Degarelix (Injectable GnRH Antagonist)

Editor’s Note: In December 2020, the first oral GnRH antagonist, relugolix, was approved by the U.S. Food and Drug Administration (FDA).^1,2 Although mechanisms, efficacy, and side effects of both GnRH antagonist formulations (ie, injectable and oral) are similar, information about relugolix is also included here as a service to our readers.

Defining Advanced Prostate Cancer

Prostate cancer is the most common malignancy in men, aside from non-melanoma skin cancer.³ However, the definition of advanced prostate cancer⁴ is still somewhat controversial, observed Neal D. Shore, MD, FACS, Medical Director of the Carolina Urologic Research Center in Myrtle Beach, South Carolina.

“Some would consider the category of ‘advanced’ disease to be limited to those with imaging-positive metastatic disease. Others would also consider patients with biochemical relapse [ie, prostate-specific antigen (PSA) relapse] after active treatment, such as surgery or radiation, to have advanced disease, as well as all patients with metastatic castration-sensitive and castration-resistant prostate cancer,” he told JNCCN 360.

Testosterone Suppression

Prostate cancer is one of the most exquisitely hormone-sensitive tumors in men, and since the 1940s, testosterone suppression has been the treatment of choice for advanced prostate cancer.⁵ Bilateral orchiectomy was associated with a marked clinical benefit in symptom palliation for those with metastatic disease.

Ultimately, the responsiveness of biomarkers [ie, prostatic acid phosphatase, PSA] in patients with advanced prostate cancer was observed when testosterone suppression was achieved. Therapy with luteinizing hormone–receptor hormone (LHRH) agents was approved in the 1980s to achieve testosterone suppression without surgery—and termed androgen-deprivation therapy (ADT).⁶ [Editor’s Note: LHRH and gonadotropin-releasing hormone (GnRH) are used interchangeably. We will use “GnRH” in this Spotlight.]

A series of formulations were developed, with subcutaneous or intramuscular delivery given monthly (in continuous-release doses), extending to every 3 months, every 4 months, every 6 months, and every 12 months. These formulations were approved for the treatment of patients with advanced prostate cancer based on a pharmacologic endpoint of testosterone suppression.

Androgen-Deprivation Therapy

“ADT is used in many prostate cancer settings and is initiated after a shared decision-making process between patient and provider that covers the benefits and risks of disease regression versus the side effects of testosterone suppression,” Dr. Shore explained.

GnRH antagonists and agonists are the backbones of modern ADT, noted Jessica Campaign-Mauser, PharmD, BCOP, an oncology pharmacist with the Huntsman Cancer Institute in Salt Lake City. The agonist drugs cause an initial flare of testosterone, followed by negative feedback with a subsequent drop in testosterone, she explained to JNCCN 360. Other types of drugs, such as bicalutamide, apalutamide, and enzalutamide—also under the broad umbrella of ADT—are classified as androgen-receptor blockers.

“These oral drugs work by blocking the binding of any remaining testosterone to their receptors,” Dr. Campaign-Mauser said. “In some disease settings, ADT may consist of both the injectable GnRH agonist or antagonist plus an oral androgen-receptor blocker,” she explained. Rarely, she noted, a patient who cannot tolerate the side effects of a GnRH agonist or antagonist might receive an androgen-receptor blocker alone. However, that is considered off-label use and is not recommended by the NCCN,⁷ as it appears less effective than medical or surgical suppression of testosterone production.  

The GnRH Antagonist Degarelix

Degarelix, a GnRH antagonist, was approved by the FDA in 2008.⁸ This represented a different parenteral formulation for testosterone suppression. The GnRH antagonist drug class blocks the pituitary gland from producing follicle-stimulating hormone (FSH) and luteinizing hormone, causing suppression in testosterone production.^9,10 [Editor’s Note: A previously approved agent, abarelix,¹¹ also a GnRH antagonist, was associated with some anaphylactoid reactions, less consistent testosterone suppression at 6 months, and less convenient dosing.¹² Promotion and marketing for the agent were discontinued in the United States, although it remains a treatment option in some countries.]

Degarelix is administered once a month as a deep subcutaneous injection.¹³ The first dose comprises two injections and, after that, one injection monthly.

Compared with the GnRH agonists, degarelix is not associated with a supraphysiologic surge of testosterone, which reduces the risk for clinical flare and results in a faster decline in testosterone. This is especially important in patients with symptomatic, large-volume, metastatic disease.⁹

Despite the pharmacologic endpoint for drug approvals, which is testosterone suppression to 50 ng/dL, Dr. Shore pointed out that some prostate cancer guidelines and consensus papers emphasize the importance of profound suppression to less than 20 ng/dL. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prostate Cancer use less than 50 ng/dL as the castration level of testosterone. Measurement of testosterone at baseline and during ADT treatment is essential to gauge the efficacy of treatment.⁶

In general, patients on ADT have a somewhat higher risk for cardiovascular abnormalities. Jaelyn Westfield, PharmD, an oncology resident pharmacist, also with Huntsman Cancer Institute, reported: “Chest pain, shortness of breath, and other signs of cardiac issues or stroke should be promptly evaluated by an appropriate medical team, such as the emergency department.”

