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Benefits and Risks of GnRH/LHRH Agonists and Antagonists in Advanced Prostate Cancer Patients John Trachtenberg, MD Director, Prostate Cancer Princess Margaret Hospital Professor, Department of Surgery University of Toronto Toronto, Ontario, Canada Leuprolide vs Diethylstilbestrol for Metastatic Prostate Cancer Increased incidence of flare Decreased rate of initial response Better adverse event profile No difference in objective response No difference in 1-year survival Leuprolide Study Group. N Engl J Med. 1984;311(20):1281. Alternatives to Surgical Castration in the Treatment of Advanced Prostate Cancer LHRH agonists Combined androgen blockade (CAB) LHRH (GnRH) antagonists Comparison of Goserelin with Orchiectomy in Metastatic Prostate Cancer Study compared goserelin with orchiectomy in 358 patients with metastatic prostatic carcinoma (292 evaluable) Randomized 1:1 to treatment with goserelin acetate implant 3.6 mg or bilateral orchiectomy Endpoints – Subjective responses – Objective responses – Overall survival – Effects of testosterone withdrawal – Adverse effects Kaisary AV, et al. Br J Urol. 1991;67:502. Comparison of Goserelin with Orchiectomy in Metastatic Prostate Cancer: Study Results Goserelin Acetate Orchiectomy (n = 148) (n = 144) Response* (%) Complete and partial No change Disease progression 71 18 11 72 22 6 Mean time to response (wk) 9.0 10.2 Median duration of response in responding pts (wk) 53.7 50.1 Median time to treatment failure in all pts (wk) 26.9 40.3 *All between-group P values were nonsignificant. Kaisary AV, et al. Br J Urol. 1991;67:502. Comparison of Goserelin with Orchiectomy in Metastatic Prostate Cancer: Study Results (cont’d) Goserelin Acetate Orchiectomy All Patients* No. of patients No. of deaths Median survival (wk) 176 102 110 182 116 99 “Depot period” patients* No. of patients No. of deaths Median survival (wk) 148 84 115 144 89 104 *No significant between-group differences. Kaisary AV, et al. Br J Urol. 1991;67:502. Physiologic Effects of Testosterone Withdrawal 73% (37/51) 79% (34/43) Decrease in libido Decrease in erections 84% (43/51) 85% (41/48) 63% (96/152) 58% (94/163) Hot flashes Breast swelling 4.8% (8/168) 4% (7/173) Goserelin acetate implant 0.6% (1/167) 1.2% (2/173) Breast tenderness 0 20 Orchiectomy 40 60 Percentage Kaisary AV, et al. Br J Urol. 1991;67:502. 80 100 Clinical Efficacy of 3-Month Depot of Goserelin Acetate Two randomized, multicenter trials compared pharmacodynamics and tolerability of the 10.8 mg and 3.6 mg goserelin acetate depots Patients with histologically confirmed prostate cancer, either locally advanced (T3, T4) or metastatic disease (M1) and life expectancy >6 months (N = 160) Primary endpoint: mean serum testosterone level (between weeks 4 and 12, and at the end of weeks 4, 8, and 12) del Moral FP, et al. Urology. 1996;48:894. Mean Testosterone (nmol/L) Clinical Efficacy of 3-Month Depot of Goserelin Acetate Mean Serum Testosterone Levels over 48 Weeks 20.0 Goserelin acetate 17.5 10.8 mg depot 15.0 3.6 mg depot 12.5 10.0 7.5 5.0 Castrate level 2.5 0.0 0 1 2 3 4 6 8 10 12 14 16 18 20 22 24 36 48 Nominal Study Week del Moral FP, et al. Urology. 1996;48:894. Combined Androgen Blockade LHRH Agonist Plus Anti-androgen Eliminate flare – 5%–33% incidence in patients with metastatic disease Improve survival by decreasing effect of adrenal androgens – A controlled trial of leuprolide with and without flutamide in prostatic carcinoma Improved PFS (16.5 vs 13.9 mo) Improved survival (35.6 vs 28.3 mo) Crawford et al, N Engl J Med. 1989;321:418. Combined Androgen Blockade LHRH Agonist Plus Anti-androgen (cont’d) Eliminate flare – Modest QOL cost (diarrhea, anemia) Improve survival by decreasing effect of adrenal androgens (bilateral orchiectomy with or without flutamide for metastatic prostate cancer) Shows no clinically important survival advantage Eisenberger et al, N Engl J Med. 1998;339:1036. GnRH Antagonists in Advanced Prostate Cancer Abarelix Studies 2 phase III studies of abarelix – 149-98-021: compared abarelix with leuprolide – 149-98-032: compared abarelix with leuprolide plus bicalutamide Study objectives – Compare rates of avoidance of testosterone surge – Compare rates of reduction of testosterone to castrate level 1. McLeod D, et al. Urology. 