1. Endocrinology of Prostate Cancer
Initially, prostate cancer is a hormone-dependent disease responding to testosterone, as demonstrated in the following slides.

2. Hormonal 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:

3. sex-hormone-binding globulin
Testosterone
Origin
Distribution
5% from adrenals
2% not bound
95%
from testes
54% bound with albumin
44% bound with
sex-hormone-binding globulin
The 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:

4. Circulating Androgens
Daily Production
Relative Potency
Ratio
DHT
(1.1%)
2.0
1.2
0.0
0.2
0.4
0.6
1.6 T
(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%) T
DHT
AND
DHEA
Sources: 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):

5. Testosterone 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.

6. Hormonal 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.

7. Hormonal Therapy Bilateral orchiectomy LHRH analogs Antiandrogens
Combined Androgen Blockade (CAB)
Androgen antagonist
Hormonal 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:

8. Bilateral Orchiectomy
In 1941, Huggins and Hodges made original discovery of hormonal effect on prostate cancer
Same studies also showed that bilateral orchiectomy improved pain or neurological symptoms in 71% of patients with metastatic disease
Advantages:
Immediate castration without testosterone surge
Outpatient procedure, general anesthesia not required
No compliance issues
Disadvantages:
Irreversible
Over 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:

9. Hormonal Therapy in Metastatic Disease
HT has been most widely used in metastatic disease
When to initiate HT is often debated
MRC (UK) Study
938 patients with locally advanced and asymptomatic, metastatic prostate cancer
Early HT (89% orchiectomy; within 6 weeks of entry) vs Deferred HT (71.5% orchiectomy)
Survival, local and distant progression, major complications evaluated
The 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:

10. MRC Trial: Results 934 evaluable patients results
469 in the immediate HT group and 465 in the deferred HT
Deferred ARM
(# of patients)
Immediate ARM (# of patients)
P values
Death
361
328
P=0.02
Two-tailed
Cause Specific Death
257
203
P=0.001
TUR
141 65
P<0.001
Nine 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:

11. Mechanism of Action of LHRH Analogs
HYPOTHALAMUS
Testosterone
LHRH-As
Cortisol
LHRH
CRH LH
ACTH
PITUITARY
TESTES
ADRENAL
Testosterone
Adrenal
androgens
Luteinizing 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.
PROSTATE
Testosterone
DHT
Induction/Stimulation
Feedback/Regulation
Adapted from Foote JE, Crawford ED. Semin Urol.1988;6(4):

12. Time to Induction of Castration with Long-Term LHRH Analog Therapy
Mean Serum Testosterone Levels 4
Level with ZOLADEX® (goserelin acetate implant) mg depot
Castrate level 3
Mean serum
testosterone
(ng/mL) 2 1
Debruyne 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: 4 8 1 2 1 6 2 2 4 3 2 3 6
Time (weeks)
No. of patients
Adapted from Debruyne FMJ, et al. J Urol.1988;140:

13. 24 RCT involving 6600 patients, (1966 - 1998) Results
Single-Therapy Androgen Suppression in Men with Advanced Prostate Cancer: A Systematic Review and Meta-Analysis
24 RCT involving 6600 patients, ( )
Results
LHRHa are equivalent to orchiectomy (10 trials, n=1908, HR , 95% CI, ).
There was no difference in OS among the LHRH analogues
Leuprolide (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:

14. Pivotal Trial Overall Survival
All Eligible Patients
Eligible “Depot Period” Patients
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
n = 176 ZOLADEX® (goserelin acetate implant)
n = 182 bilateral orchiectomy
n = 148 ZOLADEX
n = 144 bilateral orchiectomy
Estimated Survival Probability
Estimated Survival Probability
ZOLADEX
ZOLADEX
Patients 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 Orchiectomy
Bilateral Orchiectomy
p = 0.23
p = 0.33 24 48 72 96
120
144
168
192
216 24 48 72 96
120
144
168
192
216
Length of Survival (Weeks)
Length of Survival (Weeks)
Adapted from: Kaisary AV, et al. Br J Urol. 1991;67:

