Diseminovaný karcinom prostaty – kdy a jakou indikovat hormonální deprivaci a chemoterapii a jejich kombinace? Doc. MUDr. Vladimír Študent, Ph.D. Urologická klinika FN a LFUP Olomouc

karcinom prostaty přirozený průběh Lokálně pokročilý PIN N+ Orgánově ohraničený M+ Objem, mL 1 4 25 100 1000 PSA, ng/mL 3 10 20 200 700 300 Rozmezí vyléčitelnosti PIN, prostatic intraepithelial neoplasia 2

Predikované hodnoty pro rok 2009 Incidenece KP Karcinom prostaty (C61) Predikované hodnoty pro rok 2009 Incidence (90 % interval spolehlivosti) Stadium I+II 2 138 (1 948; 2 328) Stadium III 604 (505; 703) Stadium IV 562 (503; 621) Klinické stadium neznámo z objektivních důvodů * 1 354 (1 120; 1 588) CELKEM 4 658 (4 335; 4 981)

Predikované hodnoty pro rok 2009 Prevalence KP Karcinom prostaty (C61) Predikované hodnoty pro rok 2009 Prevalence (90 % interval spolehlivosti) Stadium I+II 13 677 (13 446;13 908) Stadium III 2 753 (2 643;2 863) Stadium IV 2 855 (2 721;2 989) Klinické stadium neznámo z objektivních důvodů * 7 648 (7 504;7 792) CELKEM 26 933 (26 314;27 552)

Úvod karcinom prostaty (KP) je nejčastější maligní nádor u mužů Nejčastější výskyt u mužů > 50 let věku karcinom prostaty Lokalizovaný Lokálně pokročilý Metastatický Worldwide, prostate cancer is the most common form of cancer in men, excluding skin cancer, and is the second leading cause of cancer death (Jones 1993; American Cancer Society 2003; Jemal et al 2003). Prostate cancer commonly occurs in men aged over 50 years, and diet and family history may play a role in the development of the disease. Androgen deprivation is the mainstay of advanced treatment for advanced hormone-sensitive prostate cancer, using surgical (orchiectomy) or endocrine therapy. ‘Zoladex’ (goserelin) is an endocrine therapy (luteinising hormone-releasing hormone [LHRH] agonist) for prostate cancer developed by AstraZeneca. Unlike other clinically available LHRH agonists, ‘Zoladex’ (goserelin) is licensed for use in all stages of advanced cancer on the basis that the agent has a proven survival benefit in both the adjuvant setting and advanced hormone-sensitive prostate cancer. This slide kit reviews the robust evidence base from large, randomised, controlled and long-term clinical trials that supports the universal use of ‘Zoladex’ (goserelin) in this indication to explain why ‘Zoladex’ (goserelin) is a popular treatment amongst patients and physicians alike. References: American Cancer Society. http://www.cancer.org/docroot/stt/stt_0.asp. Accessed October 2003. Jemal A et al. CA Cancer J Clin 2003; 53: 5-26. Jones GW. Cancer Suppl 1993; 71: 887-890.

Léčba lokálně pokročilého a metastatického KP jedná se ve většině případů o hormonálně závislý (dependentní) nádor Androgenní deprivace je hlavním způsobem léčby hormonálně dependentního pokročilého a metastatického KP Androgenní deprivace – blokáda účinku mužských pohlavních hormonů: 1. Kastrace chirurgická (orchiektomie) medikamentozní (agonisté LHRH +antagonisté LHRH) 2. Blokáda androgenních receptorů - antiandrogeny

Místa zásahu hormonální léčby Estrogeny Progesteron testosteron Blok hypofýzární produkce FSH,LH FSH + LH Ovarium varlata LHRH prostata Kortikosteroidy Hypofýza Progesteron Hypothalamus Androgeny Estrogeny ACTH Nadledviny Blok receptoru v cílové tkáni Blok periferní konverze 7

Lokálně pokročilý KP Důvod pro adjuvantní terapii Pánevní lymfatické uzliny měchýř Prostata CA prostaty adjuvantní hormonální terapie Hormonální terapie jako přídavná terapie zasáhne nedetekovatelné buňky nádoru v lymfatických uzlinách a mimo cílového místa radioterapeutické léčby, zabrání tak další progresi onemocnění.

