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Cardiovascular Risk with ADT for Advanced Prostate Cancer

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 2014 Genitourinary Cancers Symposium

San Francisco, California / January 30-February 1, 2014

San Francisco - The principal goal of androgen deprivation therapy (ADT) is to reduce testosterone to castrate levels, thereby depriving prostate cancer cells of their key growth substrate. However, several studies have shown that ADT induces metabolic disturbances that can lead to increased adiposity, weight gain, and metabolic syndrome, heightening a patient’s risk of cardiovascular disease (CVD). ADT strategies — which target among others the gonadotropin-releasing hormone (GnRH), also called luteinizing-hormone releasing hormone (LHRH) — may differ in their effects on CVD risk. A pooled analysis of six randomized prospective trials showed that ADT with a GnRH antagonist was associated with a 56% lower risk of a CV event or death compared with GnRH agonists. Data reported at the Genitourinary Cancers Symposium provided additional insight into the CV effects of different ADT regimens. A laboratory study showed that a LHRH agonist increased levels of follicle-stimulating hormone (FSH), which has been associated with increased adiposity. In contrast, treatment with the LHRH antagonist degarelix lowered FSH levels. In vivo studies showed that degarelix was associated with less weight gain, adiposity, metabolic change, and CVD compared with an LHRH agonist and orchiectomy.  Additionally, pooled data from two randomized trials showed that the combination of an LHRH agonist and antiandrogen was less effective than degarelix for controlling testosterone flare in men with high-risk prostate cancer.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

During menopause women experience a rise in FSH levels as estrogen declines. This rise is accompanied by increased adiposity;a similar occurence in men remains unclear.

“We hypothesized that castration-induced elevation in FSH levels can similarly result in adipogenesis and that GnRH antagonists, which lower FSH levels, will associate with reduced adiposity as compared to GnRH analogues and orchiectomy,” said Dr. Jehonathan Pinthus, McMaster University, Hamilton, Ontario.

To confirm this effects, investigators introduced different FSH concentrations into a mouse fibroblast cell line during differentiation. After 8 days, examination of the cells showed FSH-induced differentiation of murine pre-adipocyte into fat cells, increasing fatty acid synthase expression and lipid production.

In vivo studies examined several metabolic effects associated with different ADT therapies. Mice were randomly divided into four groups: sham surgery plus vehicle, orchiectomy plus vehicle, sham surgery plus degarelix, and sham surgery plus leuprolide. Beginning 2 days after surgery, the mice received vehicle, degarelix, or leuprolide every 2 weeks for 4 months, at which time levels of testosterone, FSH, LH, and 17 beta-estradiol were measured.

Mice in the orchiectomy, leuprolide, and degarelix groups had mean testosterone levels of 0.18 to 0.27 ng/mL as compared with 5.18 ng/mL in the control group. Testosterone levels did not differ significantly among the three groups receiving active therapy.

Orchiectomy resulted in the highest mean FSH level (99.25 ng/mL), significantly higher than the mean in the control group (44.38 ng/mL, P<0.05). The leuprolide group had a mean FSH value of 5.56 ng/mL, significantly lower as compared with the control and orchiectomy groups (P<0.05). FSH levels averaged 3.02 ng/mL in the degarelix group, significantly lower than the other three groups, including leuprolide (P<0.005).

The orchiectomy group had a mean LH value of 6.14 ng/mL, significantly higher than each of the other three groups (P<0.05). The degarelix-treated animals had the lowest mean LH level (0.02 ng/mL, P<0.05 versus each of the other groups). The mean 17 beta-estradiol level ranged from 3.25 to 4.98 pg/mL and did not differ significantly among the four groups.

Additional metabolic parameters were monitored throughout the study. As compared with the other three groups, animals given degarelix had significantly less longitudinal weight gain, as determined by body mass index (P<0.0005), and a more favourable distribution of lean and fat body mass and smaller adipocyte size.

Assessment of parameters associated with metabolic syndrome showed lower triglyceride levels, a more favourable lipid profile, and better glucose tolerance in the degarelix group. Analyses of ascending aorta specimens showed that degarelix-treated mice had significantly less atherosclerotic plaque compared with the orchiectomy and leuprolide groups (P<0.05), including total plaque area and necrotic plaque.

“When you look at the atherosclerotic plaque, obviously you can see that androgen deprivation is associated with atherosclerosis,” said Dr. Pinthus. “Degarelix was associated with the smallest plaque size, but more importantly, the lipid core or necrotic area—which is a marker for the vulnerability of the plaque—is significantly lower with degarelix.”