15. Pivotal 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 Orchiectomy
Illustrated 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 Rate
Adapted from: Kaisary AV, et al. Br J Urol. 1991;67:

16. Median follow-up at 4.5 years and 6.7 years
RTOG Radiotherapy + Neoadjuvant/Concomitant ZOLADEX® (goserelin acetate implant) Study Design
Locally Advanced T2 – 4, N+/-, M0
(N = 471)
Median follow-up at 4.5 years and 6.7 years
Randomized
RTOG 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 castration
Pilepich 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 I
Goserelin 3.6 mg/ Flutamide 250 mg + RT (n = 226)
ARM II
RT Alone (n = 230)
Pilepich MV, et al. Int J Radiat Oncol Biol Phys 2001; 50: Reprinted with permission.

17. Years from Date of Randomization
RTOG Local Failure
100 75 50 25
Failed/Total
p = 0.016
RT + Hormones 72/226
RT Alone 98/230
Percent
At 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:
116
104 63 52
At risk 1 2 3 4 5 6 7 8 9
Years from Date of Randomization
Pilepich MV, et al. Int J Radiat Oncol Biol Phys. 2001;50:

18. Median follow-up at 4.5 years and 5.6 years
RTOG Trial
Radiotherapy + Adjuvant ZOLADEX® (goserelin acetate implant) Study Design
Locally Advanced (T1-2, N+; T3)
(N=945)
Median follow-up at 4.5 years and 5.6 years
Randomized
RTOG 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:

19. Years from Date of Randomization
RTOG Local Failure
100 75 50 25
Failed/Total
RT + Adjuvant ZOLADEX® 92/477 (goserelin acetate implant)
RT + ZOLADEX at Relapse 155/468
p <
Percent
At 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 < ). 1 2 3 4 5 6 7 8 9
Years from Date of Randomization
Reprinted 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.

20. RTOG 85-31 Distant Metastases
100 75 50 25
Failed/Total
RT + Adjuvant ZOLADEX® 103/477 (goserelin acetate implant)
RT + ZOLADEX at Relapse 154/468
p <
Percent
Also 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 < ). 1 2 3 4 5 6 7 8 9
Years from Date of Randomization
Reprinted 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.

21. RTOG 85-31 Disease-Free Survival
Median follow-up of 5.6 years
100 75 50 25
p <
Percent
At 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/Total
RT + Adjuvant goserelin 244/477
RT Alone 306/468 1 2 3 4 5 6 7 8 9
Years from Date of Randomization
Lawton et al. Int J Radiat Oncol Biol Phys. 2001; 49: Reprinted with permission.

22. EORTC 22863 T1-4, N0, M0 (n=415) Randomized Radiotherapy +
Radiotherapy + Adjuvant ZOLADEX® (goserelin acetate implant)
vs Radiotherapy Alone Study Design
T1-4, N0, M0
(n=415)
Median follow-up at 45 months and 66 months
Randomized
Radiotherapy +
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 Therapy
at Progression
EORTC = European Organization for Research and Treatment of Cancer
Radiation: 50 Gy over 5 weeks + 20 Gy over 2 weeks
ZOLADEX 3.6 mg sc every 4 weeks starting day 1 of radiation and continuing for 3 years
Cyproterone acetate: 150 mg po qd for 1 month starting 1 week prior to ZOLADEX
Bolla M, et al. NEJM. 1997;

23. EORTC 22863 Biochemical Disease Free Survival 66-Month Follow-up
100 90 80 70 60 50 40 30 20 10
Disease-Free Survival (%)
Biochemically Defined
Combined Treatment
Log-rank test p < .0001
Hazard ratio 0.42
(95% Cl: )
Radiotherapy Alone
This 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: 1 2 3 4 5 6 7 8
Time Since Randomization (Years)
O N Number of Patients at Risk
Bolla M, et al. Lancet. 2002;360:

24. EORTC 22863 Overall Survival (OS)
At 66-month follow-up
OS 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:

25. EORTC 22863 Overall Survival 66-Month Follow-up
100 90 80 70 60 50 40 30 20 10
Combined Treatment
Overall Survival (%)
Radiotherapy Alone
Log-rank test p < .0001
Hazard 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. 1 2 3 4 5 6 7 8
Time Since Randomization (Years)
O N Number of Patients at Risk
Bolla M, et al. Lancet. 2002;360:

26. Antiandrogens

27. Antiandrogen Dosing Regimen
Combination therapy with an LHRH-A
Flutamide
2 capsules (125 mg each) 3 times daily
Half-life (T½) = 4-7 hours
CASODEX® (bicalutamide) Tablets
1 tablet (50 mg) once daily
T½ = 5.8 days
Combination therapy with bilateral orchiectomyNilutamide
2 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 hours
Montherapy 150mg casodex
Flutamide, 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:

28. Combined 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.

29. CASODEX® (bicalutamide) 50 mg CAB Trial Overall Survival
Median Follow-up 160 weeks
1.0
0.9
0.5
0.3
0.0
0.8
0.7
0.6
0.4
0.2
0.1
p = 0.15
Proportion Surviving
At 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)
365
730
1095
1460
1825
Day
Reprinted 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.

30. Overall Survival for Four CAB Groups
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
n = 136
n = 268
n = 272
n = 137
Proportion Surviving
leuprolide + CASODEX® (bicalutamide)
ZOLADEX® (goserelin acetate implant) + CASODEX
ZOLADEX + flutamide
leuprolide + flutamide
p = 0.26
p = 0.99
p = 0.047
p = 0.008
This 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.
365
730
1095
1460
1825
Time 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.

31. Overview 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.

32. PCTCG Meta-analysis Treatments Tested
27 trials involving 8275 patients
Flutamide, 4803
Nilutamide, 1688
Cyproterone acetate, 1784
88% with metastatic disease, 12% with locally
advanced disease
Usual dosages: nilutamide 300 mg/daily, flutamide 750 mg/daily, cyproterone acetate 150 to 200 mg/daily
Updated 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:

33. Meta-analyses CAB vs Castration
Overview of Published CAB Meta-analyses
8% to 22% lower risk of death over a given time period than castration
PCTCG1: overall n = 8215 P > 0.1
PCTCG1: nilutamide n = 1751 P > 0.1
PCTCG1: flutamide n = 4803 P = 0.02
PCTCG1: flutamide + nilutamide n = 6354 P = 0.004
PCTCG1: CPA n = 1661 P = 0.04
Caubet2: NSAA PCTCG n = 3732 P = 0.005
Caubet2: NSAA (PH) n = 1978 P < 0.001
Caubet2: NSAA (LR) n = 2357 P < 0.001
Klotz3: NSAA n = 3015 P > 0.041
Debruyne4: nilutamide n = 1191 P > 0.038
Bennett5: flutamide n = 1128 P = 0.05
Shown 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).
0.5
CAB Better
1.0
CAB Worse
1.5
Hazard Ratio and 95% Confidence Limits
PCTCG = 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.

34. Meta-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)
100 80 60 40 20 5 10
Androgen Suppression Only
Androgen Suppression + Antiandrogen
Treatment Better
by 0.7% (SE 1.1)
Logrank p > 0.1
Absolute
Difference
1.8% (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:

35. Meta-Analyses 20 Randomized Trials of CAB vs AS Alone
5-Year Survival
6500 Men in 20 Trials of Nilutamide/Flutamide
Proportion Alive (%)
Time Since Randomization (Years)
100 80 60 40 20 2 5
Androgen Suppression Only
Androgen Suppression Antiandrogen
Treatment Better
by 2.9% (SE 1.3)
Logrank p = 0.005
27.6%
24.7% 1 3 4
Five-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:

36. CAB Conclusions
CAB may improve absolute 5-year survival by about 2% to 3%
Choice of antiandrogen
Nonsteroidal antiandrogens improve outcomes while steroidal antiandrogens (CPA, not approved in the US) do not
Various CAB regimens similarly well tolerated
This 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:

37. Antiandrogen monotherapy

38. Figur utarbeidet av AstraZeneca AS
Efficacy and tolerability of bicalutamide in early localy advanced, non-metastatic prostate cancer.SPGC 6
Median F.U 7.1 year
HR 0.47 p<0.001 8 B i c a l u t a m i d 7 P l a c e b o 6
progresjon
%patiant 5 4 3 2 1
Lokalavansert
Figur utarbeidet av AstraZeneca AS
Iversen 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

39. Overall survival– locally advanced PC SPCG-6
HR=0.65 (0.50, 0.85) p=0.001
Bicalutamid events = 105 (41.2%)
placebo events = 131 (52.4%)
Placebo
Bicalutamid
1.0
0.8
0.6
0.4
0.2
0.0 1 2 3 4 5 6
Time to death (year)
Overall survival 7 8 9 10
Median F. U: 7.1 year
Figur utarbeidet av AstraZeneca AS
Iversen 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

40. Wilt T, et al Cochrane Reviews 2001, Issue 4.
Early versus Late ADT
4 trials (n=2,167)
All trials were conducted prior to use of PSA testing & were heterogenous
All studies found PFS was consistently better in the early intervention group at all time points.
Overall Survival (%)
1 yr
2 yr
5 yr
10 yr
Early ADT 88 73 44 18
Deferred ADT 86 71 37 12 OR
1.16
95% CI: 0.90 to 1.49
1.08
95% CI: 0.89 to 1.33
1.19
95% CI: 0.95 to 1.50
1.50
95% CI: 1.04 to 2.16
Wilt T, et al Cochrane Reviews 2001, Issue 4.

41. Timing of ADT Conclusions
Early ADT offers a statistically significant benefit in PFS & OS
Early ADT reduces disease progression and complications due to progression.
There was no statistically significant difference in prostate cancer specific survival
Early ADT leads to higher costs
Treatment is most cost effective when started after the onset of symptoms
Complications 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.

42. Is intermittent ADT better than continuous ADT?
Rationale
Prolonged ADT may cause androgen independence
Side effects are lesser with intermittent ADT
No prospective randomized trials
No guidelines for starting & stopping therapy
No data available on testosterone levels, QOL, BMD & sexual function
Two phase III studies are underway

43. Osteoporosis Risk Factors for men
Hormonal changes associated with aging correlate with bone loss
Lower testosterone levels
Leads to less aromatization (conversion) of testosterone to estradiol
Estradiol protects / strengthens bone
Therefore lower levels = less protection E2
However, 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.

44. Hormonal Therapy Decrease T by >95% Decrease E2 by >80%
BMD loss with hormonal therapy
Decrease T by >95%
Decrease E2 by >80%
With orchiectomy the BMD loss is 2.4% at 1 year and 10% at 2 years
With GnRH Agonist, the BMD loss is 3.4% at 1 year and 6.5% at 2 years
1 yr
2 yr
Orchiectomy
2.4%
10%
GnRH Agonist
3.4%
6.5%

45. Hormonal Therapy
This decrease in BMD is associated with an increase in fractures
Men without prostate cancer over the age of 65 who are not on hormonal therapy have a fracture rate of 0.5% per year
With hormone therapy there was a 5% incidence of osteoporotic fractures seen in a median of 22 months
In 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

46. Overall Conclusions
Numerous options available for treatment of prostate cancer at different stages of disease
No consensus on therapy of curative intent
Treatment options should be discussed with patients
Risk and benefits of treatment need to be carefully considered
Hormonal therapy for locally advanced and metastatic prostate cancer is effective but not curative
Further clinical studies in localized, locally advanced and metastatic prostate cancer need to be considered
Approaches 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.