Dr. Shore pointed out that the profound and prolonged suppressive effect of degarelix on FSH may positively impact effects of therapy on the coronary vascular system. A retrospective review of six prospective trials comparing GnRH agonist preparations with degarelix suggested that degarelix was associated with an enhanced cardiovascular safety profile.¹⁴ Margel and colleagues suggested that a significant cardiovascular event is less likely with degarelix than with other GnRH agonists.¹⁵

Degarelix Monthly Injections

According to Dr. Shore, the downside of degarelix is the monthly injection schedule compared with other GnRH agonists, which may be given every 3, 4, or 6 months, or even once a year. Previous literature reported painful injection-site reactions in roughly 30% of patients treated with degarelix.^9,16 

“In our experience, injection-site pain with degarelix is less than the 30% reported in the literature. What appears to be key is the expertise of the person, usually a nurse, administering the injection,” Dr. Shore remarked. “It needs to be given as a deep subcutaneous injection (rather than superficial subcutaneous) at the correct angle. Prophylactic ice packs applied to the injection site for the first 12 hours, plus nonsteroidal anti-inflammatory medication can help reduce pain.”

Moreover, he underscored the importance of educating patients about the potential of developing a thickening and/or a reddening of the skin at the injection site for a few days. “By training those who administer the injection, educating patients, and judiciously using ice and pain medications, we have reduced painful injection-site reactions to approximately 10%,” Dr. Shore told JNCCN 360.

Dr. Campaign-Mauser agreed that pain and redness at the injection site were the most often reported side effects, and they occurred more frequently with the subcutaneous degarelix injection than with agents administered intramuscularly. She suggests some caution might be needed concerning cold (ice pack) or heat therapy (warm compress) at the site, because extreme temperatures may affect drug distribution from the subcutaneous depot.

For the most part, those painful injection-site reactions were classified as mild to moderate and resolved within 2 to 3 days. General advice from Dr. Campaign-Mauser is to keep the site clean, wear loose-fitting clothing to reduce friction at the site, and take nonprescription pain relievers, as needed. The injection site should also be rotated monthly. Signs and symptoms of infection at the injection site should be immediately reported to the clinical team.

By training those who administer the injection, educating patients, and judiciously using ice and pain medications, we have reduced painful injection-site reactions to approximately 10%.

Administration Details

Confirming Dr. Shore’s description of degarelix administration, Dr. Westfield provided additional details. “Because degarelix must be administered within 1 hour of reconstitution, most facilities designate the nurse responsible for both the preparation and administration of the injection(s),” she said. “And, because the first dose of degarelix requires two deep subcutaneous injections given slowly over 15 to 30 seconds into the abdomen, it is often ideal to have them administered simultaneously by two nurses.

If resources permit, it is somewhat more comfortable and less anxiety-producing for the patient to undergo both injections simultaneously. If the injections are given sequentially by one nurse, the pain of the first injection amps up the patient’s anxiety while waiting to receive the second injection. “Patients can be reassured,” noted Dr. Westfield, “that after the initial two-dose injection, they will receive only one every month thereafter.”

The patient should be in a comfortable sitting or semireclining position, such that the nurse can access enough abdominal skin and subcutaneous fat for proper administration, Dr. Westfield recommended. Patients should be instructed not to let a waistband or belt press or rub at the injection site. “Unlike with some anticancer therapies such as monoclonal antibodies, if patients do not report unusual pain or discomfort, they can leave shortly after their injection,” she said.

Because the first dose of degarelix requires two deep subcutaneous injections given slowly over 15 to 30 seconds into the abdomen, it is often ideal to have them administered simultaneously by two nurses.

Managing Toxicity

In addition to injection-site reactions, testosterone suppression’s side effects are well known and include symptoms such as hot flashes, Dr. Westfield told JNCCN 360. Patients who suffer from hot flashes are generally advised to dress in layers, take warm rather than hot showers, drink cool fluids, and keep their home cool. Pharmacologic options for patients with significant hot flashes may include serotonin/norepinephrine-reuptake inhibitors or gabapentin.¹⁷

GnRH blockers can cause alterations in liver function tests and liver enzymes—especially if they are combined with oral androgen-receptor blockers. Laboratory findings should be monitored regularly.

At a minimum, “labs should be checked monthly when patients come to the clinic for their injections. In some patients, labs will first be assessed twice a month,” Dr. Westfield told JNCCN 360. Symptoms of liver dysfunction or damage include abdominal pain and yellowing of the skin or eyes. 

