Relugolix Is Available, but Additional Clinical Trial Investigation Is Ongoing

The idea of oral androgen deprivation therapy (ADT) sounds great!  Why take a big needle when you can take a pill?  That certainly makes a lot of sense, but there are some major disadvantages to oral medications in the United States.  Most importantly is that oral prescription coverage for high-cost oncologic medications is less than ideal, and our patients can be left with large copays.  Even with copay assistance from sponsors and foundations, the overall cost to the health care system may be significant.  Also, the risk of non-compliance is real, and patients may forget to take their medications.  Yet, these are pragmatic considerations.  In the field of oncology, the most important drivers tend to still be efficacy and tolerability.

An important question is whether there is enough rationale to drive the regular use of relugolix,¹ FDA approved on December 18, 2020, as an oral luteinizing hormone releasing hormone (LHRH) antagonist, to substitute for injectable LHRH agonists like leuprolide or degarelix, the other commonly used LHRH antagonist?  Unlike many oncologic medications, agents used for androgen deprivation therapy (ADT) are not held to extremely high efficacy bars.  Regulatory agencies will accept sustained testosterone suppression to castrate levels (<50 ng per deciliter) without the need for demonstration of long-term superior or non-inferior efficacy when compared to standard agents used for ADT.

This opened the door for the 2:1 randomized, phase 3 HERO trial of patients with advanced prostate cancer to receive relugolix 120 mg po qd or leuprolide injections q3 months for 48 weeks.²  A total of 930 patients were randomized, with 622 to relugolix and 380 to leuprolide.  Of the men who received relugolix, 96.7% (95% CI 94.9-97.9) maintained castrate testosterone levels through 48 weeks, compared with 88.8% (95% CI 84.6-91.8) of men who received leuprolide.  This was statistically significant both for non-inferiority and superiority of relugolix (p<0.001).  Testosterone recovery was more rapid at 90 days after treatment discontinuation for relugolix over leuprolide, which could be viewed as either an advantage or disadvantage and I will address this later.  Major adverse cardiovascular events (MACE) were 2.9% in the relugolix group and 6.2% in the leuprolide group (HR 0.46; 95% CI 0.24-0.88).

To understand the implications of this efficacy data, one must consider clinical differences between LHRH agonists and antagonists.  First off, it is well known that LHRH antagonists, including degarelix and relugolix, cause a more rapid decline in testosterone levels when compared to LHRH agonists.  This is seen in this randomized, phase 3 trial as well, although the key clinical implication of this is the ability for an antagonist to prevent a clinical testosterone flare that can lead to bone pain or urinary obstruction in certain patients with advanced prostate cancer.  The long-term benefits of rapid, early castration are unknown and unlikely to be significant. 

It is also felt that “microsurges,” or breakthrough of testosterone levels above castrate levels, are more rare occurrences with antagonists.  Some older, small, retrospective series may generate some hypotheses that prevention of these breakthroughs is beneficial.  In a retrospective database series of 73 patients with non-metastatic prostate cancer, receiving 3 months of LHRH agonists, breakthrough testosterone increases above 50 and 20 ng/dL had correlation with development of castration-resistant prostate cancer (CRPC).³ 

Other manuscripts support the concept that reaching lower testosterone levels on treatment are better for men with prostate cancer.  A prospective cohort series of 32 patients undergoing LHRH agonist or antagonist therapy showed mean testosterone levels <32 ng/dl seemed to have improved CRPC-free survival compared to those between 32-50 ng/dl (patients with testosterone levels >50 ng/dl were excluded from analysis).⁴  Another manuscript that implied lower testosterone levels as being better, was a retrospective analysis of 129 patients with bone metastasis-only prostate cancer who were treated with goserelin.  After 6 months, the multivariable analysis was significant for a higher testosterone level with increased risk of death, with a HR of 1.33.⁵  Some of the strongest data comes from the randomized phase 3 PR.7 trial that showed intermittent ADT to be non-inferior in terms of overall survival to continuous ADT for patients with biochemically-recurrent prostate cancer after prior radiation therapy.  Exploratory analyses from patients randomized to continuous ADT and who had at least 3 testosterone levels recorded during the first 12 months on trial, led to over 600 patients analyzed.  Notable findings included the first-year nadir testosterone correlated with improved cancer specific survival and time to castration-resistance, with lower nadir corresponding with improved outcomes.⁶

Of course, none of this is very surprising.  One need only look at the abiraterone acetate story to recognize that lower testosterone suppression is beneficial.  Recent advances have shown benefit of abiraterone acetate in even earlier disease states than metastatic hormone sensitive prostate cancer,^{7, 8} including those patients with extremely high-risk characteristics (e.g. 2 of 3 criteria of Gleason score 8-10, T3-4 status, and PSA level > or = 40 ng/mL) in conjunction with radiation therapy.⁹  In totality, it is believable that as long as an appropriate patient population is selected for study, a population where harm from ADT is less likely to occur and the patient is expected to die of prostate cancer, then the benefits of greater suppression of testosterone can be experienced. 