Šance PSA 0 Urologická klinika LF-UP a FN Olomouc Roky po RRP

Conclusion 9 th CEM EAU Ljubjana oct.2009 Prostate cancer is not associated with an increased number of additional malignancies. The data suggests a modest increase in secondary cancers associated with radiation for prostate cancer. As approximately one in 70 patients undergoing radiation and surviving more than 10 yr will develop secondary cancer. The most common sites for secondary cancers are bladder and rectum. An increase of cancers in distant sites, such as lung.

Lokálně pokročilý KP Antiandrogeny Steroidní (Cyproteron acetát) Nesteroidní antiandrogeny - bicalutamid - flutamid - nilutamid (blokují vazbu testosteronu na specifické receptory v jádře prostatických buněk) bicalutamid navíc suprimuje co-aktivátoty a aktivuje ko-represory . Afinita bicalutamidu k androgennímu receptoru je 2-4x větší než afinita flutamidu nebo nilutamidu

Bicalutamide EPC Program (n=8113) EPC Program: design Bicalutamide EPC Program (n=8113) Cíl: zhodnotit účinek přidání bicalutamidu ke standardní léčbě v porovnání se standardní léčbou samotnou v léčbě časného karcinomu prostaty (T1-T4, M0, Nx) Standardní léčba (radioterapie, radikální prostatektomie nebo pozorné vyčkávání) podle investigatora dle zvyklostí pracoviště. studie 23 S. America (n=3292) studie 24 Evropa /zbytek světa (n=3603) studie 25 Skandinavie (n=1218) The ongoing EPC Programme is the world’s largest prostate cancer treatment trial programme to date, with over 8100 patients enrolled.1 The programme is examining the role of adding early hormonal therapy to standard care (radiotherapy, radical prostatectomy or watchful waiting) in the treatment of localised or locally advanced prostate cancer.1 The programme comprises three complementary, double-blind, randomised, placebo-controlled clinical trials, which were prospectively designed and powered for a stratified, combined analysis (Trial 23, 24 and 25).1 Patients were randomised in a 1:1 ratio to receive bicalutamide plus standard care (n=4052) or standard care alone (n=4061).1 The primary endpoints of the EPC Programme are time to overall survival and objective progression.1 Further background information Objective progression was defined as the time from randomisation to the earliest occurrence of objective progression (confirmed by either bone scan, CT scan, ultrasound or MRI scan, or by histological evidence of distant metastases) or death from any cause without progression. Changes in prostate-specific antigen (PSA) level or clinical examination findings alone are not considered to be evidence of progression. To avoid potential bias in the analysis, death from any cause is also considered as a progression event. Therefore, the analysis of time to objective progression is a measure of how long patients live free from prostate cancer (ie progression-free survival, PFS). All patients were followed-up every 12 weeks until progression and bone scans were performed at regular intervals. A Cox proportional hazards regression model is used for analysis of time to objective progression, using covariates for randomised treatment, primary treatment of curative intent, baseline PSA level, tumour grade and stage.1 Reference See WA et al. The bicalutamide Early Prostate Cancer Program. Demography. Urol Oncol 2001; 6: 43-47. 1:1 bicalutamide 150 mg nebo standardní léčba samotná Sledování celkového přežívání a prodloužení doby do progrese See et al 2001