47. CASTRATED RESISTANCE PC. CRPC

48. Hormone refractory prostate carcinoma
Definition: Disease progression despite castrate serum levels of testosterone
Progression’ is defined by:
Increase in size of measurable lesions
Appearance of new measurable lesions
Increase in PSA >50% on at least 2 consecutive measurements
Increase in pain associated with new bony lesions
Duration of response
Limited or no metastases-5 years
Metastatic disease-2 years
Median survival approximately 1 year

49. CRPC :Progresjon av PSA, Symptomer

50. Androgen deprivation therapy (ADT) Androgen action
Figure 1.  Androgen action.
Testosterone circulates in the blood bound to albumin (not shown) and SHBG, and exchanges with free testosterone. Free testosterone enters prostate cells and is converted to DHT by the enzyme 5-reductase. Binding of DHT to the AR induces dissociation from HSPs and receptor phosphorylation. The AR dimerizes and can bind to androgen-response elements in the promoter regions of target genes. Coactivators (such as ARA70) and corepressors (not shown) also bind the AR complex, facilitating or preventing, respectively, its interaction with the GTA. Activation (or repression) of target genes leads to biological responses including growth, survival and the production of PSA. Potential transcription-independent actions of androgens are not shown. Reproduced, with permission, from Feldman BJ and Feldman D (2001) Nat Rev Cancer 1: 34–45 © Macmillan Publishers Ltd. All rights reserved. Abbreviations: AR, androgen receptor; ARA70, androgen receptor associated protein 70; DHT, dihydrotestosterone; GTA, general transcription apparatus; HSP, heat-shock protein; SHBG, sex-hormone-binding globulin.
Harris W P et al. (2009) Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion
Nat Clin Pract Urol doi: /ncpuro1296

51. Mechanisms 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 depletion
Nat Clin Pract Urol doi: /ncpuro1296

52. Treatment of CRCP Casteration? Testestron? <20 ng
1-Total androgen blokade(TAB)
-LHRH +Antiandrogen response ca.25% i ca 6-8 man
2- Withdrawal .
3-Antiandrogen "switching (bicalutamide flutamide )
Biochemist response up to 40% ca 6 man
4-Stroid (Prednisolon)
5-Østrogen (Response rate ca 86%) cardivasculare side effect
6-Ketoconazole (hemmer steroid synthesis) % response
7-Abiratern

53. Definition of Castrate Testosterone: A Treatment Decision Algorithm from NCCN 2003 Guidelines
Orchiectomy
Hormone
ablation
(advanced PCa)
Testosterone
Continue
LHRH
therapy
< 20
ng/dL
LHRH
agonist
> 20 ng/dL
Consider
orchiectomy
The 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 patients
changed the testosterone trigger from
20 ng/dL to 50 ng/dL due to lack of level 1 evidence
If patient refuses orchiectomy, add antiandrogen or change LHRH dose or product
NCCN, National Comprehensive Cancer Network; PCa, prostate cancer.
Adapted from Oefelein MG et al. J Urol. 2000;164:

54. Ketoconazole (KC)
Ketoconazole (KC) is an antifungal drug that is a nonspecific inhibitor of P450 enzymes
Inhibition 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)

55. Abiraterone Acetate: A Promising Drug for the Treatment of Castration-resistant Prostate Cancer Neeraj Agarwal; Thomas E Hutson; Nicholas J Vogelzang; Guru Sonpavde Authors and Disclosures Posted: 06/18/2010; Future Oncology. 2010;6(5):  © 2010 Future Medicine Ltd.
An orally administered small molecule that irreversibly inhibits a rate-limiting enzyme in androgen biosysnthesis, CYP17, and blocks the synthesis of androgens in the testes, adrenal glands and prostate without causing adrenal insufficiency.
 Randomised phase III trial . OS
Abiraterone + prednisone: 14.8 months
Placebo + prednisone:       10.8 months
The PSA response
Abiraterone + prednisone: 38.0%
Placebo + prednisone:      10.1%
Adverse
Adverse events with abiraterone treatment were obviously higher than for placebo, but in general it appeared well tolerated and an important common side effect was fluid retention (30.5% of patients, with 2.4% of them being severe ie grade 3/4 in severity)

57. Medical University of Vienna
Firmagon® - A novel GnRH receptor blocker for hormonal treatment of prostate cancer
Gero Kramer
Clinic for Urology
Medical University of Vienna

