A Phase II, Randomized, Open-Label Study of Neoadjuvant Degarelix versus LHRH Agonist in Prostate Cancer Patients Prior to Radical Prostatectomy

Abstract

Degarelix, a new gonadotropin-releasing hormone (GnRH) receptor antagonist with demonstrated efficacy as first-line treatment in the management of high-risk prostate cancer, possesses some theoretical advantages over luteinizing hormone-releasing hormone (LHRH) analogues in terms of avoiding "testosterone flare" and lower follicle-stimulating hormone (FSH) levels. We set out to determine whether preoperative degarelix influenced surrogates of disease control in a randomized phase II study. Thirty-nine patients were randomly assigned to one of three different neoadjuvant arms: degarelix only, degarelix/bicalutamide, or LHRH agonist/bicalutamide. Treatments were given for 3 months before prostatectomy. Patients had localized prostate cancer and had chosen radical prostatectomy as primary treatment. The primary end point was treatment effect on intratumoral dihydrotestosterone levels. Intratumoral DHT levels were higher in the degarelix arm than both the degarelix/bicalutamide and LHRH agonist/bicalutamide arms (0.87 ng/g vs. 0.26 ng/g and 0.23 ng/g, < 0.01). No significant differences existed for other intratumoral androgens, such as testosterone and dehydroepiandrosterone. Patients in the degarelix-only arm had higher AMACR levels on immunohistochemical analysis ( = 0.01). Serum FSH levels were lower after 12 weeks of therapy in both degarelix arms than the LHRH agonist/bicalutamide arm (0.55 and 0.65 vs. 3.65, < 0.01), and inhibin B levels were lower in the degarelix/bicalutamide arm than the LHRH agonist/bicalutamide arm (82.14 vs. 126.67, = 0.02). Neoadjuvant degarelix alone, compared with use of LHRH agonist and bicalutamide, is associated with higher levels of intratumoral dihydrotestosterone, despite similar testosterone levels. Further studies that evaluate the mechanisms behind these results are needed. .

Antiandrogens Reduce Intratumoral Androgen Concentrations and Induce Androgen Receptor Expression in Castration-Resistant Prostate Cancer Xenografts

“…A similar observation was recently demonstrated for clinical CRPC because the treatment with luteinizing hormoneereleasing hormone agonist together with bicalutamide was associated with lower intratumoral DHT levels compared with the tumors from patients treated with the luteinizing hormoneereleasing hormone agonist alone. 33 In contrast to our study with VCaP xenografts, no difference in the intratumoral testosterone concentrations was identified in the tumors of luteinizing hormoneereleasing hormone agonist-treated patients with or without bicalutamide. 33 However, it is possible that the assay used in the study was not sensitive enough to reliably detect the potential differences between the low testosterone concentrations in these tumors.…”

Applying mass spectrometric methods to study androgen biosynthesis and metabolism in prostate cancer

“…While the VCaP model displays several hallmarks of CRPC, presently it is not known whether the effects of antiandrogens on intratumoral androgen levels translate into clinical CRPC. However, a recent study demonstrated that patients treated for 3 months with GnRH agonist or antagonist combined with antiandrogen (bicalutamide) prior to radical prostatectomy were associated with lower intratumoral DHT levels measured by LC-MS/MS compared to the patients who were treated with one of the GnRH antagonists only (Sayyid et al 2017). No differences in the intratumoral T levels were observed between the treatment groups in this study.…”

Comparison of the roles of estrogens and androgens in breast cancer and prostate cancer

“…Leuprolide and goserelin are LHRH agonists used to treat advanced PC or in combination with radiation therapy . LHRH agonists may induce increased uremia and neurologic sequelae; thus, they are always combined with an antiandrogen, such as flutamide and bicalutamide …”

“…[112][113][114] LHRH agonists may induce increased uremia and neurologic sequelae; thus, they are always combined with an antiandrogen, such as flutamide and bicalutamide. 112,115 Abiraterone and 3-beta-O-acetate are CYP17A1 inhibitors (also known as 17α-hydroxylase and C17-20 lyase). CYP17A1 is a key enzyme for androgen synthesis 88 and is used to treat metastasized PC, while excess mineralocorticoids are produced and induce hypertension, hypokalemia, and fluid overload.…”