Presentation on theme: "Endocrinology of Prostate Cancer"— Presentation transcript:
1Endocrinology of Prostate Cancer Initially, prostate cancer is a hormone-dependent disease responding to testosterone, as demonstrated in the following slides.
2Hormonal Pathways of the Male Endocrine System Shown is the hypothalamic-pituitary-gonadal axis, which determines the endocrine environment of the prostate gland.In response to luteinizing hormone (LH) stimulation from the anterior pituitary gland, testosterone is produced by the Leydig cells of the testes. Gonadotropins (LH and follicle stimulating hormone) are secreted in the anterior pituitary gland by the action of LH releasing hormone (LHRH), which is produced by the hypothalamus.Operating as a negative feedback mechanism, LHRH is released from the hypothalamus when levels of testosterone fall, thereby increasing levels of LH and, consequently, testosterone. This rise in testosterone, in turn, results in a reduction of hypothalamic LHRH.Adrenocorticotropic hormone (ACTH) stimulates the adrenal to secrete 3 androgens: dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S) and androstenedione (AND). These are inactive DHT precursors that enter prostate cells where they are converted to DHT. The adrenal gland produces approximately 5% of androgens.Schlegel PN, Hardy M. Male reproductive physiology. In: Walsh PC, Retik AB, Vaughn ED Jr, eds. Campbell’s Urology. 8th ed. Philadelphia, Pa. WB Saunders; 2002:
3sex-hormone-binding globulin TestosteroneOriginDistribution5% from adrenals2% not bound95%from testes54% bound with albumin44% bound withsex-hormone-binding globulinThe testes account for 95% of total androgens, or male hormones, in the form of testosterone. The adrenal glands produce the remaining 5%.Most testosterone circulates in the bloodstream, bound to either sex- steroid-binding globulin or albumin.About 44% is bound with sex-hormone-binding globulin, and 54% is bound with albumin. A small percentage of testosterone, about 2%, is unbound.The plasma concentration of sex-hormone-binding globulin (SHBG) is determined by several hormones, and is elevated in hypergonadal men. While unbound testosterone has long been regarded as the biologically active portion, it is now known that dissociation of protein-bound testosterone can also occur. Hence the unbound, active fraction may be larger than that measured in vitro.Partin AW, Rodriguez R. The molecular biology, endocrinology, and physiology of the prostate and seminal vesicle. In: Walsh PC, Retik AB, Vaugh ED Jr, eds. Campbell’s Urology. 8th ed. Philadelphia, Pa. WB Saunders; 2002:Griffin JE, Wilson JD. Disorders of the testes and the male reproductive tract. In: Wilson JD, Foster DW, Krenenberg HM, Larsen PR, eds. Williams Textbook of Endocrinology. 9th ed. Philadelphia, Pa. WB Saunders; 1998:Dunn JF, Nisula BC, Rodbard D. Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma. J Clin Endocrinol Metab. 1981;53:58-68.Pardridge WM. Serum bioavailability of sex steroid hormones. Clin Endocrinol Metab. 1986;15:Plymate SR, Leonard JM, Paulsen CA, et al. Sex hormone-binding globulin changes with androgen replacement. J Clin Endocrinol Metab. 1983;57:Source: Adapted from Coffey DS. In: Walsh PC, et al, eds.Campbell’s Urology. 6th ed. 1992:
4Circulating Androgens Daily ProductionRelative PotencyRatioDHT(1.1%)2.01.20.00.18.104.22.168T(20.7%)AND(5.4%)Unbound testosterone is metabolized by 5-reductase within the prostatic cell membrane to dihydrotestosterone (DHT), a hormone far more potent as an androgen than testosterone. Though relatively little DHT is produced in comparison with other androgens (about 1% of total daily production), DHT is more potent than other androgens (ie, testosterone) and its interaction with the adrenal is more efficient and therefore activates cell growth and replication. Although relative potencies of adrenal androgens are low vs testosterone and DHT, metabolic conversion of androgens and DHEA may contribute to as much as 40% of the total DHT pool produced within the prostate.DHEA(72.7%)TDHTANDDHEASources: Adapted from Partin AW, Rodriguez R. In: Walsh PC, et al, eds. Campbell’s Urology. 8th ed. 2002: ; Labrie F, et al. Cancer.1993; 71(Suppl 3):
5Testosterone Pathway in Prostatic Cells (Free)The majority of testosterone circulates in the bloodstream bound either to sex hormone binding globulin (SHBG) or to albumin. Approximately 2% to 3% of circulating testosterone is unbound (free testosterone) and is thought to be the functionally active form of testosterone that is incorporated into the prostate gland.As free testosterone passes through the prostatic cell membrane, it is metabolized to dihydrotestosterone (DHT) by the enzyme 5-reductase. Intracellular DHT is much more potent as an androgen than testosterone is.Within the cell nucleus, DHT binds to a receptor and activates prostatic cell functions. It is the action of DHT that activates the growth of prostatic tumors.Although castration (LHRH-analog or bilateral orchiectomy) causes a 95% reduction in testosterone serum concentrations, the intraprostatic concentration of DHT is less affected. The amount of androgen detectable in prostatic cancer tissue following castration (LHRH-A or bilateral orchiectomy) may be up to 40% of normal levels.Partin AW, Rodriguez R. The molecular biology, endocrinology, and physiology of the prostate and seminal vesicles. In: Walsh PC, Retik AB, Vaughn Ed Jr, eds. Campbell’s Urology. 8th ed. Philadelphia, Pa. WB Saunders; 2002:Auclerc G, Antoine EC, Cajfinger F, et al. Management of advanced prostate cancer. Oncologist. 2000;5:36-44.
6Hormonal Therapy Options The use of hormonal therapy options has gained widespread currency in the treatment of metastatic and recurrent prostate cancer, and is being explored as an adjuvant or neoadjuvant treatment with those therapies we’ve just discussed. The following slides explore this treatment option.
