Radiation with Hormonal Therapy

Gonadotropin Releasing Hormone Analogs

GnRH agonists and antagonists are both synthetic analogs of the GnRH peptide hormone, and achieve castrate testosterone levels by shutting down the GnRH-mediated release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary. GnRH antagonists achieve this effect through direct blockade of the GnRH receptor. In contrast, GnRH agonists function through their interruption of the normal pulsatile signaling of physiologic GnRH. Persistent elevation of GnRH agonist activity leads to downregulation of the GnRH receptor, thereby causing decreased levels of LH, FSH, and testosterone. GnRH agonists often cause an initial surge in LH, FSH, and testosterone before this downregulation occurs. In contrast, GnRH antagonists do not cause this androgen surge. Available GnRH agonists include leuprolide, goserelin, and triptorelin. Available GnRH antagonists include abarelix and degarelix.

GnRH Agonist Versus GnRH Antagonist

Most trials that have combined radiation therapy with androgen deprivation therapy have used a GnRH agonist. The recent development of GnRH antagonists may provide an alternative option. In the CS21 trial, 610 patients with prostate cancer (including those with metastatic and nonmetastatic disease) in whom ADT was indicated were randomized to 12 months of degarelix versus 12 months of leuprolide (with bicalutamide allowed at the discretion of the treating physicians to prevent androgen flares). The primary endpoint was suppression of testosterone below 0.5 ng/mL during the 12 months, and degarelix showed noninferiority to leuprolide in this regard. Moreover, degarelix demonstrated faster time to castrate levels of testosterone, and faster suppression of prostate-specific antigen (PSA). Over 95% of patients receiving degarelix achieved castrate levels of testosterone at 3 days after starting treatment, compared to none of the patients in the leuprolide arm. Similarly, PSA levels in the degarelix arm declined by a greater percentage than in the leuprolide arm at both 14 days (65% degarelix vs. 18% leuprolide) and 28 days (83% degarelix vs. 68% leuprolide). Eighty-one percent of patients receiving leuprolide had a testosterone surge upon initiating therapy, while no patients receiving degarelix had a testosterone surge. Investigators also reported similar rates of adverse effects between both groups.

This trial demonstrates that a GnRH antagonist is able to achieve faster testosterone suppression than a GnRH agonist. However, it is unknown whether this translates to an improvement in oncologic outcomes (cancer control, survival) when used with radiation therapy.

Antiandrogens

The other main class of drugs used with EBRT is the antiandrogens. These synthetic compounds bind the testosterone receptor in target tissues, and competitively inhibit the binding of testosterone and dihydrotestosterone. Antiandrogens are often used together with GnRH agonists to block the androgen surge and to achieve maximal androgen blockade, and it is uncommon to use antiandrogen alone with radiation therapy. Available formulations include flutamide, bicalutamide, and nilutamide.