As with other cancer therapies and malignancies, Dr. Campaign-Mauser highlighted fatigue as a major issue for many patients. Therefore, activity at any level is best. “I tell patients that a short walk around the neighborhood or even light household chores will be better than sitting or lying down all day.”

Intermittent ADT

Most patients with metastatic prostate cancer will be on ADT continuously. For those who have a biochemical relapse (ie, PSA relapse), Dr. Shore noted, a decision may need to be made about continuous versus intermittent therapy.

According to Dr. Westfield: “Intermittent ADT is a strategy that allows patients to take a break from the unwanted effects of testosterone suppression while maintaining surveillance of PSA levels and potential disease progression.”

Intermittent dosing is usually reserved for patients with a low disease burden who are asymptomatic or minimally symptomatic, who have low PSA levels, and “who ‘hate’ ADT,” Dr. Campaign-Mauser added. “After a risk/benefit calculation, giving low-risk patients a break from ADT will probably not endanger them or alter their outcomes significantly. We watch testosterone and PSA levels. When the PSA level reaches whatever threshold has been established, we will have a discussion with the patient about reinstating ADT,” she said. 

In patients with earlier-stage disease, limited adjuvant ADT (4 months to 3 years) may be offered as part of radiation therapy, in which case degarelix will be given only for the established adjuvant period.

Approval of the First Oral Option

In December 2020, relugolix, a once daily GnRH antagonist, was approved by the FDA^1,2 and represented the first oral formulation in this drug class. The mechanism of action (ie, GnRH antagonism) is essentially the same for relugolix as for degarelix. Relugolix is initiated with a single dose of 360 mg on day 1, followed by a maintenance dose of 120 mg daily thereafter.¹

The HERO Trial

The HERO trial¹⁸ is the largest study of an antagonist versus an agonist (a GnRH agonist formulation administered quarterly) to date in patients with varying definitions of advanced prostate cancer. The patient population included those with metastatic disease, those with biochemical relapse, and those with high-risk localized disease.

The 48-week cumulative evaluation of testosterone suppression first demonstrated noninferiority with relugolix and later demonstrated superiority versus the parenteral GnRH agonist. Dr. Shore was the first author for the HERO trial, published in The New England Journal of Medicine, and he reported that secondary endpoints, such as PSA decline, confirmed these findings. Of note, he stressed, “a prespecified safety analysis showed a 54% decrease in the risk of major cardiovascular events (myocardial infarction, stroke, ischemic heart disease, significant arrhythmia) in those who received relugolix versus the GnRH agonist.”

Adherence With Oral Therapy

“Patients and providers can now discuss this oral option, which eliminates the need to visit the clinic for injectable treatment. This is a factor that has taken on greater significance during the COVID-19 pandemic,” Dr. Shore told JNCCN 360. However, it may not be a suitable option for patients who are unable to swallow pills.

With regard to adherence and the potential for missing a dose—a risk with any oral therapy—the half-life of relugolix is 25 hours. “This means that even if a patient forgets his medication, a missed dose is not likely to affect his testosterone level,” Dr. Shore noted. Nonetheless, “it is a given that patients taking any oral medication need to adhere to instructions about how to take the medication properly.”

“One of our concerns about switching to an oral agent is adherence, because many men don’t like ADT,” Dr. Campaign-Mauser observed. “If patients reduce their doses by not adhering with the daily schedule, we might find a complete loss of testosterone suppression.”

Patients who discontinued relugolix in the HERO trial experienced rapid recovery of testosterone to more than 50 ng/dL within 2 weeks.¹⁸ “If relugolix is delayed for 7 days or more, the testosterone level will likely increase, which puts the patient at increased risk for progressive disease,” she cautioned. According to relugolix prescribing information, therapy should be reinitiated with the day-1 loading dose in those who have missed therapy for more than 1 week.¹

Almost all patients using ADT for prostate cancer also take other oral medications, whether for diabetes, hypertension, cardiac conditions, hyperlipidemia, depression, or other conditions. Therefore, “these patients already have some sort of routine in place regarding daily oral medications and could easily add something like relugolix into their existing daily habit,” Dr. Shore told JNCCN 360.

Drug Interactions With Relugolix

From a pharmacist’s perspective, Dr. Westfield says relugolix has a significant list of drug interactions because it is a substrate of P-glycoprotein and CYP3A4. The relugolix prescribing information¹ advises avoiding the use of P-glycoprotein inhibitors (eg, carvedilol, verapamil, and amiodarone) but suggests dosing schedule changes if concomitant use is required. These timing issues substantially complicate adherence.

