Relugolix, an oral gonadotropin-releasing hormone antagonist for the treatment of prostate cancer

2021 ◽  
Author(s):  
Daniel J George ◽  
David P Dearnaley
Keyword(s):  
Prostate Cancer ◽  
Advanced Prostate Cancer ◽  
Gnrh Antagonist ◽  
Gonadotropin Releasing Hormone ◽  
Leuprolide Acetate ◽  
Phase Iii ◽  
Major Adverse Cardiovascular Events ◽  
Gnrh Analogues ◽  
Releasing Hormone ◽  
Testosterone Levels

Androgen deprivation therapy using gonadotropin-releasing hormone (GnRH) analogues is standard treatment for intermediate and advanced prostate cancer. GnRH agonist therapy results in an initial testosterone flare, and increased metabolic and cardiovascular risks. The GnRH antagonist relugolix is able to reduce serum testosterone levels in men with prostate cancer without inducing testosterone flare. In the HERO Phase III trial, relugolix was superior to leuprolide acetate at rapidly reducing testosterone and continuously suppressing testosterone, with faster post-treatment recovery of testosterone levels. Relugolix was associated with a 54% lower incidence of major adverse cardiovascular events than leuprolide acetate. As the first oral GnRH antagonist approved for the treatment of advanced prostate cancer, relugolix offers a new treatment option.

HERO phase III trial: Results comparing relugolix, an oral GnRH receptor antagonist, versus leuprolide acetate for advanced prostate cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5602-5602 ◽  
Author(s):  
Neal D. Shore ◽  
Daniel J. George ◽  
Fred Saad ◽  
Michael Cookson ◽  
Daniel R. Saltzstein ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Receptor Antagonist ◽  
Advanced Prostate Cancer ◽  
Gnrh Receptor ◽  
Leuprolide Acetate ◽  
Phase Iii ◽  
Major Adverse Cardiovascular Events ◽  
Pivotal Phase ◽  
Phase Iii Trial ◽  
Depot Injection

5602 Background: LHRH agonists are the mainstay for medical castration in advanced prostate cancer; however, they cause an initial testosterone (T) surge with a delayed onset of castration and require depot injection. Relugolix is the first oral GnRH receptor antagonist, which was previously shown to rapidly suppress T levels. The HERO trial compared the safety and efficacy of relugolix with leuprolide acetate in advanced prostate cancer patients. Methods: HERO is a 48-week, global, pivotal phase III trial that randomized 934 patients with androgen-sensitive advanced prostate cancer in a 2:1 ratio to receive relugolix 120 mg orally QD after a single l or leuprolide acetate 3-month depot injection. The primary endpoint was to achieve and maintain serum T suppression to castrate levels (< 50 ng/dL) through 48 weeks. Key secondary endpoints included castration rates at Day 4, profound castration (< 20 ng/dL) rates at Days 4 and 15, PSA response rate at Day 15 and FSH levels at Week 25. Testosterone recovery was evaluated in a subset of 184 patients. Results: A total of 96.7% (95% CI: 94.9%, 97.9%) of men on relugolix achieved and maintained castration through 48 weeks compared to 88.8% on leuprolide. The difference of 7.9% (95% CI: 4.1%, 11.8%) demonstrated non-inferiority (margin -10%) and superiority (P < 0.0001) of relugolix to leuprolide. All key secondary efficacy endpoints tested demonstrated superiority over leuprolide (P < 0.0001) (Table). In the testosterone recovery subset, median T levels were 270.76 ng/dL in the relugolix compared to 12.26 ng/dL in the leuprolide group 90 days after discontinuation of therapy. In a prespecified analysis, the incidence of major adverse cardiovascular events (MACE) was lower in the relugolix group than in the leuprolide group (2.9% vs. 6.2%, respectively); otherwise the safety and tolerability profiles were generally similar. Conclusion: Relugolix achieved castration as early as Day 4 and demonstrated superiority over leuprolide in sustained T suppression through 48 weeks, faster T recovery after discontinuation and a 50% reduction in MACE. Relugolix has the potential to become a new standard for T suppression for patients with advanced prostate cancer. Clinical trial information: NCT03085095 . [Table: see text]

scholarly journals Relugolix: a novel androgen deprivation therapy for management of patients with advanced prostate cancer

2021 ◽  
Vol 13 ◽  
pp. 175883592199858
Author(s):  
Fred Saad ◽  
Neal D. Shore
Keyword(s):  
Prostate Cancer ◽  
Androgen Deprivation Therapy ◽  
Advanced Prostate Cancer ◽  
Gnrh Antagonist ◽  
Androgen Deprivation ◽  
Phase Iii ◽  
Intermittent Therapy ◽  
Gnrh Antagonists ◽  
Releasing Hormone ◽  
Lhrh Agonists