Bicalutamide plus standardní terapie Standardní léčba samotná Bicalutamide 150mg statisticky významně zlepšuje dobu do progrese (PFS) bez ohledu na standardní léčbu Lokálně pokročilé onemocnění při mediánu sledování 7,4 let Bicalutamide plus standardní terapie Standardní léčba samotná Radioterapie HR 0.56 (p<0.001) Radikální prostatektomie HR 0.75 (p=0.004) This slide summarises the objective PFS data at 7.4 years’ median follow-up for locally advanced patients receiving bicalutamide as adjuvant to radical prostatectomy or radiotherapy, or as an alternative to watchful waiting. Consistent with the earlier findings (5.4 years’ median follow-up),1 bicalutamide continues to significantly improve objective PFS, irrespective of standard care received. These data indicate that patients with locally advanced disease derive the greatest benefit from bicalutamide. References Wirth MP et al. Bicalutamide 150 mg in addition to standard care in patients with localized or locally advanced prostate cancer: results from the second analysis of the early prostate cancer program at median followup of 5.4 years. J Urol 2004; 172: 1865-1870. Sledování HR 0.60 (p<0.001) 0.00 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00

Bicalutamide 150 mg v adjuvanci ke standardní léčbě nabízí významný přínos pro pacienty s lokálně pokročilým karcinomem prostaty Statisticky významně prodlužuje dobu do progrese (PFS) bez ohledu na standardní léčbu Výrazně zlepšuje celkové přežití (OS) v adjuvanci k radioterapii (nižší riziko úmrtí o 35%, než při léčbě samotnou radioterapií) Naznačen trend k zlepšení celkového přežívání (OS) v adjuvanci k pozornému sledování (WW) Bicalutamide should be considered for all patients with locally advanced disease as monotherapy or as adjuvant to radiotherapy or radical prostatectomy. Consistent with earlier findings (5.4 years’ median follow-up),2 bicalutamide continues to improve objective PFS in patients with locally advanced disease, irrespective of the standard care received. At 7.4 years’ median follow-up, bicalutamide adjuvant to radiotherapy significantly improves overall survival by 35% compared with radiotherapy alone (0.65; 95% CI 0.44, 0.95; p=0.03). This difference was driven by a lower risk of prostate cancer-related deaths (16.1% vs 24.3%, respectively). The impressive overall survival benefit observed with bicalutamide in the radiotherapy subgroup compares favourably with that observed with goserelin adjuvant to radiotherapy in the RTOG 85-31 study at a similar length of follow-up.1 There was no significant difference in overall survival when bicalutamide was added to radical prostatectomy (HR 1.09; 95% CI 0.85, 1.39; p=0.51). However, there was a trend towards improved overall survival with bicalutamide as an alternative to watchful waiting. This trend very closely approached statistical significance (HR 0.81; 95% CI 0.66, 1.01; p=0.06). In summary, these data indicate that patients with locally advanced disease derive the greatest benefit from bicalutamide. References Pilepich M et al. Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma - Long-term results of Phase III RTOG 85-31. Int J Radiat Oncol Biol Phys 2005; 61: 1285-1290. Wirth MP et al. Bicalutamide 150 mg in addition to standard care in patients with localized or locally advanced prostate cancer: results from the second analysis of the early prostate cancer program at median followup of 5.4 years. J Urol 2004; 172: 1865-1870. Terapie bicalutamidem 150mg by měla být zvážena u všech pacientů s lokálně pokročilým onemocněním

Nežádoucí účinky bicalutamid Gynekomastie

Bicalutamid 150 mg – zachovává kostní denzitu Bicalutamid (‘Casodex’) 150 mg LHRH analog Změna kostní denzity z původní hodnoty % 3.0 2.0 1.0 0.0 -1.0 -2.0 -3.0 -4.0 Reference Sieber PR et al. Bone mineral density is maintained during bicalutamide ('Casodex') treatment. Proc Am Soc Clin Oncol 2002; 21: 196a (abstr 783). -5.0 -6.0 24 48* 72* 96* Follow-up (týdny) *Statisticky signifikantní rozdíl mezi oběma skupinami p<0.0001 Studie US0004: Sieber et al 2002

Místa zásahu hormonální léčby Estrogeny Progesteron testosteron Blok hypofýzární produkce FSH,LH FSH + LH Ovarium varlata LHRH prostata Kortikosteroidy Hypofýza Progesteron Hypothalamus Androgeny Estrogeny ACTH Nadledviny Blok receptoru v cílové tkáni Blok periferní konverze 17