With the use of combined P-glycoprotein and CYP3A4 inducers such as apalutamide or rifampin, the dosage of relugolix has to be doubled. [Editor’s Note: The NCCN Guidelines for Prostate Cancer⁷ do not recommend relugolix in combination with apalutamide or any other drug.] Many of these medications are commonly used in patients with prostate cancer. Dosage adjustments may be necessary if the patient switches to the oral GnRH antagonist preparation.

The issue of drug interactions is already a major problem with apalutamide and enzalutamide, Dr. Campaign-Mauser added, “and these kinds of situations are exacerbated when patients don’t tell us about new medications that have been prescribed. Patients may wind up at risk for toxicity due to drug interactions or risk of disease progression, if drug interactions or poor adherence affect the efficacy of testosterone suppression.”

Intermittent ADT With Oral Agents

The HERO trial demonstrated that in patients administered relugolix and who opted for intermittent treatment, 50% achieved normal testosterone levels after 90 days compared with 3% of those in the control arm who received the injectable agonist. “The ‘on/off’ switch appears to be much faster with the oral formulation,” Dr. Shore explained, “which makes it useful for intermittent therapy.”

Switching Agents

Switching from an injectable agonist to an antagonist has been a long-time issue, Dr. Shore indicated. “Sometimes, it is a matter of injection tolerability, and sometimes it is related to insurance coverage.”

There have been studies that explored these switches (ie, from one testosterone-suppressing agent to another).^19,20 “It will be important to look at this question in the context of switching from injectable formulations to the newly approved oral preparation,” he suggested.  

Although degarelix was not directly compared with relugolix in a clinical trial, GnRH antagonism’s overall side effects were similar, Dr. Westfield noted. The only differences were a higher incidence of diarrhea with relugolix and the risk of injection site reactions with degarelix.

Cost Concerns: Injectables Versus Oral Drugs

“As soon as relugolix was approved, some providers at our institution were asking to have it added to our formulary,” Dr. Campaign-Mauser said. She explained that there are still outstanding questions around payment issues at this point, such as whether third-party insurers will cover the cost of the oral formulation as a prescription agent versus a preference for medical insurance coverage of an injectable agent in the clinic.

Prescription out-of-pocket costs for new therapies may be substantial, especially for those on Medicare, and co-pay concerns for a prescription drug may affect patient adherence with therapy. Patient costs for oral versus injectable ADT should be assessed and considered when selecting or changing therapy.

“Although we do not have experience yet with switching treatments, we assume the best time to transition from an injectable to an oral formulation would be when the patient is scheduled for his next [injectable] dose. At that time, the blood levels [of the injectable agent] are decreasing, and initiation of the next dose via the oral route makes the most sense,” Dr. Campaign-Mauser speculated.

ADT Decisions

The decision to treat a patient with degarelix or relugolix versus some of the other options for ADT in the setting of advanced prostate cancer depends on several factors, Dr. Westfield told JNCCN 360. This includes the route of administration, namely subcutaneous versus intramuscular.

Degarelix is associated with a higher incidence of injection-site pain and is dosed once a month. In contrast, the GnRH agonist leuprolide may be dosed once a month, once every 3 months, once every 4 months, or once every 6 months.

However, Dr. Westfield stressed, “there are certain patients who cannot afford the initial testosterone flare that occurs with leuprolide. Those with severe symptoms, for instance, such as spinal cord compression, should not be treated with anything that might increase their testosterone, even briefly, and thus could escalate their symptoms.” Degarelix would be useful in any patient who needs to have testosterone levels lowered immediately, she added.

Concerning anticipating and managing a potential testosterone flare from GnRH agonists, “clinically, patients often start bicalutamide at least a week before leuprolide injection to block most of the symptoms of the testosterone flare, continuing the bicalutamide for about a week after injection,” Dr. Campaign-Mauser told JNCCN 360. “However, there are a few patients whose symptoms are so severe that we do not want to risk the possibility that androgen-receptor blockade will not be sufficient. Those patients should receive [a GnRH agonist such as] degarelix.”

Degarelix would be useful in any patient who needs to have testosterone levels lowered immediately.

Disclosures

Neal D. Shore, MD, FACS, has served as a consultant to Abbie, Amgen, Astellas, AstraZeneca, Bayer, BMS, Boston Scientific, Clovis Oncology, Dendreon, Exact Imaging, FerGene, Foundation Medicine, CG Oncology, Invitae, Janssen, MDxHealth, Merck, Myovant Sciences, Myriad Genetics, Nymox, Pfizer, Propella, Sanofi Genzyme, Sesen Bio, and Tomar. He has also participated in speakers’ bureaus for Astellas, AstraZeneca, Bayer, Clovis Oncology, Janssen, Pfizer, and Guardant Health.

Jessica Campaign-Mauser, PharmD, BCOP, has reported no conflicts of interest.

Jaelyn Westfield, PharmD, has reported no conflicts of interest.

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