7Hormonal Therapy Bilateral orchiectomy LHRH analogs Antiandrogens Combined Androgen Blockade (CAB)Androgen antagonistHormonal therapy to achieve testosterone suppression may involve surgical castration (bilateral orchiectomy) or medical castration with luteinizing hormone-releasing hormone analogs (LHRH-A).Bilateral orchiectomy is a simple outpatient procedure with few complications; however, the operation is irreversible and side effects including hot flashes, decreased libido, and erectile dysfunction (60%-90% of patients) do occur. Given a choice between bilateral orchiectomy and LHRH-A therapy, only 22% (32/147) of patients elected to undergo bilateral orchiectomy compared to LHRH-A therapy in 2 clinical studies. Bilateral orchiectomy is not as acceptable to many patients for psychological reasons.LHRH-A or bilateral orchiectomy may be used in combination with an antiandrogen to achieve a combined androgen blockade (CAB). Low plasma concentration of androgens, primarily of adrenal origin, may remain after castration, having a stimulating effect on hormone-sensitive prostate cancer cells. Antiandrogens act as specific androgen receptor antagonists, thereby blocking endogenous androgen binding to prostate receptors.Cassileth BR, Soloway MS, Vogelzang NJ, et al. Patients’ choice of treatment in stage D prostate cancer. Urology. 1989;33(suppl):59-62.Kirby R. Treatment options for early prostate cancer. Urology. 1998;52:
8Bilateral Orchiectomy In 1941, Huggins and Hodges made original discovery of hormonal effect on prostate cancerSame studies also showed that bilateral orchiectomy improved pain or neurological symptoms in 71% of patients with metastatic diseaseAdvantages:Immediate castration without testosterone surgeOutpatient procedure, general anesthesia not requiredNo compliance issuesDisadvantages:IrreversibleOver 60 years ago, Huggins and Hodges published landmark studies on the effects of androgen suppression on advanced prostate cancer. For decades after, bilateral orchiectomy remained the gold standard of hormonal therapy for advanced disease. This outpatient surgery requires only local anesthesia and is simple, effective, and immediate. Drawbacks of bilateral orchiectomy include irreversibility and the psychological distress that body-altering surgery causes the patient.Huggins C, Hodges CV. Cancer Res. 1941;1: Huggins C, et al. Arch Surgery. 1941;43:209. Schroder FH. Campbell’s Urology, 8th ed. Philadelphia, Pa. WB Saunders;2002:
9Hormonal Therapy in Metastatic Disease HT has been most widely used in metastatic diseaseWhen to initiate HT is often debatedMRC (UK) Study938 patients with locally advanced and asymptomatic, metastatic prostate cancerEarly HT (89% orchiectomy; within 6 weeks of entry) vs Deferred HT (71.5% orchiectomy)Survival, local and distant progression, major complications evaluatedThe optimal timing of HT for prostate cancer treatment remains controversial, and whether earlier treatment is preferable to withholding it until symptoms or metastases occurs was studied by the Medical Research Council, in the UK.Nine hundred thirty-eight men with locally advanced and metastatic prostate cancer were randomized to early HT (within 6 weeks of entry) or to deferred treatment. No definitive local therapy was administered. Hormonal therapy consisted of either orchiectomy or LHRH-A. Data on survival, local and distant progression, and major complications were gathered annually.MRC Prostate Cancer Working Group Party Investigators Group Br J Urol. 1997;79:
10MRC Trial: Results 934 evaluable patients results 469 in the immediate HT group and 465 in the deferred HTDeferred ARM(# of patients)Immediate ARM (# of patients)P valuesDeath361328P=0.02Two-tailedCause Specific Death257203P=0.001TUR14165P<0.001Nine hundred thirty-four patients were evaluable, 469 in the immediate HT group and 465 in the deferred HT group. In patients without metastases, immediate HT resulted in a significant advantage in overall survival and improvement in cause-specific mortality. Patients treated with immediate HT had a reduction in comorbid sequelae of progressive disease, such as pathologic fractures, spinal cord compression, ureteral obstruction, extraskeletal metastases, and the necessity of palliative prostate resection.The results of the MRC study support the immediate use of HT for locally advanced disease, before the onset of symptoms.MRC Prostate Cancer Working Group Party Investigators Group Br J Urol. 1997;79:
11Mechanism of Action of LHRH Analogs HYPOTHALAMUSTestosteroneLHRH-AsCortisolLHRHCRHLHACTHPITUITARYTESTESADRENALTestosteroneAdrenalandrogensLuteinizing hormone-releasing hormone agonists (LHRH-As) have become the preferred alternative to bilateral orchiectomy for achieving androgen suppression.Testosterone is a product of Leydig cells in the testes. The secretion of testosterone is stimulated by the direct action of luteinizing hormone on high-affinity LH receptors located on Leydig cells. LH secretion from the pituitary is, in turn, stimulated by LHRH produced in the hypothalamus and delivered to the pituitary via the pituitary portal blood vessels. Thus, LHRH indirectly regulates the secretion of testosterone from the testes.Continuous exposure to LHRH-A by the pituitary, (shown in red) normally sensitive to LHRH release from the hypothalamus, results in the pituitary becoming refractory or desensitized to the hypothalamic stimulation of LHRH, and in the downregulation of pituitary LHRH receptors. This ultimately leads to suppression of LH and testosterone. The effects of LHRH-A are limited to the suppression of testicular androgen, as seen on the left side of this slide. Androgens of adrenal origin, as seen on the right side of the schematic, are not suppressed with LHRH-A therapy.PROSTATETestosteroneDHTInduction/StimulationFeedback/RegulationAdapted from Foote JE, Crawford ED. Semin Urol.1988;6(4):
12Time to Induction of Castration with Long-Term LHRH Analog Therapy Mean Serum Testosterone Levels4Level with ZOLADEX® (goserelin acetate implant) mg depotCastrate level3Mean serumtestosterone(ng/mL)21Debruyne et al sought to confirm the long-term cessation of serum testosterone to castrate levels using ZOLADEX depot 3.6 mg q28d sc. At a median follow-up of 49 weeks, a constant castrate level of serum testosterone, without any evidence of fluctuation throughout the day, was found after 1, 3, and 6 months of treatment. Results up to 36 weeks, with serum testosterone levels below the castrate level, are shown on this slide.The investigators concluded that ZOLADEX depot is effective for long-term suppression of serum testosterone to castrate levels (equivalent to orchiectomy), and is a suitable alternative to other forms of HT for patients with prostate cancer.Debruyne FMJ, Denis L, Lunglmayer G, et al. Long-term therapy with a deopt luteinizing hormone-releasing hormone analogue (Zoladex) in patients with advanced prostatic carcinoma. J Urol. 1988;140:4812162243236Time (weeks)No. of patientsAdapted from Debruyne FMJ, et al. J Urol.1988;140:
1324 RCT involving 6600 patients, (1966 - 1998) Results Single-Therapy Androgen Suppression in Men with Advanced Prostate Cancer: A Systematic Review and Meta-Analysis24 RCT involving 6600 patients, ( )ResultsLHRHa are equivalent to orchiectomy (10 trials, n=1908, HR , 95% CI, ).There was no difference in OS among the LHRH analoguesLeuprolide (hazard ratio, [CI, to 5.835])Buserelin (hazard ratio, [CI, to 2.404])Goserelin (hazard ratio, [CI, to 1.390]).Nonsteroidal antiandrogens are associated with lower OS( 8 trials, 2717 patients, HR [CI, to 1.496]).Treatment withdrawals are less frequent with LHRHa (0% to 4%) than with nonsteroidal antiandrogens (4% to 10%).Seidenfield et al Annals of Intern Med 2000, 132; 7:
14Pivotal Trial Overall Survival All Eligible PatientsEligible “Depot Period” Patients1.00.90.80.22.214.171.124.30.20.10.01.00.90.80.70.126.96.36.199.20.10.0n = 176 ZOLADEX® (goserelin acetate implant)n = 182 bilateral orchiectomyn = 148 ZOLADEXn = 144 bilateral orchiectomyEstimated Survival ProbabilityEstimated Survival ProbabilityZOLADEXZOLADEXPatients receiving ZOLADEX (goserelin acetate implant) had a median survival of 110 weeks, compared with 99 weeks for patients undergoing bilateral orchiectomy.In the intent-to-treat analysis,* no statistically significant difference existed in median survival between the treatment arm receiving ZOLADEX and the treatment arm undergoing bilateral orchiectomy.*All eligible patients were evaluated; some randomized patients who did not meet inclusion criteria were not included in the intent-to-treat analysis.Kaisary AV, Tyrrell CJ, Peeling WB, et al. Comparison of LHRH analogue (Zoladex) with orchiectomy in patients with metastatic prostatic carcinoma. Br J Urol. 1991;67:Bilateral OrchiectomyBilateral Orchiectomyp = 0.23p = 0.332448729612014416819221624487296120144168192216Length of Survival (Weeks)Length of Survival (Weeks)Adapted from: Kaisary AV, et al. Br J Urol. 1991;67:
15Pivotal Trial Pharmacological Adverse Events 73% (37/51)79% (34/43)84% (43/51)85% (41/48)63% (96/152)58% (94/163)4.8% (8/168)4% (7/173)ZOLADEX® (goserelin acetate implant)Bilateral OrchiectomyIllustrated in this slide are the percentages of patients from each treatment arm with the physiologic effects of therapeutic testosterone suppression to castrate levels. Among these effects are decrease in libido, decrease in erections, hot flashes, breast swelling, and breast tenderness.In this study, decrease in libido and erections, and hot flashes were the most common physiologic effects associated with therapeutic testosterone withdrawal.No statistically significant differences existed in the occurrence of these effects in the treatment arm receiving ZOLADEX compared with the treatment arm undergoing bilateral orchiectomy.0.6% (1/167)1.2% (2/173)Percent of Event RateAdapted from: Kaisary AV, et al. Br J Urol. 1991;67:
16Median follow-up at 4.5 years and 6.7 years RTOG Radiotherapy + Neoadjuvant/Concomitant ZOLADEX® (goserelin acetate implant) Study DesignLocally Advanced T2 – 4, N+/-, M0(N = 471)Median follow-up at 4.5 years and 6.7 yearsRandomizedRTOG was a randomized, prospective companion study to RTOG Patients had bulky primary tumors (>25 cm3), clinical stage T2 to T4. Patients with positive regional lymph nodes below the common iliac level were also eligible for admission to the study.Patients in Arm I received goserelin monthly beginning 2 months prior to the start of RT and continuing until the completion of treatment. Flutamide was started with the goserelin, or combined androgen blockade (CAB),* and also discontinued at the end of the 16-week treatment period. Patients treated in Arm II received RT alone. Of 471 patients randomized, 456 were evaluable (Arm I, 226; Arm II, 230).*Combined androgen blockade refers to maximal androgen ablation achieved by antiandrogen combined with medical or surgical castrationPilepich MV, Winter K, John MJ, et al. Phase III radiation therapy oncology group (RTOG) trial of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys. 2001;50:ARM IGoserelin 3.6 mg/ Flutamide 250 mg + RT (n = 226)ARM IIRT Alone (n = 230)Pilepich MV, et al. Int J Radiat Oncol Biol Phys 2001; 50: Reprinted with permission.
