What is Relugolux?

What is Relugolix?

Relugolix is an oral gonadotropin-releasing hormone (GnRH) receptor antagonist approved for treating advanced prostate cancer in men and, when combined with estradiol and norethindrone acetate (relugolix combination therapy), for managing heavy menstrual bleeding associated with uterine fibroids and moderate to severe pain associated with endometriosis in women. 1, 2

Mechanism of Action

• Relugolix competitively binds to GnRH receptors in the pituitary gland, preventing the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) into systemic circulation 1
• In men, this suppresses testosterone production to castration levels, which is therapeutic for advanced prostate cancer 2
• In women, the reduction in FSH prevents follicular development and suppresses ovarian estrogen production, while LH suppression prevents ovulation and progesterone production 1

Approved Indications and Formulations

For Men (Relugolix Monotherapy)

• Relugolix 120 mg (ORGOVYX) is approved in the United States, European Union, and United Kingdom for advanced prostate cancer as the first oral androgen-deprivation therapy 1
• The dosing regimen consists of a single 360 mg loading dose followed by 120 mg orally once daily 3
• In Japan, relugolix 40 mg monotherapy (RELUMINA) was the first GnRH receptor antagonist approved for uterine fibroids and endometriosis-associated pain 1, 4

For Women (Relugolix Combination Therapy)

• Relugolix 40 mg combined with estradiol 1 mg and norethindrone acetate 0.5 mg as a single fixed-dose combination tablet is approved for women's health indications 1
• In the United States, this combination (MYFEMBREE) is indicated for managing heavy menstrual bleeding associated with uterine fibroids and moderate to severe pain associated with endometriosis 1
• In the European Union and United Kingdom, this combination (RYEQO) is approved for managing symptoms associated with uterine fibroids 1
• The hormone add-back therapy (estradiol and norethindrone acetate) mitigates hypoestrogenic side effects including bone mineral density loss and vasomotor symptoms, enabling longer-term treatment 5, 1

Clinical Efficacy

In Prostate Cancer

• Relugolix achieves rapid suppression of testosterone to sustained castration levels (below 50 ng/dL) 3, 6
• In the phase III HERO trial, relugolix demonstrated superior cardiovascular safety compared to leuprolide (a GnRH agonist) 2
• Castration resistance-free survival at 48 weeks was similar between relugolix (74.3%) and leuprolide (75.3%) in men with metastatic disease 3
• Relugolix allows for rapid testosterone recovery upon discontinuation, making it suitable for intermittent androgen deprivation therapy 2

In Uterine Fibroids

• Relugolix combination therapy significantly reduces bleeding symptoms and fibroid volume by 18-30% 5, 7
• The American College of Radiology recommends oral GnRH antagonists (including relugolix) as effective second-line treatments for reducing both bleeding symptoms and fibroid volume 5, 8
• Combination hormone add-back therapy is FDA-approved to mitigate hypoestrogenic side effects while maintaining efficacy for fibroid-related heavy menstrual bleeding 5, 7

Safety Profile

In Men

• Most side effects of relugolix combination therapy (with novel hormonal therapies or chemotherapy) are mild or moderate 6
• Patients receiving relugolix with enzalutamide or docetaxel had higher rates of serious side effects compared to relugolix monotherapy 6
• Relugolix has a superior cardiovascular safety profile compared to GnRH agonists, making it preferable for patients with preexisting cardiovascular comorbidities 2

In Women

• As monotherapy, relugolix causes hypoestrogenic symptoms including bone mineral density loss and vasomotor symptoms 1
• The addition of estradiol and norethindrone acetate maintains systemic estradiol in a therapeutic range, mitigating bone loss and vasomotor symptoms 5, 1
• Long-term use of GnRH antagonists without add-back therapy can lead to significant bone mineral density loss 5

Important Clinical Considerations

• Fertility is suppressed during treatment with relugolix, and symptoms typically recur rapidly after cessation of therapy 5
• Relugolix's safety has not been established in combination with many androgen-receptor-axis targeted therapies (abiraterone, apalutamide), cabazitaxel, or lutetium Lu 177 vipivotide tetraxetan in prostate cancer patients 2
• As an oral medication, relugolix may present challenges with affordability, adherence, and compliance, particularly in elderly populations 2
• For uterine fibroids, relugolix provides temporary symptom relief with recurrence after discontinuation, requiring ongoing management 5