The other discussion is regarding MACE and whether LHRH antagonists may cause less than agonists.  Part of the theory has been that LHRH antagonists lower follicle stimulating hormone (FSH) rapidly, while agonists cause increases of FSH that may persist for a year.¹⁰  FSH receptor is present on adipocytes on endothelial cells, hence, one can begin to draw conclusions that this process may promote the development of atherosclerotic plaque formation, metabolic syndrome and insulin resistance;¹⁰ ultimately, this may result in more patients with MACE from LHRH agonists than with antagonists.  However, this question was addressed in the PRONOUNCE randomized controlled trial of degarelix vs. leuprolide, with the primary endpoint of MACE through 12 months.  Although 900 randomized patients were planned, enrollment was slow and 545 patients were ultimately analyzed.  A MACE occurred in 15 (5.5%) patients with degarelix and 11 (4.1%) with leuprolide (HR 1.28, 95% CI 0.59 – 2.79; p=0.53).  Hence, the LHRH antagonist, degarelix, was not superior in preventing MACE over the LHRH agonist, leuprolide.  Recall, however, that in the randomized phase 3 trial of relugolix vs. leuprolide, relugolix did have statistically fewer MACE.  This issue likely requires more investigation to reach a definitive conclusion.

Although there are many hints that improved suppression of testosterone with relugolix may lead to improved outcomes, there is no definitive long-term data.  Additionally, many situations now warrant the addition of abiraterone, and it is not clear that the agonist vs. antagonist testosterone suppression debate matters at all once abiraterone is added to the combination since abiraterone is known to be able to lower testosterone 1-2 logs lower than LHRH therapy alone can.

Another proposed benefit of relugolix is the “rapid-off switch.”  This is the fact that cessation of oral therapy leads to more rapid testosterone recovery.  This may be applicable in situations where ADT is used in conjunction with radiation therapy for localized disease or when ADT is used for intermittent therapy.  The hypothesis is that with more rapid testosterone recovery, patient quality of life may be improved.  However, we have long known that the effects of giving a depot LHRH agonist have longer lasting testosterone suppression effects than the actual duration of treatment.  Therefore, will we be compromising efficacy when testosterone recovers more rapidly in patients undergoing concomitant radiation or those undergoing intermittent ADT? 

Ongoing research from clinical trials, listed below, with relugolix, may help address some of the issues above by evaluating relugolix in combination with other novel hormonal therapy agents, with radiation therapy, and by providing more information on MACE.

Clinical Trials Focused on relugolix for Men with Prostate Cancer

• Phase 1 trial of relugolix in metastatic castration-sensitive, non-metastatic or metastatic castration-resistant prostate cancer in combination with abiraterone, apalutamide, or docetaxel (NCT04666129)
• Randomized phase 2, double-blinded trial of relugolix vs. placebo in patients undergoing stereotactic ablative radiation therapy with biochemically recurrent, oligometastatic, castration-sensitive prostate cancer (NCT05053152)
• Phase 4 trial of relugolix vs. LeUprolide in patients with non-metastatic localized prostate cancer to assess cardiac factors (REVELUTION) (NCT05320406)

References:

1. ND, et al. "Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer." N Engl J Med 2020; 382:2187-96.
2. Morote J, et al. "Redefining clinically significant castration levels in patients with prostate cancer receiving continuous androgen deprivation therapy." J Urol 2007; 178:1290-5.
3. Dason S, et al. "Defining a new testosterone threshold for medical castration: Results from a prospective cohort series." Can Urol Assoc 2013; 7:e263-7.
4. Perachino M, et al. "Testosterone levels in patients with metastatic prostate cancer treated with luteinizing hormone-releasing hormone therapy: prognostic significance?" BJU Int 2010; 105:648-51.
5. Klotz L, et al. "Nadir testosterone within first year of androgen-deprivation therapy (ADT) predicts for time to castration-resistant progression: a secondary analysis of the PR-7 trial of intermittent versus continuous ADT." J Clin Oncol 2015; 33:1151-6.
6. Fizazi K, et al. "Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer." N Engl J Med 2017; 377:352-60.
7. James N, et al. "Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy." N Engl J Med 2017; 377:338-51.
8. Attard G, et al. "Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: a meta-analysis of primary results from two randomised controlled phase 3 trials of the STAMPEDE platform protocol."Lancet 2022; 399:447-60.
9. Crawford ED, et al. "The potential role of follicle-stimulating hormone in the cardiovascular, metabolic, skeletal, and cognitive effects associated with androgen deprivation therapy."Urol Oncol 2017; 35:183-91.
10. Lopes RD, et al. "Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Prostate Cancer: The Primary Results of the PRONOUNCE Randomized Trial."Circulation 2021; 144:1295-307.