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Benefits and Risks of GnRH/LHRH Agonists and Antagonists in Advanced Prostate Cancer Patients

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.

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Benefits and Risks of GnRH/LHRH Agonists and Antagonists in Advanced Prostate Cancer Patients

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  1. Benefits and Risks of GnRH/LHRH Agonists and Antagonists inAdvanced Prostate Cancer Patients John Trachtenberg, MD Director, Prostate Cancer Princess Margaret Hospital Professor, Department of Surgery University of Toronto Toronto, Ontario, Canada

  2. 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.

  3. Alternatives to Surgical Castration in the Treatment of Advanced Prostate Cancer • LHRH agonists • Combined androgen blockade (CAB) • LHRH (GnRH) antagonists

  4. 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.

  5. Response* (%) Complete and partial 71 72 No change 18 22 Disease progression 11 6 Mean time to response (wk) 9.0 10.2 Median duration of response 53.7 50.1 in responding pts (wk) Median time to treatment 26.9 40.3 failure in all pts (wk) Comparison of Goserelin with Orchiectomy in Metastatic Prostate Cancer: Study Results Goserelin Acetate Orchiectomy (n = 148) (n = 144) *All between-group P values were nonsignificant.Kaisary AV, et al. Br J Urol. 1991;67:502.

  6. All Patients* No. of patients 176 182 No. of deaths 102 116 Median survival (wk) 110 99 “Depot period” patients* No. of patients 148 144 No. of deaths 84 89 Median survival (wk) 115 104 Comparison of Goserelin with Orchiectomy in Metastatic Prostate Cancer: Study Results (cont’d) Goserelin Acetate Orchiectomy *No significant between-group differences. Kaisary AV, et al. Br J Urol. 1991;67:502.

  7. Physiologic Effects ofTestosterone Withdrawal 73% (37/51) Decrease in libido 79% (34/43) Decrease inerections 84% (43/51) 85% (41/48) 63% (96/152) Hot flashes 58% (94/163) 4.8% (8/168) Breast swelling Goserelin acetate implant Orchiectomy 4% (7/173) 0.6% (1/167) Breast tenderness 1.2% (2/173) 0 20 40 60 80 100 Percentage Kaisary AV, et al. Br J Urol. 1991;67:502.

  8. Clinical Efficacy of 3-Month Depot of Goserelin Acetate • Two randomized, multicenter trials compared pharmacodynamics and tolerability of the 10.8 mgand 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.

  9. 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 3.6 mg depot 15.0 12.5 Mean Testosterone (nmol/L) 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.

  10. Combined Androgen Blockade LHRH Agonist Plus Anti-androgen • Eliminate flare • 5%–33% incidence in patients with metastatic disease • Improve survival by decreasing effect ofadrenal 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.

  11. 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.

  12. GnRH Antagonists in Advanced Prostate Cancer

  13. Abarelix Studies • 2 phase III studies of abarelix • 149-98-021: compared abarelixwith 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.

  14. 24% < .001 57% < .001 72% < .001 75% < .001 25% < .001 54% < .001 68% < .001 72% < .001 Abarelix Studies: Surge and Castrate Levels Comparator P-value† Abarelix Surge* 82% 0% < .001 86% 0% < .001 149-98-02 (vs L)1 149-98-03 (vs L + B)2 Comparator P-value1 Abarelix Castrate‡ Day 2 Day 4 Day 8Day 15 Day 2 Day 4 Day 8Day 15 0% 0% 0% 10% 0% 0% 0% 21% 149-98-021(vs L) 149-98-032(vs L + B) *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.

  15. 1 8 15 29 Abarelix Studies:Median Testosterone Levels Study 149-98-03 Through Day 29 Leuprolide+ Bicalutamide Abarelix 600 600 * * 500 500 * 400 400 T Level (ng/dL) T Level (ng/dL) 300 300 200 200 * 100 100 0 0 1 8 15 29 Study Day 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

  16. Abarelix Studies: Median Percentage Change from Baseline PSA Study 149-98-02 0 * Leuprolide -20 Abarelix Median PercentageChange in PSA -40 * -60 -80 -100 n - LD 88 87 85 n - AD 174 179 176 1 7 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.

  17. 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.

  18. ABACAS 1 • Comparison of the efficacy andsafety of abarelix vs goserelinplus bicalutamide • 177 patients with advanced or metastatic prostate cancer • 1-year, randomized, open-label, multicenter, phase III trial

  19. ABACAS 1Patient Demographics Goserelin + Abarelix Bicalutamide Total (n = 87) (n = 90) (N = 177) PCa stage N1–M0 (D1) 17 (20%) 19 (21%) 36 (20.3%) Nx–M1 (D2) 39 (44.8%) 39 (43.3%) 78 (44.1%) Rising PSA 30 (34.5%) 31 (34.4%) 61 (34.5%) Gleason score 7–10 47 (54%) 50 (56%) 97 (55%)

  20. ABACAS 1 Study Results Goserelin Total + Endpoint Abarelix Bicalutamide Median time to medical castration 7 days 21 days Castration rates (day 3) 36% 0% Testosterone surge 0% 96% Testosterone fluctuations above castrate levels 22% 8% Disease progression rates 9% 9%

  21. 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.

  22. 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 prostatecancer management. • Development of the LHRH agonists offered an effective alternative to surgical castration. • Clinical trials demonstrated comparable efficacy between an LHRH agonist andbilateral orchiectomy.

  23. Summary (cont’d) • The discovery and development of the GnRH antagonists have advanced treatment ofprostate cancer. • The GnRH antagonist abarelix has demonstrated favorable efficacy and tolerability in phase IIIclinical 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

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