2001;58:756. 2. Trachtenberg J, et al. J Urol. 2002;167:1670. Abarelix Studies: Surge and Castrate Levels Surge* 149-98-02 (vs L)1 149-98-03 (vs L + B)2 Castrate‡ 149-98-021 (vs L) 149-98-032 (vs L + B) Day 2 Day 4 Day 8 Day 15 Day 2 Day 4 Day 8 Day 15 Comparator Abarelix P-value† 82% 86% 0% 0% < .001 < .001 Comparator Abarelix P-value1 0% 0% 0% 10% 0% 0% 0% 21% 24% 57% 72% 75% 25% 54% 68% 72% < .001 < .001 < .001 < .001 < .001 < .001 < .001 < .001 *Calculation of T surge: 2 of 3 testosterone level measurements between days 2 and 8 exceeded PT baseline level by ≥10%. †Fisher’s exact test ‡Definition of castration: Testosterone ≤50 ng/dL 1. McLeod D, et al. Urology. 2001;58:756. 2.Trachtenberg J, et al. J Urol. 2002;167:1670. Abarelix Studies: Median Testosterone Levels Study 149-98-03 Through Day 29 Leuprolide + Bicalutamide Abarelix 600 600 500 * T Level (ng/dL) T Level (ng/dL) * * 400 300 200 * 100 8 15 400 300 200 100 0 1 500 29 0 1 Study Day *P < .001 when compared with abarelix. Trachtenberg J, et al. J Urol. 2002;167:1670. With permission from Lippincott, Williams, & Wilkins. www.lww.com 8 15 Study Day 29 Abarelix Studies: Median Percentage Change from Baseline PSA Study 149-98-02 Median Percentage Change in PSA 0 * Leuprolide -20 Abarelix -40 * -60 -80 -100 n - LD n - AD 88 174 1 87 179 7 85 176 13 19 25 31 37 43 49 55 61 67 73 79 85 Time (Days) Note: Bars represent interquartile range. *P .001. Reprinted from McLeod D, et al. Urol. 2001;58:756. With permission from Elsevier Science. Abarelix Studies: Clinical Relevance of Testosterone Fluctuations 2%–3% of abarelix patients per month had testosterone fluctuations after 6 months compared with no leuprolide patients. 1.8% (4/221) of patients did not have the intended therapeutic benefit of abarelix, as correlated with testosterone values >50 ng/dL. In US studies, testosterone fluctuations after 6 months of treatment were of little clinical relevance. ABACAS 1 Comparison of the efficacy and safety of abarelix vs goserelin plus bicalutamide 177 patients with advanced or metastatic prostate cancer 1-year, randomized, open-label, multicenter, phase III trial ABACAS 1 Patient Demographics PCa stage N1–M0 (D1) Nx–M1 (D2) Rising PSA Abarelix (n = 87) Goserelin + Bicalutamide (n = 90) Total (N = 177) 17 (20%) 39 (44.8%) 30 (34.5%) 19 (21%) 39 (43.3%) 31 (34.4%) 36 (20.3%) 78 (44.1%) 61 (34.5%) 50 (56%) 97 (55%) Gleason score 7–10 47 (54%) ABACAS 1 Study Results Endpoint Median time to medical castration Castration rates (day 3) Testosterone surge Testosterone fluctuations above castrate levels Disease progression rates Total Abarelix Goserelin + Bicalutamide 7 days 21 days 36% 0% 0% 96% 22% 8% 9% 9% Immediate-Onset Systemic Allergic Reactions Of 1400 patients treated with abarelix, systemic reactions requiring discontinuation occurred in 6 patients. Reactions occurred within 10 minutes of receiving abarelix. All patients recovered. Rates of allergic reactions requiring medical intervention are similar in comparative clinical studies. Summary Objective of androgen ablation in prostate cancer treatment is to deprive prostate cancer cells of testosterone. Surgical castration (orchiectomy) was the initial treatment of choice for prostate cancer management. Development of the LHRH agonists offered an effective alternative to surgical castration. Clinical trials demonstrated comparable efficacy between an LHRH agonist and bilateral orchiectomy. Summary (cont’d) The discovery and development of the GnRH antagonists have advanced treatment of prostate cancer. The GnRH antagonist abarelix has demonstrated favorable efficacy and tolerability in phase III clinical trials. GnRH antagonists – Cause an immediate and rapid suppression of testosterone levels – Are not associated with testosterone surge and clinical flare – Can be used in patients for whom LHRH agonists are contraindicated – Are well tolerated and have an acceptable safety profile