58. GnRH agonists: disadvantages
Testosterone surge delay in castration1 flare symptoms2
Testosterone microsurges
Testosterone breakthroughs
Testosterone control not comparable with orchiectomy
Despite 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-S14
Heidenreich A et al. EAU Guidelines on prostate cancer
Sharifi 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 58

59. Objectives for Firmagon development
To mimic the effects of surgical castration No testosterone surge Fast and sustained suppression of testosterone and PSA
Similar or better safety profile compared with GnRH agonists

60. Firmagon a GnRH blocker Direct mode of actionx
Immediate onset with fast testosterone and PSA suppression
No testosterone surge
Firmagon
In 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.1
Following 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.2
FIRMAGON® 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
2. Broqua P et al. J Pharmacol Exp Ther 2002; 301:95–102.
Princivalle M, J Pharmacol Exp Ther 2007; 320: 60

61. Molecule A fully synthetic, linear decapeptide amide
A natural gelling depot
Requires no additional constituents
Low histamine release
White, 1st European Multidisciplinary Meeting on Urological Cancers,
Barcelona, Spain, 2007.

62. PHASE III TRIAL
A 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)

63. Dosing monthly with a total of 12 days *Anti-androgen was allowed
Dosing schedule CS21
Day 0
Starter dose
Day
Maintenance dose
Firmagon
160 mg (1x4 mL s.c)
N=610
patients
(ITT)
Firmagon
240 mg (2x3 mL s.c)
Firmagon
80 mg (1x4 mL s.c)
Leuprolide
7.5 mg (i.m.)
Leuprolide
7.5 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.1
Eligible 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, 2008
Dosing monthly with a total of 12 days
*Anti-androgen was allowed
Klotz L et al. BJU Int 2008;102:1531-8

64. CS21- study endpoints Primary endpoint:
Probability of testosterone ≤0.5 ng/mL at all monthly measurements
Secondary endpoints included:
Patients with testosterone surge and microsurges
Change in PSA from baseline to day 28 and time to PSA failure
Safety
The 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 limit
EMEA: 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. 1
1. Boccon-Gibod L et al. Poster presentation. 23rd EAU Congress, Milan, Italy, 2008

65. Demographics and disease characteristics
14-Apr-17
14-Apr-17
Demographics and disease characteristics
Firmagon 24080
207 72
4.1 (3-5.3)
20 (9-46)
Leuprolide 7.5mg
201 74
3.8 (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;102:1531-8 65 65

66. Demographics and disease characteristics
Firmagon
24080 mg
Leuprolide
7.5 mg
PCA stage
Localized
33%
31%
Loc. Advanced
31%
26%
Metastatic
18%
23%
Unclassified
18%
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.1
1. Boccon-Gibod L et al. Poster presentation. 23rd EAU Congress, Milan, Italy, 2008
Gleason Score
≤ 6
43%
44% 7
30%
31%
8-10
27%
26%
Klotz L et al. BJU Int 2008;102:1531-8

67. Firmagon is noninferior to leuprolide in suppressing testosterone to <0.5 ng/mL for 1 year
Probability of testosterone ≤0.5 ng/mL from day
Firmagon
24080 mg
Leuprolide
7.5 mg
Patients with treatment response
202
194
Response rate
97.2 %
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. 1
1. Boccon-Gibod L et al. Poster presentation. 23rd EAU Congress, Milan, Italy, 2008
Difference to leuprolide
0.9 %
(-3.2 to 5.0 %)
Klotz L et al. BJU Int 2008;102:1531-8 67

68. Firmagon – immediate testosterone reduction, no risk of clinical flare
100
T-6,3ng/ml
Degarelix 240/160mg
Degarelix 240/80mg
Leuprolide 7.5mg 75 50 25
Median percentage change in Testosterone (%)
-25
-50
T ng/ml
-75
-100 1 3 7 14 21 28
days
*P<0.001 Firmagon (both doses) versus leuprolide
Klotz L et al. BJU Int 2008;102:1531-8