Androgen deprivation therapy (ADT) is the foundation of treatment for patients with locally advanced, recurrent and metastatic prostate cancer, most commonly using luteinizing releasing hormone (LHRH) agonists. More recently, a new approach to ADT has emerged with the development of gonadotropin-releasing hormone (GnRH) antagonists, which aim to overcome some of the potential adverse physiologic effects of LHRH agonists. This article focuses on the newest GnRH antagonist, relugolix – a once-daily treatment and the only oral GnRH antagonist that has now been approved for the treatment of advanced prostate cancer. In phase II and III studies, relugolix achieved rapid and sustained castration without the testosterone surge associated with LHRH agonists, thus avoiding the potential clinical consequences of tumor flare and the necessity for concomitant anti-androgen therapy. Relugolix also achieved rapid testosterone recovery, which may potentially reduce ADT-related adverse events and offer opportunities for combination and intermittent therapy strategies. Cardiovascular safety is a particular concern in men with prostate cancer and ADT further increases cardiovascular risk: indeed, LHRH agonists are required to have a drug label warning about an increased risk of cardiovascular disease. Data from the phase III HERO study demonstrate an improved cardiac safety profile for the GnRH antagonist relugolix compared with the LHRH agonist leuprolide, including a significantly reduced risk for a major adverse cardiovascular event. Taken together, the data indicate that relugolix may mitigate some of the cardiovascular concerns surrounding ADT and has the potential to become a new standard of care for men with prostate cancer. In summary, relugolix represents a novel and recently available prostate cancer management strategy, incorporating the mechanistic advantages of GnRH antagonists and the potential benefits of oral administration.

Effect of docetaxel chemotherapy on the activity of a gonadotropin releasing hormone vaccine in patients with advanced prostate cancer

The Prostate ◽  
2005 ◽  
Vol 65 (4) ◽  
pp. 316-321
Author(s):  
Pierre L. Triozzi ◽  
Graeme B. Bolger ◽  
Jeffrey Neidhart ◽  
John J. Rinehart ◽  
Mansoor Saleh ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Advanced Prostate Cancer ◽  
Gonadotropin Releasing Hormone ◽  
Releasing Hormone ◽  
Docetaxel Chemotherapy

Correction

1992 ◽  
Vol 30 (23) ◽  
pp. 92-92
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Advanced Breast Cancer ◽  
Advanced Prostate Cancer ◽  
Serum Testosterone ◽  
Gnrh Analogue ◽  
Releasing Hormone ◽  
Testosterone Levels ◽  
Menopausal Women ◽  
Gonadotrophin Releasing Hormone

In our article Gonadotrophin releasing hormone analogues for advanced prostate cancer (17 August, page 65) we warned that testosterone levels might rebound above normal if a dose of a depot preparation of a GnRH analogue missed. In fact if the dose is delayed by 2 weeks, serum testosterone concentrations may rise above the castration range in about 30% of patients but do not rise above normal.1 In the Practice Synopsis included in the article we mentioned that goserelin (Zoladex) was licensed for advanced prostate cancer and endometriosis but omitted to mention that it was also licensed for advanced breast cancer in pre- and peri-menopausal women.

Impact of concomitant prostate cancer therapy on efficacy and safety of relugolix versus leuprolide in men with advanced prostate cancer: Subgroup analysis from the phase III HERO study.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 106-106
Author(s):  
Daniel J. George ◽  
Neal D. Shore ◽  
Fred Saad ◽  
Michael Cookson ◽  
Daniel Saltzstein ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Sensitivity Analysis ◽  
Primary Endpoint ◽  
Subgroup Analysis ◽  
Advanced Prostate Cancer ◽  
Phase Iii ◽  
Efficacy And Safety ◽  
Concomitant Therapy ◽  
Testosterone Levels ◽  
The Impact

106 Background: In the phase 3 HERO study, the oral GnRH receptor antagonist, relugolix, demonstrated suppression of testosterone to castrate levels in 96.7% of patients, which was superior to leuprolide, and a 54% lower risk of major adverse cardiovascular events relative to leuprolide. To characterize the impact of concomitant prostate cancer treatments with the use of relugolix in advanced prostate cancer from the HERO study, a subgroup analysis for patients receiving various therapies was undertaken. Methods: The HERO study was designed to evaluate relugolix in men with advanced prostate cancer. Overall, 934 patients were randomized 2:1 to receive relugolix 120 mg orally once daily or leuprolide injections every 12 weeks for 48 weeks. In the setting of rising PSA, patients could receive enzalutamide (ENZ) or docetaxel (DOC) 2 months after study initiation. Assessments included sustained testosterone suppression to castrate levels (<50 ng/dL) through 48 weeks and safety parameters. Subgroups analyzed included patients with or without concomitant ENZ, DOC, and any radiation therapy (RT). A sensitivity analysis of the primary endpoint was performed excluding patients who received concomitant therapies that may affect testosterone. Results: Overall, 125 patients (13.4%) took at least one concomitant therapy that could impact testosterone levels. RT was received by 15.9% and 18.8% of patients in the relugolix and leuprolide groups, respectively. ENZ was the most frequently used therapy in the relugolix group (2.7%), with similar use in the leuprolide group (1.9%). DOC was used by 1.3% and 1.6% of patients in the relugolix and leuprolide groups, respectively. All other relevant concomitant therapy were used in <1% of population. The sensitivity analysis results indicated that use of these concomitant therapy that could affect testosterone levels did not impact the primary endpoint. Castration rates were similar with and without concomitant use of ENZ and DOC, or RT (table). No clinically relevant differences in adverse events were observed between patients with or without concomitant use of ENZ, DOC, or RT in either treatment group. Conclusions: While the numbers are small, treatment with relugolix was associated with a similar efficacy and safety profiles in patients who received concomitant administration of ENZ, DOC, or RT to that observed in patients not receiving those concomitant treatments. Clinical trial information: NCT03085095. [Table: see text]

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