LHRH Agonists for the Treatment of Prostate Cancer: 2012

Abstract

The most recent guidelines on prostate cancer screening from the American Urological Association (2009), the National Comprehensive Cancer Network (2011), and the European Association of Urology (2011), as well as treatment and advances in disease monitoring, have increased the androgen deprivation therapy (ADT) population and the duration of ADT usage as the first-line treatment for metastatic prostate cancer. According to the European Association of Urology, gonadotropin-releasing hormone (GnRH) agonists have become the leading therapeutic option for ADT because they avoid the physical and psychological discomforts associated with orchiectomy. However, GnRH agonists display several shortcomings, including testosterone (T) surge ("clinical flare") and microsurges. T surge delays the intended serologic endpoint of T suppression and may exacerbate clinical symptoms. Furthermore, ADT manifests an adverse-event spectrum that can impact quality of life with its attendant well-documented morbidities. Strategies to improve ADT tolerability include a holistic management approach, improved diet and exercise, and more specific monitoring to detect and prevent T depletion toxicities. Intermittent ADT, which allows hormonal recovery between treatment periods, has become increasingly utilized as a methodology for improving quality of life while not diminishing chronic ADT efficacy, and may also provide healthcare cost savings. This review assesses the present and potential future role of GnRH agonists in prostate cancer and explores strategies to minimize the adverse-event profile for patients receiving ADT.

Keywords: Androgen deprivation therapy; Gonadotropin-releasing hormone, agonists; Prostate cancer.

Figure 1

Gonadotropin-releasing hormone (GnRH), secreted in pulses from the hypothalamus, stimulates release of luteinizing hormone (LH) from the pituitary gland, along with adrenocorticotropic hormone (ACTH) and prolactin. LH subsequently stimulates secretion of testosterone, predominantly by the testes. Damber JE, Acta Oncologica, 2005;44:605-609, copyright © 2005, Informa Healthcare. Reproduced with permission of Informa Healthcare.

Figure 2

Survival free of androgen-independent progression (AIP) according to serum testosterone behavior. Group 1, patients with all three serum testosterone determinations less than < 20 ng/dL. Group 2, patients with breakthrough increases between 20 and 50 ng/dL. Group 3, patients with breakthrough increases . 50 ng/dL. ADT, androgen deprivation therapy; PSA prostate-specific antigen. Reproduced with permission from Morote J et al.

Figure 3

Hazard ratio and related 95% confidence interval. PSA prostate-specific antigen. Reproduced with permission from Perachino M et al.

Figure 4

The maintenance of castration in men treated with triptorelin pamoate, 3.75 mg (green line, open circles), or leuprolide acetate, 7.5 mg (red line, open squares), for 9 months (Kaplan-Meier survival analysis). Reproduced with permission from Heyns CF et al.

Figure 5

Mean serum testosterone levels were analyzed every 28 days in 277 men receiving androgen deprivation with either leuprolide acetate or triptorelin pamoate. These levels fell below the predefined levels for medical castration (50 ng/dL) at 29 days and 57 days for 91% and 98% of subjects in the triptorelin pamoate group and 99% and 97% of the subjects in the leuprolide group. Although the mean difference was significant between the groups at 29 days, it was not significant at 57 days. Reproduced with permission from Heyns CF et al.