral GnRH antagonist relugolix, also known as TAK-385, is currently being evaluated as a potential treatment for prostate cancer. The benefits of an oral GnRH antagonist include avoiding injection site reactions and the ability to stop the medication at any time, since it is not formulated for sustained release. In a phase II trial, relugolix was compared with degarelix in patients with localized prostate cancer. The primary outcome measure was the percentage of participants with an effective castration rate over 25 weeks. Ninety-five percent of patients receiving relugolix, and 89% of patients receiving degarelix remained castrate over 25 weeks.[39] Additionally, relugolix was directly compared with leuprorelin in another phase II trial. Thirty-nine patients received relugolix 80 mg once daily, 36 patients received relugolix 120 mg once daily, and 20 patients received 22.5-mg leuprorelin subcutaneously every 12 weeks. Ninety-two percent of patients on relugolix and 95% of patients on leuprorelin achieved the primary outcome of sustained testosterone < 50 ng/dL from weeks 5–24. Adverse events were comparable.[40] Currently, there is an active phase III clinical trial (NCT03085095) comparing relugolix 120 mg daily vs leuprolide acetate 22.5 mg every 3 months for 48 weeks in patients with castration-sensitive advanced prostate cancer. The primary outcome measure for the study is a sustained castration rate.

Although relugolix has yet to be approved by the FDA, one concern regarding an oral GnRH antagonist is compliance. Patient compliance on an oral medication has been estimated to be 79%.[41] The half-life of relugolix is 36–65 hours, allowing for patients to miss a dose; however, the ease of use of a depot formulation of degarelix may be a better option.[42] If relugolix is approved, cost, compliance, and side effect profile will have to be evaluated to determine its utility in the clinical setting.

GnRH Antagonists: Treatment Recommendations and Conclusions

Based on the data we have discussed, we cannot say that degarelix is superior or inferior to GnRH agonists when it comes to prostate cancer outcomes, such as PSA response and OS. However, we would favor using degarelix over leuprolide in patients with spinal metastases to avoid the risk of cord compression. The cost differential is significant in favor of degarelix, but this may be outweighed by the injection site reactions associated with degarelix, which would occur on a monthly basis. Finally, whether degarelix is safer for patients with cardiovascular disease is unclear, but there is potential that this may be the case.

In summary, degarelix appears to be a reasonable alternative to GnRH agonists in the treatment of advanced prostate cancer. Whether degarelix will eventually be approved for an alternative indication or if it is found to be superior in efficacy to GnRH agonists remains to be seen. Having an orally available option in relugolix may serve an important role in the treatment of prostate cancer in the future. More research is needed to determine what the exact role of the GnRH antagonists are in the treatment of prostate cancer.

Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

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