69. Firmagon – very low testosterone levels maintained over 1 year
Median (± quartile) testosterone level over time 9 8 7
Degarelix 240/160mg
Degarelix 240/80mg
Leuprolide 7.5mg 6 5
Median Testosterone (ng/ml) 4 3
Med T – ng/ml vs 0.078
Testosterone 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 364.1
1. Boccon-Gibod L et al. Poster presentation. 23rd EAU Congress, Milan, Italy, 2008 2
Castration level 1 28 84
140
196
252
308
364
days
Klotz L et al. BJU Int 2008;102:1531-8

70. Firmagon - no testosterone microsurges
24080 mg
Leuprolide
7.5 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.1
1. 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

71. Firmagon – significantly faster reduction in PSA
days 7 14 28 56 84
168
364
- 18%
-20
Degarelix 240/160mg
Degarelix 240/80mg
Leuprolide 7.5mg
-40
Median 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 protection
Klotz L et al. BJU Int 2008;102:1531-8

72. 14-Apr-17
14-Apr-17
PSA failures
Two consecutive increases of more than 50% (at least >5.0 ng/mL)
Firmagon 240/80 mg
Leuprolide 7.5 mg
No. of failures
16 / 207
26 / 201
Probability of PSA failure
8.9%
( %)
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;102:1531-8 72 72

73. 14-Apr-17
PSA progression-free survival (time to PSA failure/death: ITT population)
100 95
Probability (%) 90
Firmagon 240/80 mg 85
Leuprolide 7.5 mg 80 28 56 84
112
140
168
196
224
252
280
308
336
364
Time (days)
Number at risk
Firmagon
Leuprolide
HR=0.664; P= (log-rank test)
Tombal B et al. EAU 2009; poster #38
ITT, intent-to-treat; HR, hazard ratio 73

74. CS21 adverse events Firmagon 24080 mg Leuprolide 7.5 mg Any AE 79%
78%
Injection site AEs
35%
<1%***
Arthralgia 5%
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.1
1. Boccon-Gibod L et al. Poster presentation. 23rd EAU Congress, Milan, Italy, 2008
Urinary tract infection 5%
9%**
Chills 5%
0%**
*p<0.05, **p<0.01, and ***p<0.001 versus Firmagon pooled 74

75. Injection site reactions – predominantly with starter dose
Firmagon
24080 mg N n %
Any injection site reaction(s)
Starter dose
207 66
32%
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, 2008
Maintenance dose(s)
2244 82 4%
Klotz et al 2008 75

76. Musculoskeletal events
14-Apr-17
Musculoskeletal events
Firmagon
Leuprolide
7.5 mg
Musculoskeletal and connective tissue disorders
Patients with localised disease
20 (16%)
16 (25%)
Patients with locally advanced disease
Musculoskeletal and connective tissue disorders
The 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 pain
6 (5%)
4 (8%)
Arthralgia
2 (2%)
7 (13%)
Iversen P et al. CURy 2009; poster #618148 76

77. Musculoskeletal events
Firmagon
Leuprolide
7.5 mg
Patients with metastatic disease
Musculoskeletal and connective tissue disorders
16 (21%)
17 (36%)
Back pain
4 (5%)
6 (13%)
Arthralgia
4 (5%)
6 (13%)
Pain in extremity
1 (1%)
4 (9%)
Iversen P et al. CURy 2009; poster #618148

78. FIRMAGON efficacy
Fast testosterone suppression without a surge or micro-surges
Fast and sustained PSA suppression
No need for flare protection
Lower risk of PSA failure 78

79. FIRMAGON conclusions
Incidence of adverse events similar with leuprolide
Related to androgen suppression
Higher incidence of injection site reactions and chills
Lower incidence of urinary tract infections and musculoskeletal events
No immediate-onset systemic allergic reactions 79

80. Options for short term treatment for Firmagon®
Neoadjuvant + adjuvant
Intermittent
Phase III studies ongoing

81. QUESTIONS Is firmagon the best castration therapy ?
What is the absolute minimal level of testosterone to effectively prevent prostate cancer growth (20 ng/ml) ? 81