Hypotalamo-hypofyzární osa, mechanismus účinku LHRH Gonadoliberin (LHRH – Luteinising Hormone Releasing Hormone) – je produkován v hypothalamu, uvolňován pulzní sekrecí do krevního oběhu Cílové místo účinku LHRH – sekretorické buňky v adenohypofýze, které působením LHRH produkují luteinizační (LH) a folikuly-stimulující (FSH) hormony LH a FSH – řídí sekreci pohlavních hormonů v pohlavních žlazách (androgeny ve varlatech, estrogeny v ovariích) tvorba LH a FSH zpětnovazebně řízena hladinou androgenů nebo estrogenů

LHRH analoga (LHRHa) Syntetické analogy fyziologického LHRH Jejich účinkem je medikamentozní kastrace, která je na rozdíl od chirurgické kastrace reverzibilní Indikace LHRHa - léčba hormonálně závislých nádorů prostaty a prsu + další gynekologické a endokrinologické indikace

Mechanismus účinku LHRH (goserelin) P LH 1. Normal LH release 2. Hypersecretion of LH 3. Hyposecretion of LH LHRH is produced by the hypothalamus and stimulates the anterior pituitary gland to secrete the gonadotrophins, luteinising hormone (LH) and follicle-stimulating hormone into the blood stream. For normal LH release, LHRH binds to LHRH receptors on the pituitary gland cell membrane leading to the release of LH and subsequently testosterone from the testes. ‘Zoladex’ (goserelin) mimics the action of LHRH. Following a single injection of ‘Zoladex’ (goserelin) a very high proportion of LHRH receptors are occupied by the drug. This results in a transient rise in plasma LH which leads to a short-lived increase in testosterone production by the testes. This may cause ‘tumour flare’. As a result of constant interaction of ‘Zoladex’ (goserelin) with LHRH receptors, the receptors disappear from the surface of the pituitary cell. Although new receptors are synthesised and appear on the cell surface, the continuous administration of ‘Zoladex’ (goserelin) causes receptor downregulation. Thus ‘Zoladex’ (goserelin) prevents the reappearance of LHRH receptors and consequently inhibits the secretion of LH from the pituitary and testosterone from the testes. The overall result is a medical castration. Reference: Furr BJA, Hutchinson FG. In: Eds Kotake T et al. Current Therapy for Prostate Cancer: Focus on Goserelin. Proceedings of the ‘Zoladex’ International Symposium, Kobe, 20-21 Sept 1991. Current Clinical Practice Series 1992; 64: 47-60. LH, luteinising hormone; P, pituitary cell (adenohypofýza); Z, 'Zoladex' (goserelin) Furr and Hutchinson 1992

Účinek goserelinu (Zoladex) - suprese testosteronu na kastrační hladinu Průměrná koncentrace testosteronu (nmol/L) 18 ‘Zoladex’ (goserelin) 3.6 mg (n=42) ‘Zoladex’ (goserelin) 10.8 mg (n=38) 16 14 12 10 8 6 4 Horní kastrační limit Dijkman et al (1995) evaluated the effects of the ‘Zoladex’ (goserelin) 3.6 mg and 10.8 mg depots on testosterone suppression. Between Weeks 0 and 12 the testosterone profiles relate to the administration of one ‘Zoladex’ (goserelin) 10.8 mg depot and three ‘Zoladex’ (goserelin) 3.6 mg depots (one every 4 weeks). Between Weeks 12 and 48, all patients received one ‘Zoladex’ (goserelin) 10.8 mg depot every 12 weeks. As expected, an initial increase in mean serum testosterone levels was observed during the first week of therapy. The mean testosterone concentrations were then suppressed to a level within the castrate range. These low testosterone concentrations were maintained throughout the comparative phase of the study (0-12 weeks) and for a further 36 weeks, during which time all patients received the ‘Zoladex’ (goserelin) 10.8 mg depot only. The 10.8 mg depot formulation was found to be well tolerated and have a similar safety profile to that of the 3.6 mg depot. Dijkman et al (1995) concluded that the ‘Zoladex’ (goserelin) 10.8 mg depot offers a more convenient dosing regimen for both patient and doctor. Reference: Dijkman GA et al. Eur Urol 1995; 27: 43-46. 2 4 8 12 16 20 24 26 28 32 36 40 44 Čas (týdny) Dijkman et al 1995