17Years from Date of Randomization RTOG Local Failure100755025Failed/Totalp = 0.016RT + Hormones 72/226RT Alone 98/230PercentAt a median follow-up of 6.7 years for all patients and 8.6 years for living patients, there was a highly significant improvement in local control and reduction in disease progression among patients in Arm I (RT + HT). As shown, there was a 30% local failure rate among patients in Arm I vs a failure rate of 42% among patients who received RT alone, in Arm II (P = 0.016).In addition, reduction in distant metastases, disease-free survival, biochemical disease-free survival, and cause-specific mortality were each statistically significantly improved in Arm I patients.Pilepich MV, Winter K, John MJ, Mesic JB, Sause W, Rubin P, et al. Phase III radiation therapy oncology group (RTOG) trial of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys. 2001;50:1161046352At risk123456789Years from Date of RandomizationPilepich MV, et al. Int J Radiat Oncol Biol Phys. 2001;50:
18Median follow-up at 4.5 years and 5.6 years RTOG TrialRadiotherapy + Adjuvant ZOLADEX® (goserelin acetate implant) Study DesignLocally Advanced (T1-2, N+; T3)(N=945)Median follow-up at 4.5 years and 5.6 yearsRandomizedRTOG randomized patients with locally advanced prostate cancer to either RT plus adjuvant ZOLADEX (Arm I) or to RT followed by ZOLADEX treatment begun at relapse (Arm II).Stage T3 patients were eligible regardless of lymph node involvement, and patients with stage T1/T2 disease were eligible if there was either radiologic or histologic evidence of regional lymph node involvement. Patients with bulky tumors were ineligible, unless there was evidence of spread to regional lymph nodes. Patients who had undergone RP were eligible if surgical margins were positive or there was invasion of seminal vesicles.Radiotherapy +goserelin 3.6 mg (n=477)Radiotherapy Alone(n=468)Pilepich MV et al. J Clin Oncol. 1997; 15:Lawton CA, et al. Int J Radiat Oncol Biol Phys. 2001;49:
19Years from Date of Randomization RTOG Local Failure100755025Failed/TotalRT + Adjuvant ZOLADEX® 92/477 (goserelin acetate implant)RT + ZOLADEX at Relapse 155/468p <PercentAt 8 years, 23% of patients receiving ZOLADEX® (goserelin acetate implant) plus radiotherapy (Arm I) exhibited incidence of local failure, compared with 37% of patients receiving radiotherapy alone (Arm II).This difference is statistically significant (P < ).123456789Years from Date of RandomizationReprinted from the International Journal of Radiation Oncology Biology and Physics, Vol. 49, CA Lawton, K Winter, K Murray, et al. Updated results of the Phase III radiation therapy for unfavorable prognosis carcinoma of the prostate, pp , with permission from Elsevier Science.
20RTOG 85-31 Distant Metastases 100755025Failed/TotalRT + Adjuvant ZOLADEX® 103/477 (goserelin acetate implant)RT + ZOLADEX at Relapse 154/468p <PercentAlso at 8 years follow-up, 27% of patients receiving ZOLADEX + RT exhibited evidence of metastatic disease, compared with 37% of patients receiving radiotherapy alone. This difference was also highly statistically significant (P < ).123456789Years from Date of RandomizationReprinted from the International Journal of Radiation Oncology Biology and Physics, Vol. 49, CA Lawton, K Winter, K Murray, et al. Updated results of the Phase III radiation therapy for unfavorable prognosis carcinoma of the prostate, pp , with permission from Elsevier Science.
21RTOG 85-31 Disease-Free Survival Median follow-up of 5.6 years100755025p <PercentAt 4.5 years, ZOLADEX + RT significantly improved disease-free survival compared with radiotherapy alone (P < ) in patients with locally advanced prostate cancer (T1-2, N+, or T3) and a high risk of metastatic disease. Sixty percent of patients on adjuvant goserelin and 44% of patients on RT alone remained disease-free at 5 years (P < ).At 5.6 years follow-up, ZOLADEX + RT maintained the improvement in disease-free survival compared with radiotherapy alone (P < ).Twenty-five percent of those patients on observation remain disease-free compared with 36% of patients who received ZOLADEX adjuvant therapy (P < ).Failed/TotalRT + Adjuvant goserelin 244/477RT Alone 306/468123456789Years from Date of RandomizationLawton et al. Int J Radiat Oncol Biol Phys. 2001; 49: Reprinted with permission.
