Drs. Crawford and Hou provide an important clinical introduction to a novel class of hormonal agents that have been under development for several decades for the treatment of advanced and metastatic prostate cancer. Known as antagonist decapeptides, these drugs immediately suppress the luteinizing hormone-releasing hormone (LHRH) 7-transmembrane receptor in the pituitary to shut off luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and concomitantly, testosterone and dihydrotestosterone.
These agents were the original pharmaceutical candidates for analog development after the specific peptidic and amino acid structure of LHRH, or gonadotropin-releasing hormone (GnRH), was elucidated by Dr Andrew Schally of Tulane University.
Unfortunately, this class of agents had technical drawbacks in terms of solubility properties and nonspecific histamine-release properties, measured in vitro by histamine release in peritoneal mast cells and clinically by localized or more generalized allergic reactions.
Approval and Marketing
Unlike LHRH agonists, which generally have a single D-amino acid substitution in the peptide chain, LHRH antagonists often have both D-amino acid and nonnatural amino acid substitutions, leading to solubility challenges and requirements for larger dosing on a milligram-for-milligram basis, compared to doses of agonists. Nevertheless, both abarelix and degarelix have characteristics that have allowed them to become commercially approved and acceptable for clinical use (unlike earlier analogs).
Abarelix was initially approved in the United States for the management of advanced symptomatic prostate cancer and is now approved and marketed in Europe. Despite extensive clinical experience across a wide spectrum of patient populations with prostate cancer, its commercial distribution was halted in the United States in 2006, not for any safety or efficacy concerns, as implied by Drs. Crawford and Hou, but rather for economic reasons related to regulatory reporting and risk management obligations. Such obligations were not imposed on the use of abarelix in Europe, and hence, its commercialization and clinical uptake has been most satisfactory there.
Clinicians need to consider several important questions if they elect to use a GnRH antagonist in practice: First, for which prostate cancer patient populations are these agents most likely to be helpful? Second, what data support their clinical use in these populations? Third, are there any safety or efficacy differences between agonists and antagonists?
Patient Populations Likely to Benefit
The patient populations most likely to experience immediate benefit are those with locally advanced or metastatic prostate cancer who are at risk of experiencing disease worsening that may accompany the obligate testosterone surge inherent in the use of LHRH agonists. Included are those with impending spinal cord compression, hydronephrosis from ureteral obstruction due to metastatic spread in the retroperitoneum, anticipated worsening urinary obstruction due to an enlarged prostate gland, and metastatic pain requiring narcotic analgesics. Indeed, the US approval of abarelix was indicated specifically for these patient populations, and although relatively uncommon, the availability of a pharmacologic agent that addresses these important clinical situations is welcome.
From a physiologic perspective, all patients with prostate cancer who are undergoing initiation of hormonal therapy with an LHRH agonist, with or without an antiandrogen, would be an appropriate candidate for GnRH antagonist therapy. After all, the obligate testosterone surge that accompanies LHRH agonist use was not an intended action, but an unfortunate consequence of its use. Indeed, this undesired characteristic and its potential and partial physiologic (not pharmacologic) avoidance by concomitant or pretreatment antiandrogen therapy underscored much of the popularity of short-term antiandrogen use today. For short-term hormonal therapy use in the neoadjuvant setting and for intermittent hormonal therapy, GnRH antagonists make excellent sense and should be a welcome addition to the clinician’s armamentarium.
Drs. Crawford and Hou nicely outline the data supporting the use of degarelix in terms of more rapid testosterone suppression and rapid prostate-specific antigen (PSA) decline—actions that are the backbone of hormonal therapy for the disease. Similar physiologic effects on testosterone and PSA were seen in studies of abarelix. In addition, meaningful clinical outcomes, such as reduction in narcotic analgesic use, avoidance of spinal cord compression, and avoidance of bilateral surgical orchiectomy—the only other alternative for symptomatic metastatic prostate cancer patients—were amply demonstrated in studies performed with abarelix.
The differential effect of FSH between agonists and antagonists are of interest. As pointed out by Drs. Crawford and Hou, the more enduring action of lowered FSH with both degarelix and abarelix may have beneficial effects on bone health. Others have suggested that FSH may have independent effects on prostate cancer growth as well. We await additional studies to confirm or refute these potential benefits.
The ability to completely avoid the testosterone surge may be of benefit in longer-term use of hormonal therapy when used intermittently. Consider that each time a patient initiates a cycle of therapy, he will generally experience a testosterone surge, especially if his baseline testosterone and LH have returned to normal during the “drug holiday” period. It will be important to study the differential aspects of chronic intermittent use of an antagonist vs an agonist as well as the potential impact of avoiding multiple testosterone surges with cyclical treatment.
Safety and Efficacy Differences
The comparative safety data for LHRH agonist use with or without an antiandrogen and antagonist that emerged from the phase III studies of degarelix and abarelix are well outlined in the publications cited by the authors. Several points are worth noting. Immediate-onset systemic allergic reactions were not seen in any of the formal phase III studies that compared abarelix to leuprolide or leuprolide plus bicalutamide (Casodex). These rare reactions occurred only in the setting of patients who had previously received therapy or who served as the population with advanced symptomatic prostate cancer. Postmarketing data collected during the commercial phases of abarelix in the United States and now in Europe suggest that these reactions are quite rare and readily managed. The degarelix safety profile includes a high incidence of local reactions with chills. Whether these represent a milder form of allergic reaction or a reaction to the larger volume of injectate that is required in the subcutaneous space is speculative.
It is difficult to directly compare longer-term testosterone efficacy among studies, since each study has unique definitions of maintaining castrate levels of testosterone. Regardless, it will be prudent for every clinician to periodically monitor testosterone levels in patients undergoing long-term administration of either an agonist or antagonist, as testosterone fluctuations and “escape” from castration can occur with each and every formulation that is approved for clinical use.
Finally, we have seen a recent renewal of interest in the issues surrounding the cardiovascular and metabolic consequences of hormonal therapies for prostate cancer, important concerns that should be in the forefront of clinicians’ minds. While a review of these issues is beyond the scope of this commentary, one fascinating finding that emerged from our studies with abarelix was that all hormonal therapies—agonist alone or with antiandrogen or antagonist—can prolong the QTc interval on the electrocardiogram. Thus, this is a call for all clinicians using these agents to select patients appropriately and consider the risks and benefits of each class of agent in formulating the safest and most effective treatment plans.
Financial Disclosure: Dr. Garnick helped develop the first commercially approved GnRH antagonist, Abarelix, for prostate cancer and now serves as a consultant to Speciality European Pharma, a European company that markets Abarelix (Plenaxis).