Suprese testosteronu - LHRHa vs orchiektomie (OE) Po orchiektomii je pokles testosteronu okamžitý, trvalý, ale ireverzibilní (nevratný) Po aplikaci LHRHa pokles testosteronu pozvolný, po dosažení kastrační hladiny trvalý, ale účinek je reverzibilní Po aplikaci LHRHa nejdříve vzestup hladin pohlavních hormonů (flare up fenomen), po 14 dnech pokles postupně na kastrační hladinu, po 30.dni od aplikace dosažena kastrační hladina (Zoladex) Flare up fenomén – nežádoucí jev, kterému se brání současným podáváním antiandrogenů

LHRH agonisté goserelin (Zoladex, AstraZeneca) buserelin (Suprefact, Aventis) leuprorelin (Eligard,Astelas) (Lucrin, Abbott/Axonia) triptorelin (Dipherelin, Ipsen) (Decapeptyl, Ferring) Several LHRH agonists are available (including leuprolide) for use in prostate cancer, but only ‘Zoladex’ (goserelin) is licensed for all stages of hormone-sensitive prostate cancer. The registered broad-ranging use of ‘Zoladex’ (goserelin) in prostate cancer is supported by robust evidence from controlled clinical trials (Kaisary et al 1991; Vogelzang et al 1995; Bolla et al 2002; Messing et al 2003; Pilepich et al 2003). Unlike ‘Zoladex’ (goserelin), data are not available that demonstrate the clinical effects of other LHRH agonists. ‘Zoladex’ (goserelin) is the only LHRH agonist that has been demonstrated to improve cost-effectiveness as adjuvant treatment (Neymark et al 2001). Of all the clinically available LHRH agonists, only ‘Zoladex’ (goserelin) has been shown to improve patient’s quality of life (QoL) compared with orchiectomy (Cassileth et al 1992). ‘Zoladex’ (goserelin) has a standard dosage worldwide whereas leuprolide is used at a variable dosage in different countries. Unlike leuprolide, ‘Zoladex’ (goserelin) is supplied ready-to-use in pre-filled syringes that require no mixing or further preparation before administration. References: Bolla M et al. Lancet 2002; 360: 103-108. Cassileth BR et al. Qual Life Res 1992; 1: 323-329. Kaisary AV et al. Br J Urol 1991; 67: 502-508. Messing EM et al. J Urol 2003; 169 (Suppl): 396 (Abstr 1480). Neymark N et al. Eur J Cancer 2001; 37: 1768-1774. Pilepich MV et al. Proc Am Soc Clin Oncol 2003; 22: 381 (Abstr 1530). Vogelzang NJ et al. Urology 1995; 46: 220-226.

LHRH– jednoduchá s.c. aplikace The depot is injected subcutaneously into the anterior abdominal wall

LHRH analoga A/ V léčbě lokálně pokročilého karcinomu prostaty (LPKP) Neoadjuvance K radioterapii (RT) Adjuvance K radikální prostatektomii (RP) B/ V léčbě metastatického karcinomu prostaty v monoterapii v kombinaci s antiandrogenem (CAB)

LHRH V léčbě lokálně pokročilého karcinomu prostaty (LPKP) Neoadjuvance K radioterapii (RT) Adjuvance K radikální prostatektomii (RP) B/ V léčbě metastatického karcinomu prostaty v monoterapii v kombinaci s antiandrogenem (CAB)