22EORTC 22863 T1-4, N0, M0 (n=415) Randomized Radiotherapy + Radiotherapy + Adjuvant ZOLADEX® (goserelin acetate implant)vs Radiotherapy Alone Study DesignT1-4, N0, M0(n=415)Median follow-up at 45 months and 66 monthsRandomizedRadiotherapy +adjuvant goserelin 3.6 mg (n=207)Radiotherapy Alone(n=208)To assess the value of long-term androgen suppression in patients with locally advanced prostate cancer, Bolla et al randomized 415 previously untreated, node-negative patients to either radiotherapy (RT) alone (208 patients) or to RT plus adjuvant androgen suppression with goserelin, starting on day 1 of RT and continuing for 3 years (207 patients). Measurement of outcomes was performed at a median of 45 and 66 months follow-up.Hormonal Therapyat ProgressionEORTC = European Organization for Research and Treatment of CancerRadiation: 50 Gy over 5 weeks + 20 Gy over 2 weeksZOLADEX 3.6 mg sc every 4 weeks starting day 1 of radiation and continuing for 3 yearsCyproterone acetate: 150 mg po qd for 1 month starting 1 week prior to ZOLADEXBolla M, et al. NEJM. 1997;
23EORTC 22863 Biochemical Disease Free Survival 66-Month Follow-up 100908070605040302010Disease-Free Survival (%)Biochemically DefinedCombined TreatmentLog-rank test p < .0001Hazard ratio 0.42(95% Cl: )Radiotherapy AloneThis statistically significant difference in biochemical disease-free survival between the treatment groups, found at the last analysis in 2002, is shown here graphically.At 66 months’ follow-up, RT + ZOLADEX extended biochemical disease-free survival compared with RT alone, with 76% of the combined treatment patients free of disease versus 45% of the patients treated with RT alone (hazard ratio [HR]): 0.42; 95% CI: 0.28 to 0.64, P < .0001).PSA-determined progression was defined as PSA>1.5 ng/ml and increasing on 2 consecutive measurement.Bolla M, Collette L, Blank L, et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet. 2002;380:12345678Time Since Randomization (Years)O N Number of Patients at RiskBolla M, et al. Lancet. 2002;360:
24EORTC 22863 Overall Survival (OS) At 66-month follow-upOS was 78% in the RT + ZOLADEX group and 62% for RT alone (p = )Overall, survival differed significantly between treatment groups at 66 months’ follow-up. Survival in the RT + ZOLADEX group is 78% versus 62% in the RT-alone group (HR: 0.51; 95% CI: 0.36 to 0.73, P < .0002). Seventy-eight patients in the RT alone group died, and 50 patients died in the combined treatment group.Bolla M, et al. Lancet. 2002;360:
25EORTC 22863 Overall Survival 66-Month Follow-up 100908070605040302010Combined TreatmentOverall Survival (%)Radiotherapy AloneLog-rank test p < .0001Hazard ratio 0.51(95% Cl: )The improvement in overall survival at 66 months’ follow-up among patients treated with adjuvant ZOLADEX was still statistically significant (62% [95% CI 52%-72%] vs 78% [95% CI 72%-84%]) and is shown here graphically.In the RT group, the treatment given at the time of progression was ZOLADEX in 65 cases (72%), surgical castration in 7, another LHRH analog in 5, delayed treatment in 5, unspecified treatment in 1 case.12345678Time Since Randomization (Years)O N Number of Patients at RiskBolla M, et al. Lancet. 2002;360:
27Antiandrogen Dosing Regimen Combination therapy with an LHRH-AFlutamide2 capsules (125 mg each) 3 times dailyHalf-life (T½) = 4-7 hoursCASODEX® (bicalutamide) Tablets1 tablet (50 mg) once dailyT½ = 5.8 daysCombination therapy with bilateral orchiectomyNilutamide2 tablets (150 mg each) once a day (300 mg) for 30 days followed by 1 tablet (150 mg each) once a day (150 mg)T½ = 56 hoursMontherapy 150mg casodexFlutamide, the first available nonsteroidal pure antiandrogen, has a relatively short half-life and therefore requires administration three times daily.CASODEX (bicalutamide) Tablets have a long half-life that enables once-daily administration.Nilutamide 150-mg tablet, also indicated in combination with orchiectomy, has a long half-life that allows for once-daily dosing (2 150-mg tablets 1/day for 30 days followed by 1 tablet 1/day).Kennealey GT, Furr BJA. Use of the nonsteroidal anti-androgen Casodex in advanced prostatic carcinoma. Urol Clin North Am. 1991;18:Sarosdy MF. Which is the optimal antiandrogen for use in combined androgen blockade of advanced prostate cancer? The transition from a first- to second-generation antiandrogen. Anti-Cancer Drugs ;10:
28Combined Androgen Blockade CAB Combined androgen blockade refers to maximal androgen ablation achieved by antiandrogen combined with medical or surgical castration.Castration decreases only the androgens produced by the testes, which account for approximately 95% of circulating androgens, without affecting androgens produced by the adrenal glands (approximately 5%). Adding an antiandrogen to castration will block the androgen receptors and therefore block the action of residual circulating androgens from any source.
29CASODEX® (bicalutamide) 50 mg CAB Trial Overall Survival Median Follow-up 160 weeks1.00.90.50.30.00.80.70.188.8.131.52p = 0.15Proportion SurvivingAt median follow-up of 160 weeks, 213 of the 404 (53%) patients in the CASODEX (bicalutamide) 50-mg tablets group had died vs 235 of the 409 (57%) in the group randomized to flutamide + LHRH-A (HR 0.87, 95% CI , P = .15).Disease progression occurred in 287 of the 404 (71%) patients receiving CASODEX + LHRH-A, vs 296 of the 409 (72%) patients receiving flutamide + LHRH-A (HR 0.93, 95% CI , P = .41).CASODEX + LHRH-A (n = 404)Flutamide + LHRH-A (n = 409)365730109514601825DayReprinted from Urology, Vol. 50, P Schellhammer, R Sharifi, N Block, et al. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy in patients with advanced phase prostate cancer, pp , 1997, with permission from Elsevier Science.
30Overall Survival for Four CAB Groups 1.00.90.80.184.108.40.206.220.127.116.11n = 136n = 268n = 272n = 137Proportion Survivingleuprolide + CASODEX® (bicalutamide)ZOLADEX® (goserelin acetate implant) + CASODEXZOLADEX + flutamideleuprolide + flutamidep = 0.26p = 0.99p = 0.047p = 0.008This analysis compared the four CAB regimens that resulted from the two-by-two factorial design. Administration was double-blind for antiandrogen therapy and open-label for LHRH-A therapy.The lowest percentages of progression events and deaths were seen in the leuprolide + CASODEX group; the highest were observed in the leuprolide + flutamide group.Survival rates were similar for ZOLADEX + CASODEX and ZOLADEX + flutamide. There was no statistically significant difference in survival between the leuprolide + CASODEX vs the ZOLADEX + CASODEX groups (P = 0.99).As shown on this slide, significantly better survival outcomes occurred with leuprolide + CASODEX relative to leuprolide + flutamide (P = 0.008) and ZOLADEX + flutamide relative to leuprolide + flutamide (P = 0.047). Leuprolide + flutamide was significantly inferior to the other three groups.Sarosdy MF, Schellhammer PF, Sharifi R, et al. Comparison of goserelin and leuprolide in combined androgen blockade therapy. Urology. 1998;52:82-88.365730109514601825Time to Death (Days)Reprinted from Urology, Vol. 52, MF Sarosdy, PF Schellhammer, R Sharifi, et al. Comparison of goserelin and leuprolide in combined androgen blockade therapy, pp 82-88, 1998, with permission from Elsevier Science.
31Overview of CAB Trials Meta-Analyses A major controversy regarding the hormonal treatment of prostate cancer centers on the question of whether there is a demonstrated benefit of CAB versus monotherapy with orchiectomy or LHRH-A. As shown in the following slides, a number of meta-analyses have been performed in an effort to answer this question.