The results complement previous findings showing that patients with prostate cancer and pre-existing CVD had a 56% reduction in the risk of CV event or death with a gonadotropin-releasing hormone (GnRH) antagonist versus agonist (Albertsen PC et al. J Eur Urol 2014 Mar; 65(3):565-73), Dr. Pinthus added.

Duration of PSA Response - High-risk Patients

Two multicenter, randomized trials evaluated symptomatic flare with LHRH agonist/antiandrogen combination therapy versus degarelix monotherapy. Primary outcomes were mean percentage change in testosterone and PSA, PSA-progression free survival (pPFS), and mean absolute change in serum alkaline phosphatase in the degarelix and combination-therapy groups during 1 year of treatment and follow-up. PSA recurrence was defined as two consecutive measurements showing ≥50% increase from nadir and ≥5 ng/mL.

In the two trials combined, 974 patients received the LHRH antagonist, 414 patients received LHRH agonist monotherapy, and 69 patients received both an LHRH agonist and antiandrogen, reported Dr. Bertrand Tombal, Université Catholique de Louvain, Brussels, Belgium. A higher proportion of patients treated with combination therapy had Gleason score 7-10, metastatic disease, and baseline PSA >50 ng/mL as compared with degarelix-treated patients.

Pre-injection change in testosterone was similar between groups;after 1 month of treatment, both groups had >90% testosterone suppression, which was maintained over the course of the study.

As compared with the combination-therapy group, men receiving degarelix monotherapy had a 51% hazard reduction for pPFS (HR 0.49, P=0.003). A similar difference in favour of degarelix was seen in the subgroup of men who had baseline PSA levels >20 ng/mL (HR 0.50, P=0.0198). Among patients with metastatic disease, serum alkaline phosphatase levels were significantly lower in degarelix-treated men. (P=0.0025) as well as a reduced mortality hazard versus those receiving combination ADT (HR 0.37, P=0.049).

“Most of the data on degarelix comes from the registration trial that compared degarelix to leuprolide,” said Dr. Tombal. “But here we report a pooled analysis of degarelix versus LHRH agonist data. It confirms on a larger dataset that an LHRH antagonist extends the duration of PSA response in patients with a PSA >20 ng/mL and, as previously demonstrated, is associated with less skeletal side effects and urinary infection.”

Neoadjuvant Hormonal Therapy

LHRH agonists have been used extensively as neoadjuvant therapy prior to radical prostatectomy. By comparison, monotherapy with antiandrogens maintains near-normal serum testosterone levels, thereby reducing the adverse effects on sexual function, physical function, and quality of life.

Despite the potential advantages versus LHRH agonists, antiandrogens have no evidence to support their use in the neoadjuvant setting, said Dr. Darren M. Mitchell, Belfast City Hospital, Northern Ireland. Nonetheless, anecdotal experience suggests the safety and efficacy of neoadjuvant antiandrogen therapy in the treatment of localized prostate cancer.

Dr. Mitchell and colleagues retrospectively reviewed records of men with localized prostate cancer treated for at least 1 month with bicalutamide prior to curative treatment with three-dimensional conformal radiotherapy, matching each patient with one who had received at least 2 months of neoadjuvant LHRH agonist therapy.

Each group included 65 men. Those in the antiandrogen group had been followed for a median duration of 44 months. PSA kinetics were compared for the two groups, using initial PSA value and pre-radiotherapy/post-hormonal treatment to calculate PSA halving time and velocity. Men treated with an antiandrogen had a mean pre-radiotherapy (nadir) PSA value of 2.0 ng/mL versus 1.0 ng/mL in the LHRH agonist group (P<0.001). PSA halving time and PSA velocity did not differ between groups.

Defining biochemical failure as PSA nadir value + 2 ng/mL, investigators found that 14 (23.4%) patients in the antiandrogen group and nine (13.8%) in the LHRH agonist group experienced PSA failure. Neither pre-radiotherapy PSA nadir nor PSA kinetics during the neoadjuvant period predicted biochemical failure at follow-up, Dr. Mitchell reported.

After a median follow-up of 72 months for all patients, two (3%) prostate cancer deaths have occurred in the LHRH agonist group and three (4.6%) in the antiandrogen group.

“In this case-matched study we found that although neoadjuvant bicalutamide monotherapy did not result in equivalent pretreatment PSA suppression, when compared to neoadjuvant LHRH agonist alone, there is no statistical difference in biochemical failure-free survival between the cohorts at an overall median follow-up of 72 months. Longer follow-up is required,” Dr. Mitchell and colleagues concluded

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