RTOG 86-10: přežití bez známek onemocnění (DFS) Radioterapie + ‘Zoladex’ (goserelin) +flutamid (n=226) Radioterapie samotná (n=230) Pacienti (%) 100 75 50 25 This slide shows the proportion of patients who had not progressed after the start of treatment. The median follow-up was 6.7 years for all patients and 8.6 years for surviving patients. Disease-free survival was defined as freedom from progression in terms of local failure, regional metastases or distant metastases. Neoadjuvant hormonal therapy (‘Zoladex’ [goserelin] plus flutamide) significantly improved disease-free survival compared with radiotherapy alone (p=0.004). The study also showed that neoadjuvant hormonal therapy (‘Zoladex’ [goserelin] plus flutamide) significantly improved biochemical disease-free survival (p<0.0001) and local control (p=0.016) as well as reducing the incidence of distant metastases (p=0.04) compared with radiotherapy alone. Reference: Pilepich MV et al. Int J Radiat Oncol Biol Phys 2001; 50: 1243-1252. 1 2 3 4 5 6 7 8 9 Trvání léčby (roky) p=0.004 Medián sledování 8.6 let DFS - disease free survival Pilepich et al 2001

EORTC 22863: celkové přežití (OS) 5-leté přežití: 62% (95% CI 52, 72%) 5-leté přežití: 78% (95% CI 72, 84%) Pacienti (%) 100 80 60 40 20 30 50 70 90 10 Doba od randomizace (roky) 1 2 3 4 5 6 7 8 Radioterapie + ‘Zoladex’ (n=207) Radioterapie samotná (n=208) snížení rizika úmrtí o 50% The EORTC 22863 study showed that the survival outcome with radiotherapy was improved by the addition of adjuvant hormonal therapy (Bolla et al 2002). Patients in this study had no evidence of distant metastases and had either T1-2 disease of WHO grade 3 or T3-4 disease of any histological grade, with or without nodal involvement. Hormonal therapy comprised ‘Zoladex’ (goserelin) 3.6 mg every month and commenced on the first day of radiotherapy and was continued for 3 years. The median follow-up was 5.5 years and 412 patients had evaluable data. Overall survival differed significantly between the two treatment groups (hazard ratio [HR] 0.51; 95% confidence intervals [CI] 0.36. 0.73). Estimates of 5-year survival were 78% (95% CI 72, 84%) in the adjuvant ‘Zoladex’ (goserelin) group and 62% (95% CI 52, 72%) in the radiotherapy-alone group (p=0.0002). 5-year disease-specific survival was 94% (95% CI 90, 98%) and 79% (95% CI 72, 86%), respectively. Results were similar when only patients with T3-4 disease were analysed (89% of the study population), with 5-year estimates of overall and disease-specific survival of 78% versus 60% and 94% versus 78%, respectively (both p=0.0001). References: Bolla M et al. N Engl J Med 1997; 337: 295-300. Bolla M et al. Eur J Cancer 1999; 35 (Suppl 4): S82 (Abstr 266). Bolla M et al. Lancet 2002; 360: 103-108. p=0.0002 Hazard ratio (HR) 0.51; 95% confidence intervals (CI) 0.36, 0.73 Medián sledování 5.5 let Bolla et al 2002

RTOG 85-31: 10-ti leté odhady výskytu recidiv a celkového přežití Pacienti (%) Radioterapie (n=468) Radioterapie + ‘Zoladex’ (goserelin) (n=477) p<0.0043 p<0.0001 p<0.0001 Median follow-up was 7.3 years. 10-year estimates of local failure (23% vs 39%; p<0.0001), distant metastases (25% vs 39%; p<0.0001) and absolute mortality (47% vs 62%; p<0.0043) were all significantly improved in the ‘Zoladex’ (goserelin) plus radiotherapy arm relative to radiotherapy alone. Reference: Pilepich MV et al. Proc Am Soc Clin Oncol 2003; 22: 381 (Abstr 1530). Lokální selhání Vzdálené metastázy celková mortalita Median follow-up 7.3 let Všichni pacienti byli s vysokým rizikem (T3 N0 / 1 nebo T1-2 N1) Pilepich et al 2003