32PCTCG Meta-analysis Treatments Tested 27 trials involving 8275 patientsFlutamide, 4803Nilutamide, 1688Cyproterone acetate, 178488% with metastatic disease, 12% with locallyadvanced diseaseUsual dosages: nilutamide 300 mg/daily, flutamide 750 mg/daily, cyproterone acetate 150 to 200 mg/dailyUpdated information on 13 previously analyzed trials* and 5 new trials, including SWOG-8894 (leuprolide flutamide)†Most of the patients in the studies included in the meta-analysis (57%) took part in trials of flutamide, with smaller numbers of patients receiving nilutamide or cyproterone acetate. The 2 nonsteroidal antiandrogens available at the time (CASODEX® [bicalutamide] was not yet approved)—flutamide and nilutamide—were usually given at their indicated dosages. (The majority of patients in the studies included in this meta-analysis had metastatic disease.) Updated follow-up information was obtained for 13 of the 22 trials included in a previous meta-analysis of CAB, and 5 newer trials were included for the first time.*Prostate Cancer Trialists’ Collaborative Group. Lancet. 1995;346:†Crawford ED, Eisenberger MA, McLeod DG, et al. NEJM. 1989;321:Prostate Cancer Trialists’ Collaborative Group. Lancet. 2000;355:
33Meta-analyses CAB vs Castration Overview of Published CAB Meta-analyses8% to 22% lower risk of death over a given time period than castrationPCTCG1: overall n = 8215 P > 0.1PCTCG1: nilutamide n = 1751 P > 0.1PCTCG1: flutamide n = 4803 P = 0.02PCTCG1: flutamide + nilutamide n = 6354 P = 0.004PCTCG1: CPA n = 1661 P = 0.04Caubet2: NSAA PCTCG n = 3732 P = 0.005Caubet2: NSAA (PH) n = 1978 P < 0.001Caubet2: NSAA (LR) n = 2357 P < 0.001Klotz3: NSAA n = 3015 P > 0.041Debruyne4: nilutamide n = 1191 P > 0.038Bennett5: flutamide n = 1128 P = 0.05Shown are results from 5 published meta-analyses that evaluated CAB regimens that used five different antiandrogens. The single point to the right of the vertical axis indicates that CAB using cyproterone acetate, a steroidal antiandrogen with progestational properties, resulted in survival results that were inferior to androgen suppression alone.Cyproterone acetate is no longer widely used in CAB regimens, and the result depicted here accounted for only 20% of the data in a recent review of the survival effects of CAB vs androgen suppression alone on more than 8000 patients with advanced disease. Nonetheless, CAB with cyproterone acetate produced significantly shorter 5-year survival compared with castration alone (P = .04). Conversely, trials in which the CAB regimen included the nonsteroidal antiandrogens (flutamide or nilutamide) resulted in significantly improved 5-year survival compared with castration alone. (P = .005).0.5CAB Better1.0CAB Worse1.5Hazard Ratio and 95% Confidence LimitsPCTCG = Prostate Cancer Trialists’ Collaborative Group; CPA = cyproterone acetate; NSAA = nonsteroidal antiandrogen; PH = proportional hazards, LR = log hazard ratio. Due to the continual analysis of survival at different time intervals, some of the analyses above contain the same patients.1. PCTCG. Lancet. 2000;355: ; 2. Caubet JF, et al. Urology. 1997;49:71-78; 3. Klotz LH, et al. Can J Urol. 1996;3: ; 4. Debruyne FM, et al. Eur Urol. 1996;30(suppl 2):264; 5. Bennett CL, et al. Prostate Cancer Prostate Dis. 1999;2:4-8.
34Meta-Analyses 27 Randomized Trials of CAB vs AS Alone 10-Year Survival>8000 Prostate Cancer Patients in 27 Trials of Antiandrogens(Nilutamide, Flutamide, or Cyproterone Acetate)Proportion Alive (%)Time Since Randomization (Years)10080604020510Androgen Suppression OnlyAndrogen Suppression + AntiandrogenTreatment Betterby 0.7% (SE 1.1)Logrank p > 0.1AbsoluteDifference1.8% (SE 1.3)23.6%25.4%6.2%5.5%As can be seen, almost all men in both treatment groups had died by 10 years. However, 5-year survival was 25.4% with CAB and 23.6% with androgen suppression (AS) alone, for an absolute difference in survival of about 2%, which is not statistically significant (P = .11). Crude mortality was similar in middle-aged and older patients, and there was no evidence of heterogeneity of treatment effect among the 3 age groups stratified (ie, <65, 65–74, >75). Only 12% of patients in the meta-analysis trials did not have metastatic disease at the time of randomization. Among these 1000 men, overall mortality was slightly, but not significantly, higher with CAB than with AS alone (death rate ratio 1.06, 95% CI 0.87–1.29).Prostate Cancer Trialists’ Collaborative Group. Lancet. 2000;355:
35Meta-Analyses 20 Randomized Trials of CAB vs AS Alone 5-Year Survival6500 Men in 20 Trials of Nilutamide/FlutamideProportion Alive (%)Time Since Randomization (Years)1008060402025Androgen Suppression OnlyAndrogen Suppression AntiandrogenTreatment Betterby 2.9% (SE 1.3)Logrank p = 0.00527.6%24.7%134Five-year survival curves for only the trials that used nilutamide or flutamide show a 3% increase for CAB over androgen suppression (AS) alone. Of patients who received CAB, 27.6% were alive at 5 years versus 24.7% of patients who received AS alone (P = .005).In contrast, 5-year survival among patients who received CAB with cyproterone acetate (not shown) was only 15.4%, vs 18.1% for patients in the AS alone group (P = .04). The poor result of cyproterone acetate may have been due to a chance adverse effect on nonprostate cancer deaths.Prostate Cancer Trialists’ Collaborative Group. Lancet. 2000;355:
36CAB ConclusionsCAB may improve absolute 5-year survival by about 2% to 3%Choice of antiandrogenNonsteroidal antiandrogens improve outcomes while steroidal antiandrogens (CPA, not approved in the US) do notVarious CAB regimens similarly well toleratedThis meta-analysis, which encompassed 98% of the existing evidence from randomized trials, suggests that CAB may improve the absolute 5-year survival of patients with advanced prostate cancer by about 2% to 3%. Any treatment effect in patients with metastases was almost the same as in M0 patients, and the effect was age-independent. When CPA is removed from the analysis, the results become slightly more favorable for CAB vs castration alone.Prostate Cancer Trialists’ Collaborative Group. Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials. Lancet. 2000;355:
38Figur utarbeidet av AstraZeneca AS Efficacy and tolerability of bicalutamide in early localy advanced, non-metastatic prostate cancer.SPGC 6Median F.U 7.1 yearHR 0.47 p<0.0018Bicalutamid7Placebo6progresjon%patiant54321LokalavansertFigur utarbeidet av AstraZeneca ASIversen P et al. Efficacy and tolerability of bicalutamide in early non-metastatic prostate cancer: Latest findings from The Scandinavian Prostatic Cancer Group study no 6 (Spcg-6) of The Early Prostate Cancer Programme. Eur Urol Suppl 2006;5(2):251, Abs 914
39Overall survival– locally advanced PC SPCG-6 HR=0.65 (0.50, 0.85) p=0.001Bicalutamid events = 105 (41.2%)placebo events = 131 (52.4%)PlaceboBicalutamid1.00.80.60.40.20.0123456Time to death (year)Overall survival78910Median F. U: 7.1 yearFigur utarbeidet av AstraZeneca ASIversen P et al. Efficacy and tolerability of bicalutamide in early non-metastatic prostate cancer: Latest findings from The Scandinavian Prostatic Cancer Group study no 6 (Spcg-6) of The Early Prostate Cancer Programme. Eur Urol Suppl 2006;5(2):251, Abs 914
40Wilt T, et al Cochrane Reviews 2001, Issue 4. Early versus Late ADT4 trials (n=2,167)All trials were conducted prior to use of PSA testing & were heterogenousAll studies found PFS was consistently better in the early intervention group at all time points.Overall Survival (%)1 yr2 yr5 yr10 yrEarly ADT88734418Deferred ADT86713712OR1.1695% CI: 0.90 to 1.491.0895% CI: 0.89 to 1.331.1995% CI: 0.95 to 1.501.5095% CI: 1.04 to 2.16Wilt T, et al Cochrane Reviews 2001, Issue 4.
