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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.

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Presentation on theme: "Benefits and Risks of GnRH/LHRH Agonists and Antagonists in Advanced Prostate Cancer Patients John Trachtenberg, MD Director, Prostate Cancer Princess."— Presentation transcript:

1 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

2 Leuprolide vs Diethylstilbestrol for Metastatic Prostate Cancer Increased incidence of flare Increased incidence of flare Decreased rate of initial response Decreased rate of initial response Better adverse event profile Better adverse event profile No difference in objective response No difference in objective response No difference in 1-year survival 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 LHRH agonists Combined androgen blockade (CAB) Combined androgen blockade (CAB) LHRH (GnRH) antagonists 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) 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 Randomized 1:1 to treatment with goserelin acetate implant 3.6 mg or bilateral orchiectomy Endpoints 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 partial7172 No change1822 Disease progression116 Mean time to response (wk) Median duration of response in responding pts (wk) Median time to treatment failure in all pts (wk) * *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 Goserelin AcetateOrchiectomy (n = 148)(n = 144)

6 All Patients * No. of patients No. of deaths Median survival (wk)11099 Depot period patients * No. of patients No. of deaths8489 Median survival (wk) *No significant between-group differences. Kaisary AV, et al. Br J Urol. 1991;67:502. Goserelin AcetateOrchiectomy Comparison of Goserelin with Orchiectomy in Metastatic Prostate Cancer: Study Results (contd) Comparison of Goserelin with Orchiectomy in Metastatic Prostate Cancer: Study Results (contd)

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

8 del Moral FP, et al. Urology. 1996;48:894. 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 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) 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) Primary endpoint: mean serum testosterone level (between weeks 4 and 12, and at the end of weeks 4, 8, and 12)

9 del Moral FP, et al. Urology. 1996;48:894. Nominal Study Week Mean Testosterone (nmol/L) 10.8 mg depot 3.6 mg depot Castrate level Goserelin acetate Clinical Efficacy of 3-Month Depot of Goserelin Acetate Mean Serum Testosterone Levels over 48 Weeks

10 Combined Androgen Blockade LHRH Agonist Plus Anti-androgen Eliminate flare Eliminate flare –5%–33% incidence in patients with metastatic disease Improve survival by decreasing effect of adrenal androgens 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 PFS (16.5 vs 13.9 mo) Improved survival (35.6 vs 28.3 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 (contd) Combined Androgen Blockade LHRH Agonist Plus Anti-androgen (contd) Eliminate flare 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) Improve survival by decreasing effect of adrenal androgens (bilateral orchiectomy with or without flutamide for metastatic prostate cancer) Shows no clinically important survival advantage 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 2 phase III studies of abarelix – : compared abarelix with leuprolide – : compared abarelix with leuprolide plus bicalutamide Study objectives 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: Trachtenberg J, et al. J Urol. 2002;167:1670.

14 24%< %< %< %< %< %< %< %<.001 Abarelix Comparator P-value (vs L) (vs L + B) Castrate Castrate 82%0%< %0%< (vs L) (vs L + B) 2 Abarelix Comparator P-value P-value Surge* *Calculation of T surge: 2 of 3 testosterone level measurements between days 2 and 8 exceeded PT baseline level by 10%. Fishers exact test Definition of castration: Testosterone 50 ng/dL Day 2 Day 4 Day 15 Day 2 Day 4 Day 15 Day 2 Day 4 Day 8 Day 15 Day 2 Day 4 Day 8 Day 15 0%0% 0%10%0%0% 21% Abarelix Studies: Surge and Castrate Levels 1. McLeod D, et al. Urology. 2001;58: Trachtenberg J, et al. J Urol. 2002;167:1670.

15 T Level (ng/dL) Study Day 15 T Level (ng/dL) Study Day 1829 Leuprolide + Bicalutamide Abarelix *P <.001 when compared with abarelix. * * * * Trachtenberg J, et al. J Urol. 2002;167:1670. With permission from Lippincott, Williams, & Wilkins. Abarelix Studies: Median Testosterone Levels Study Through Day 29

16 Study Median Percentage Change in PSA n - LD n - AD Time (Days) Abarelix Leuprolide Abarelix Studies: Median Percentage Change from Baseline PSA * * 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. 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. 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. In US studies, testosterone fluctuations after 6 months of treatment were of little clinical relevance.

18 ABACAS 1 Comparison of the efficacy and safety of abarelix vs goserelin plus bicalutamide Comparison of the efficacy and safety of abarelix vs goserelin plus bicalutamide 177 patients with advanced or metastatic prostate cancer 177 patients with advanced or metastatic prostate cancer 1-year, randomized, open-label, multicenter, phase III trial 1-year, randomized, open-label, multicenter, phase III trial

19 ABACAS 1 Patient Demographics Goserelin + Abarelix BicalutamideTotal (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 7–1047(54%)50(56%)97(55%)

20 ABACAS 1 Study Results Goserelin Total+ Endpoint Abarelix Bicalutamide Median time to medical castration7 days21 days Castration rates (day 3)36%0% Testosterone surge0%96% Testosterone fluctuations above castrate levels22%8% Disease progression rates9%9%

21 Immediate-Onset Systemic Allergic Reactions Of 1400 patients treated with abarelix, systemic reactions requiring discontinuation occurred in 6 patients. Of 1400 patients treated with abarelix, systemic reactions requiring discontinuation occurred in 6 patients. Reactions occurred within 10 minutes of receiving abarelix. Reactions occurred within 10 minutes of receiving abarelix. All patients recovered. All patients recovered. Rates of allergic reactions requiring medical intervention are similar in comparative clinical studies. Rates of allergic reactions requiring medical intervention are similar in comparative clinical studies.

22 Summary Summary Objective of androgen ablation in prostate cancer treatment is to deprive prostate cancer cells of testosterone. 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. 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. Development of the LHRH agonists offered an effective alternative to surgical castration. Clinical trials demonstrated comparable efficacy between an LHRH agonist and bilateral orchiectomy. Clinical trials demonstrated comparable efficacy between an LHRH agonist and bilateral orchiectomy.

23 Summary (contd) The discovery and development of the GnRH antagonists have advanced treatment of prostate cancer. 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. The GnRH antagonist abarelix has demonstrated favorable efficacy and tolerability in phase III clinical trials. GnRH antagonists 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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