RTOG 92-02: přežití bez známek onemocnění (DFS) Pacienti (%) At a median follow-up of 4.8 years, Hanks et al (2000) found that there was a significant improvement in disease-free survival with combined ‘Zoladex’ (goserelin) adjuvant and neoadjuvant hormonal therapy treatment vs neoadjuvant treatment alone in patients with locally advanced prostate cancer. Significant improvements with ‘Zoladex’ (goserelin) adjuvant and neoadjuvant treatment were also seen in: - local disease progression (6% vs 13%; p=0.0001) - distant metastases (11% vs 17%; p=0.01) - biochemical progression (21% vs 46%; p=0.0001). Reference: Hanks GE et al. Proc Am Soc Clin Oncol 2000; 19: 327a (Abstr 1284). Radioterapie + NHT + adjuvantně ‘Zoladex’ (goserelin) Radioterapie + NHT p=0.0001 Median follow-up 4.8 let NHT, neoadjuvantní hormonální léčba (Zoladex / flutamide) Hanks et al 2000

LHRH :  v neoadjuvantní léčbě k radioterapii hormonálně dependentního lokálně pokročilého karcinomu prostaty prokázal ve srovnání se samotnou radioterapií významně vyšší účinnost v parametru DFS Pilepich et al 2001 DFS - disease free survival

LHRH A/ V léčbě lokálně pokročilého karcinomu prostaty (LPKP) Neoadjuvance K radioterapii (RT) Adjuvance K radikální prostatektomii (RP) B/ V léčbě metastatického karcinomu prostaty v monoterapii v kombinaci s antiandrogenem (CAB)

Kaisary AV et al 1991: LHRH 3.6 mg vs orchiektomie: celkové přežití (OS) 100 Přežívající pacienti (%) ‘Zoladex’ (goserelin) 3.6 mg (n=148) Orchiektomie (n=144) 80 60 40 20 This slide compares the overall survival of patients with advanced metastatic (M1) prostate cancer receiving ‘Zoladex’ (goserelin) 3.6 mg with those who underwent orchiectomy. The median duration of follow-up for survival was 104 weeks in the 'Zoladex' (goserelin) group and 97 weeks in the orchiectomy group. Kaisary et al (1991) found that there was no significant difference in the overall survival rate between the two treatment groups (p=0.33). Reference: Kaisary AV et al. Br J Urol 1991; 67: 502-508. 24 48 72 96 120 144 168 192 Čas (týdny) p=0.33 Median follow-up: 104 týdnů 'Zoladex' (goserelin); 97 týdnů orchiektomie Kaisary et al 1991

Čas od randomizace (týdny) Vogelzang et al 1995: LHRH 3.6 mg vs orchiektomie: doba do selhání léčby (TTF) Procento pacientů bez selhání léčby (%) 1.0 ‘Zoladex’ (goserelin) 3.6 mg (n=138) Orchiektomie (n=145) 0.8 0.6 p=0.99 0.4 0.2 Vogelzang et al (1995) carried out a second major multicentre, randomised trial comparing the efficacy and tolerability of ‘Zoladex’ (goserelin) (n=138) with orchiectomy (n=145) in patients with stage D2 prostate cancer. The treatment groups were well matched for performance status, tumour differentiation, dominant disease site and pre-therapy serum testosterone levels. This study showed that ‘Zoladex’ (goserelin) 3.6 mg depot and orchiectomy were equally effective in lowering testosterone levels to within the castrate range at Week 4 (median, 20.9 ng/dL for ‘Zoladex’ [goserelin] and 20.0 ng/dL for orchiectomy) and that serum testosterone concentrations remained below castrate levels for the duration of treatment. The Kaplan-Meier curve in the slide shows that the times to treatment failure were similar in the ‘Zoladex’ (goserelin) and orchiectomy groups (52 and 53 weeks, respectively). There were 186 treatment failures. The majority (129) were for progressive disease (62 ‘Zoladex’ [goserelin], 67 orchiectomy) and 57 were for other reasons: death without progression (13 ‘Zoladex’ [goserelin], 3 orchiectomy), patient request (7 ‘Zoladex’ [goserelin], 18 orchiectomy), other illnesses (4 ‘Zoladex’ [goserelin], 3 orchiectomy), protocol violation (4 ‘Zoladex’ [goserelin], 3 orchiectomy), adverse event (1 ‘Zoladex’ [goserelin]) or no follow-up (1 orchiectomy). There was no significant difference in distributions of treatment failure time between the treatment groups (p=0.99). No deaths were attributed to either ‘Zoladex’ (goserelin) or orchiectomy. The study also found that the ‘Zoladex’ (goserelin) and orchiectomy groups had similar results for objective response (82% vs 77% [p=0.32]) and median survival (119 vs 136 weeks [p=0.42]). The survival estimate is based on a minimum follow-up time of 4 years for all patients. These studies (Kaisary et al 1991; Vogelzang et al 1995) show that ‘Zoladex’ is an effective alternative to orchiectomy for the management of patients with advanced, M1 prostate cancer. References: Kaisary AV et al. Br J Urol 1991; 67: 502-508. Vogelzang NJ et al. Urology 1995; 46: 220-226. 0.0 15 30 45 60 75 90 105 120 135 150 Čas od randomizace (týdny) Vogelzang et al 1995