41Timing of ADT Conclusions Early ADT offers a statistically significant benefit in PFS & OSEarly ADT reduces disease progression and complications due to progression.There was no statistically significant difference in prostate cancer specific survivalEarly ADT leads to higher costsTreatment is most cost effective when started after the onset of symptomsComplications due to disease progression are more frequent in the deferred treatment group.Adverse events due to treatment are more frequent in the early treatment group.
42Is intermittent ADT better than continuous ADT? RationaleProlonged ADT may cause androgen independenceSide effects are lesser with intermittent ADTNo prospective randomized trialsNo guidelines for starting & stopping therapyNo data available on testosterone levels, QOL, BMD & sexual functionTwo phase III studies are underway
43Osteoporosis Risk Factors for men Hormonal changes associated with aging correlate with bone lossLower testosterone levelsLeads to less aromatization (conversion) of testosterone to estradiolEstradiol protects / strengthens boneTherefore lower levels = less protectionE2However, recent studies have suggested that estrogen (specifically, bioavailable estradiol) levels are better predictors of BMD in men than testosterone levels. For example, the declining levels of testosterone associated with age or hypogonadism may lead to a decrease in estrogen, since peripheral aromatisation of androgens to estrogens occurs. 67 Therefore, peripheral conversion of testosterone to estradiol may be a dominant factor in age-related osteoporosis in men, and not merely a declining testosterone level.
44Hormonal Therapy Decrease T by >95% Decrease E2 by >80% BMD loss with hormonal therapyDecrease T by >95%Decrease E2 by >80%With orchiectomy the BMD loss is 2.4% at 1 year and 10% at 2 yearsWith GnRH Agonist, the BMD loss is 3.4% at 1 year and 6.5% at 2 years1 yr2 yrOrchiectomy2.4%10%GnRH Agonist3.4%6.5%
45Hormonal TherapyThis decrease in BMD is associated with an increase in fracturesMen without prostate cancer over the age of 65 who are not on hormonal therapy have a fracture rate of 0.5% per yearWith hormone therapy there was a 5% incidence of osteoporotic fractures seen in a median of 22 monthsIn one series, within 7 years 28% of prostate cancer patients treated with orchiectomy had a fracture vs. 1% of patients who did not undergo orchiectomy
46Overall ConclusionsNumerous options available for treatment of prostate cancer at different stages of diseaseNo consensus on therapy of curative intentTreatment options should be discussed with patientsRisk and benefits of treatment need to be carefully consideredHormonal therapy for locally advanced and metastatic prostate cancer is effective but not curativeFurther clinical studies in localized, locally advanced and metastatic prostate cancer need to be consideredApproaches to HT for prostate cancer have evolved significantly over the past few decades. While there is no standard treatment for prostate cancer, a heterogeneous disease whose progression varies greatly between patients, some conclusions regarding HT can be made.Androgen suppression still represents the gold standard for many prostate cancer patients, particularly those with advanced disease. It is not, however, curative. Given adjuvantly with treatments of curative intent (eg, RP, RT), HT has delayed disease progression, increased disease-free survival, and prolonged overall survival in patients with localized and locally advanced disease. Future clinical trials will continue to refine optimal neoadjuvant and adjuvant HT regimens, the time of their initiation, and the length of time they should be given.HT is associated with adverse effects (eg, fatigue, impotence, hot flushes), so the decision to prescribe it should be discussed with the patient after a prudent evaluation of the therapeutic index of the HT regimen in relation to the individual case.
48Hormone refractory prostate carcinoma Definition: Disease progression despite castrate serum levels of testosteroneProgression’ is defined by:Increase in size of measurable lesionsAppearance of new measurable lesionsIncrease in PSA >50% on at least 2 consecutive measurementsIncrease in pain associated with new bony lesionsDuration of responseLimited or no metastases-5 yearsMetastatic disease-2 yearsMedian survival approximately 1 year
51Mechanisms of castration resistance in prostate cancer Figure 2. Mechanisms of castration resistance in prostate cancer.This figure provides an overview of mechanisms demonstrated or hypothesized to be involved in the development of castration resistance in prostate cancer, divided into ligand-dependent and ligand-independent mechanisms. (1) Tissue and tumoral steroidogenesis contribute to synthesis of testosterone and DHT, and might lead to persistence of tissue-level androgen despite castration. (2) Mutations in the AR allow activation by alternate ligands or increased affinity for androgens. (3) Amplification increases AR abundance. (4) Ligand-independent activation of AR through ligand-independent modifications or cross-talk with other pathways, including phosphorylation of AR leading to hypersensitization and increased nuclear translocation. (5) Change in the balance of coactivators and corepressors augment AR activity. (6) Bypass pathways functioning independently of AR activity through upregulation of antiapoptotic molecules, such as Bcl-2. In addition, stem cells continuously produce both androgen-sensitive and castration-resistant clones (not shown). Abbreviations: AKT, akt serine/threonine kinase; AND, other androgenic steroidal precursors; AR, androgen receptor; DHEA, dehydroepiandrosterone; DHT, dihydrotestosterone; ERK, extracellular signal-regulated kinase; P, phosphorylated residues; PI3K, phosphoinositide 3-kinase; PTEN, phosphatase and tensin homolog.Harris W P et al. (2009) Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletionNat Clin Pract Urol doi: /ncpuro1296
52Treatment of CRCP Casteration? Testestron? <20 ng 1-Total androgen blokade(TAB)-LHRH +Antiandrogen response ca.25% i ca 6-8 man2- Withdrawal.3-Antiandrogen "switching (bicalutamide flutamide )Biochemist response up to 40% ca 6 man4-Stroid (Prednisolon)5-Østrogen (Response rate ca 86%) cardivasculare side effect6-Ketoconazole (hemmer steroid synthesis) % response7-Abiratern
53Definition of Castrate Testosterone: A Treatment Decision Algorithm from NCCN 2003 Guidelines OrchiectomyHormoneablation(advanced PCa)TestosteroneContinueLHRHtherapy< 20ng/dLLHRHagonist> 20 ng/dLConsiderorchiectomyThe Version VI NCCN Treatment Guidelines for patients remains essentially unchanged from the information presented in this slide.The guidelines may be accessed at:NCCN, National Comprehensive Cancer Network; PCa, prostate cancer.Adapted from : Oefelein MG et al. J Urol. 2000;164:NCCN 2008 Guidelines for patientschanged the testosterone trigger from20 ng/dL to 50 ng/dL due to lack of level 1 evidenceIf patient refuses orchiectomy, add antiandrogen or change LHRH dose or productNCCN, National Comprehensive Cancer Network; PCa, prostate cancer.Adapted from Oefelein MG et al. J Urol. 2000;164:
54Ketoconazole (KC)Ketoconazole (KC) is an antifungal drug that is a nonspecific inhibitor of P450 enzymesInhibition of (CYP17), which is a key enzyme that mediates androgen synthesis. KC in combination with hydrocortisone (HC) has been widely used to treat patients with CRPC as a secondary hormonal agent in patients whose disease is progressing following ADT and AAWD.KC is associated with significant toxicities without a definitive demonstration of improvement in overall survival. (e.g., fatigue, nausea, liver enzyme elevations and neurotoxicity)
57Medical University of Vienna Firmagon® - A novel GnRH receptor blocker for hormonal treatment of prostate cancerGero KramerClinic for UrologyMedical University of Vienna
58GnRH agonists: disadvantages Testosterone surge delay in castration1 flare symptoms2Testosterone microsurgesTestosterone breakthroughsTestosterone control not comparable with orchiectomyDespite their advantages over surgical castration, GnRH agonist therapy has a variety of drawbacks.Notably, as GnRH agonists act by over-stimulating the pituitary gland, there is an initial period when there is a large rise in LH secretion, leading to increased testosterone production by the testes.1 In advanced disease, testosterone surge can cause clinical flare effects which may include increased bone pain, spinal cord compression, obstructive renal failure, acute bladder outlet obstruction, and fatal cardiovascular events.2 GnRH agonists also exhibit a variety of hormonal adverse effects which may have a significant adverse impact on quality of life.3 Also, the speed and degree of testosterone suppression with GnRH agonists is not always comparable to that achieved with orchidectomy, with significant proportions of patients failing to achieve castrate levels of testosterone.Thompson IM. Rev Urol 2001;3 (Suppl 3):S10-S14Heidenreich A et al. EAU Guidelines on prostate cancer 2007Sharifi N, et al. JAMA. 2005;294(2):1 Thompson IM. Rev Urol 2001; 3 (Suppl 3): S10-S14; 2 Heidenreich A et al. EAU Guidelines on prostate cancer 200758
59Objectives for Firmagon development To mimic the effects of surgical castration No testosterone surge Fast and sustained suppression of testosterone and PSASimilar or better safety profile compared with GnRH agonists
60Firmagon a GnRH blocker Direct mode of action xImmediate onset with fast testosterone and PSA suppressionNo testosterone surgeFirmagonIn the brain, GnRH is released from the hypothalamus and binds to GnRH receptors on the pituitary. This stimulates the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) which act on the testes to produce testosterone.Testosterone is converted in the prostate to dihydrotestosterone, an androgenic stimulant. If prostate cells are deprived of androgenic stimulation, they undergo programmed cell death.1Following injection, the GnRH blocker FIRMAGON® (degarelix) binds to and blocks GnRH receptors in the pituitary. This prevents GnRH from the hypothalamus binding to these receptors. This in turn prevents the release of LH and FSH from the pituitary. Consequently, LH and testosterone levels are suppressed.2FIRMAGON® achieves a fast, profound and sustained suppression of testosterone. FIRMAGON® does not stimulate GnRH receptors. Consequently, there is no initial surge in the levels of these hormones, and therefore of no surge in testosterone, with FIRMAGON®. This contrasts with the initial LH, FSH and consequently testosterone surge observed with GnRH agonists.Heidenreich A et al. EAU Guidelines on prostate cancer 20072. Broqua P et al. J Pharmacol Exp Ther 2002; 301:95–102.Princivalle M, J Pharmacol Exp Ther 2007; 320:60
61Molecule A fully synthetic, linear decapeptide amide A natural gelling depotRequires no additional constituentsLow histamine releaseWhite, 1st European Multidisciplinary Meeting on Urological Cancers,Barcelona, Spain, 2007.
62PHASE III TRIALA multi-centre randomized trial comparing the efficacy and safety of FIRMAGON® (degarelix) with leuprolide 7.5 mg in patients with prostate cancer requiring androgen deprivation therapy (CS21)
63Dosing monthly with a total of 12 days *Anti-androgen was allowed Dosing schedule CS21Day 0Starter doseDayMaintenance doseFirmagon160 mg (1x4 mL s.c)N=610patients(ITT)Firmagon240 mg (2x3 mL s.c)Firmagon80 mg (1x4 mL s.c)Leuprolide7.5 mg (i.m.)Leuprolide7.5 mg (i.m.)*A 1-year, phase III, open-label, multicentre comparative study, evaluated the efficacy and safety of a degarelix 1-month dosing regimen in 610 patients with prostate cancer requiring androgen deprivation therapy.Firmagon was administered subcutaneously at a starting dose of 240 mg (40 mg/ml), followed by monthly maintenance doses of either 80 mg (20 mg/ml) (n=207) or 160 mg (40 mg/ml) (n=202) versus leuprolide 7.5 mg (n=201) administered intramuscularly monthly.1Eligible patients had histologically confirmed prostate cancer for which androgen ablation was indicated (includes patients with rising PSA after prostatectomy or radiotherapy with curative intention); baseline serum testosterone >1.5 ng/mL; ECOG (Eastern Cooperative Oncology Group) score 2; baseline PSA 2 ng/mL.Patients who had received previous or current hormonal treatment for prostate cancer were not eligible. However, patients having undergone prostatectomy or radiotherapy with curative intent, and neoadjuvant/adjuvant hormonal therapy for a maximum duration of 6 months, were accepted.1. Boccon-Gibod L et al. Poster presentation. 23rd EAU Congress, Milan, Italy, 2008Dosing monthly with a total of 12 days*Anti-androgen was allowedKlotz L et al. BJU Int 2008;102:1531-8
64CS21- study endpoints Primary endpoint: Probability of testosterone ≤0.5 ng/mL at all monthly measurementsSecondary endpoints included:Patients with testosterone surge and microsurgesChange in PSA from baseline to day 28 and time to PSA failureSafetyThe primary study end point was suppression of testosterone to ≤0.5 ng/ml at all monthly measurements between day 28 and day 364 (i.e. treatment response). This endpoint was assessed according to both US Food and Drug Administration (FDA) and European Medicines Evaluation Agency (EMEA) success criteria:FDA: ≥95% effect with >90% lower confidence limitEMEA: Non-inferior to leuprolide 7.5 mg (within 10 percentage points)Secondary endpoints were:– Proportion of patients with testosterone surge (testosterone increase of ≥15% from baseline on any 2 days during the first 2 weeks of treatment)– Serum levels of testosterone and PSA over time– Proportion of patients with testosterone ≤0.5 ng/mL at day 3 and assessment of testosterone microsurges (increase in testosterone >0.25 ng/mL at any 2 measurements 3 and 7 days after dosing late in the treatment period [after 9 months])– Percentage change in PSA from baseline to day 28 and time to PSA failure (two consecutive increases of 50%, and at least 5 ng/mL as compared to nadir)– Frequency and severity of adverse events. 11. Boccon-Gibod L et al. Poster presentation. 23rd EAU Congress, Milan, Italy, 2008
65Demographics and disease characteristics 14-Apr-1714-Apr-17Demographics and disease characteristicsFirmagon 24080207724.1 (3-5.3)20 (9-46)Leuprolide 7.5mg201743.8 (2.9-5)17 (8-56)Number of pats.Age (median), yrs.Testosterone (ng/ml)PSA (ng/ml)The probability of PSA failure (defined as 2 consecutive increases of >50% to ≥5.0 ng/mL more than 2 weeks apart) was 14.2% and 8.8% in the 240/160 and 240/80 groups, respectively, and 14.2% in the leuprolide group.Klotz L et al. BJU Int 2008;102:1531-86565
66Demographics and disease characteristics Firmagon24080 mgLeuprolide7.5 mgPCA stageLocalized33%31%Loc. Advanced31%26%Metastatic18%23%Unclassified18%19%A total of 610 patients received study medication and were included in the intent-to-treat (ITT) population.Patients were comparable between treatment groups in terms of age, weight, body mass index (BMI), disease stage and Gleason score.11. Boccon-Gibod L et al. Poster presentation. 23rd EAU Congress, Milan, Italy, 2008Gleason Score≤ 643%44%730%31%8-1027%26%Klotz L et al. BJU Int 2008;102:1531-8
67Firmagon is noninferior to leuprolide in suppressing testosterone to <0.5 ng/mL for 1 year Probability of testosterone ≤0.5 ng/mL from dayFirmagon24080 mgLeuprolide7.5 mgPatients with treatment response202194Response rate97.2 %96.4 %Both Firmagon doses (starter/maintenance) of either 240/160 mg or 240/80 mg given at monthly intervals were as effective as leuprolide 7.5 mg monthly in achieving treatment response (testosterone ≤0.5 ng/mL from day ).In addition, Firmagon was shown to be non-inferior to leuprolide 7.5 mg. 11. Boccon-Gibod L et al. Poster presentation. 23rd EAU Congress, Milan, Italy, 2008Difference to leuprolide0.9 %(-3.2 to 5.0 %)Klotz L et al. BJU Int 2008;102:1531-867
68Firmagon – immediate testosterone reduction, no risk of clinical flare 100T-6,3ng/mlDegarelix 240/160mgDegarelix 240/80mgLeuprolide 7.5mg755025Median percentage change in Testosterone (%)-25-50T ng/ml-75-100137142128days*P<0.001 Firmagon (both doses) versus leuprolideKlotz L et al. BJU Int 2008;102:1531-8
69Firmagon – very low testosterone levels maintained over 1 year Median (± quartile) testosterone level over time987Degarelix 240/160mgDegarelix 240/80mgLeuprolide 7.5mg65Median Testosterone (ng/ml)43Med T – ng/ml vs 0.078Testosterone suppression was faster with Firmagon than with leuprolide.After the first month of treatment, both Firmagon and leuprolide displayed a similar testosterone suppression profile up to 1 year.Both Firmagon regimens maintained median testosterone levels below castration levels (≤0.5 ng/ml) from day 28 to day 364.11. Boccon-Gibod L et al. Poster presentation. 23rd EAU Congress, Milan, Italy, 20082Castration level12884140196252308364daysKlotz L et al. BJU Int 2008;102:1531-8
70Firmagon - no testosterone microsurges 24080 mgLeuprolide7.5 mg> 0.25 ng/mL*8 pts (4%)**In the CS21 trial, testosterone microsurges (defined as an increase in testosterone level >0.25 ng/mL at any two measurements 3 and 7 days after dosing) were noted in 5% (n=8) of patients in the leuprolide group late in the treatment period [after 9th injection] (of these, 4 patients reached values >0.5 ng/mL).No microsurges were noted in the Firmagon groups at days 3 and 7 after the 9th injection.11. Boccon-Gibod L et al. Poster presentation. 23rd EAU Congress, Milan, Italy, 2008*Change: Day 3 and day 7 after 9th injection** 4 pts with testosterone breakthrough (>0.5 ng/ml)Klotz L et al. BJU Int 2008;102:1531-8
71Firmagon – significantly faster reduction in PSA days714285684168364- 18%-20Degarelix 240/160mgDegarelix 240/80mgLeuprolide 7.5mg-40Median percentage change in PSA (%)-60-68%- 64%-80-85%-100*P<0.001 versus leuprolide (Wilcoxon pairwise comparisons); 11% of leuprolide patients received bicalutamide as flare protectionKlotz L et al. BJU Int 2008;102:1531-8
7214-Apr-1714-Apr-17PSA failuresTwo consecutive increases of more than 50% (at least >5.0 ng/mL)Firmagon 240/80 mgLeuprolide 7.5 mgNo. of failures16 / 20726 / 201Probability of PSA failure8.9%( %)14.1%( %)The probability of PSA failure (defined as 2 consecutive increases of >50% to ≥5.0 ng/mL more than 2 weeks apart) was 14.2% and 8.8% in the 240/160 and 240/80 groups, respectively, and 14.2% in the leuprolide group.Klotz L et al. BJU Int 2008;102:1531-87272
7314-Apr-17PSA progression-free survival (time to PSA failure/death: ITT population)10095Probability (%)90Firmagon 240/80 mg85Leuprolide 7.5 mg80285684112140168196224252280308336364Time (days)Number at riskFirmagonLeuprolideHR=0.664; P= (log-rank test)Tombal B et al. EAU 2009; poster #38ITT, intent-to-treat; HR, hazard ratio73
74CS21 adverse events Firmagon 24080 mg Leuprolide 7.5 mg Any AE 79% 78%Injection site AEs35%<1%***Arthralgia5%9%*The overall incidence of adverse events was similar for Firmagon (81% in the pooled Firmagon treatment groups) and leuprolide (78%).The majority of events were of mild to moderate intensity.Firmagon–treated patients reported a higher incidence of injection-site reactions, while the incidence of hormonally related side-effects was similar between Firmagon and leuprolide 7.5 mg.Disease-related side-effects like urinary tract infection and arthralgia were reported significantly less frequently with Firmagon, possibly reflecting the faster onset of action and earlier control of disease-related side-effects. More chills were reported with Firmagon.11. Boccon-Gibod L et al. Poster presentation. 23rd EAU Congress, Milan, Italy, 2008Urinary tract infection5%9%**Chills5%0%***p<0.05, **p<0.01, and ***p<0.001 versus Firmagon pooled74
75Injection site reactions – predominantly with starter dose Firmagon24080 mgNn%Any injection site reaction(s)Starter dose2076632%Injection-site reactions in patients receiving Firmagon were mostly transient, of mild to moderate intensity and occurred primarily with the starting dose and led to very few discontinuations (<1%).Thus, 32-34% of starter doses gave rise to these reactions; of 4452 Firmagon maintenance doses delivered, only 4.0% were associated with injection-site reactions.1. Boccon-Gibod L et al. Poster presentation. 23rd EAU Congress, Milan, Italy, 2008Maintenance dose(s)2244824%Klotz et al 200875
76Musculoskeletal events 14-Apr-17Musculoskeletal eventsFirmagonLeuprolide7.5 mgMusculoskeletal and connective tissue disordersPatients with localised disease20 (16%)16 (25%)Patients with locally advanced diseaseMusculoskeletal and connective tissue disordersThe pooled incidence of disease-related adverse events for Firmagon was lower than with leuprolide for patients with both localized disease, locally advanced disease and metastatic disease.These events comprised mainly musculoskeletal and connective tissue disorders, back pain and arthralgia.13 (10%)10 (19%)Back pain6 (5%)4 (8%)Arthralgia2 (2%)7 (13%)Iversen P et al. CURy 2009; poster #61814876
77Musculoskeletal events FirmagonLeuprolide7.5 mgPatients with metastatic diseaseMusculoskeletal and connective tissue disorders16 (21%)17 (36%)Back pain4 (5%)6 (13%)Arthralgia4 (5%)6 (13%)Pain in extremity1 (1%)4 (9%)Iversen P et al. CURy 2009; poster #618148
78FIRMAGON efficacyFast testosterone suppression without a surge or micro-surgesFast and sustained PSA suppressionNo need for flare protectionLower risk of PSA failure78
79FIRMAGON conclusionsIncidence of adverse events similar with leuprolideRelated to androgen suppressionHigher incidence of injection site reactions and chillsLower incidence of urinary tract infections and musculoskeletal eventsNo immediate-onset systemic allergic reactions79
80Options for short term treatment for Firmagon® Neoadjuvant + adjuvantIntermittentPhase III studies ongoing
81QUESTIONS Is firmagon the best castration therapy ? What is the absolute minimal level of testosterone to effectively prevent prostate cancer growth (20 ng/ml) ?81