LHRH 3.6mg vs orchiektomie: Prokazatelně stejně účinný jako orchiektomie v parametrech : Přežití (OS) Doba do selhání léčby (TTF) Objektivní odpověď Symptomatická odpovědi ‘Zoladex’ (goserelin) has proven clinical benefits in advanced prostate cancer. Randomised, comparative studies have demonstrated that ‘Zoladex’ (goserelin) improves survival as effectively as orchiectomy (Kaisary et al 1991; Vogelzang et al 1995). A meta-analysis (Seidenfeld et al 2000) concluded that the trials comparing ‘Zoladex’ (goserelin) with orchiectomy (Kaisary et al 1991; Vogelzang et al 1995) are of high quality and that the data are robust. No comparative clinical data are available to demonstrate the effects of leuprolide (depot formulation) compared with orchiectomy on survival. References: Kaisary AV et al. Br J Urol 1991; 67: 502-508. Seidenfeld J et al. Ann Int Med 2000; 132: 566-577. Vogelzang NJ et al. Urology 1995; 46: 220-226. Kaisary et al 1991; Vogelzang et al 1995

LHRH (goserelin) vs CPA: doba do progrese (TTP) Pacienti bez progrese (%) 100 ‘Zoladex’ (goserelin) 3.6 mg + CPA (n=175) 90 80 ‘Zoladex’ (goserelin) 3.6 mg (n=175) CPA (n=175) 70 60 50 p=0.016 pro Zoladex vs CPA 40 30 Thorpe et al (1996) compared the efficacy of ‘Zoladex’ (goserelin) 3.6 mg (every 4 weeks) with the steroidal antiandrogen CPA (100 mg, three times daily). A total of 525 previously untreated patients with metastatic M1 prostate cancer were recruited and randomised to receive either CPA (n=175), ‘Zoladex’ (goserelin) (n=175) or 7 days’ CPA pre-treatment followed by ‘Zoladex’ (goserelin) plus CPA (n=175). There was no statistically significant difference in time to progression between combination therapy (‘Zoladex’ [goserelin] plus CPA) and monotherapy (‘Zoladex’ [goserelin]) or CPA. There was, however, a statistically significant difference in time to progression between ‘Zoladex’ (goserelin) monotherapy and CPA monotherapy (p=0.016). It was concluded that ‘Zoladex’ (goserelin) was more effective than CPA. Although combination therapy did not confer any advantage in terms of time to progression, CPA was reported to reduce the tumour flare and hot flushes caused by ‘Zoladex’ (goserelin). Reference: Thorpe SC et al. Eur Urol 1996; 29: 47-54. 20 10 200 400 600 800 1000 1200 1400 1600 Čas (dny) Thorpe et al 1996

LHRH (goserelin) vs CPA vs DES: medián přežití Čas (týdny) p=0.004 NS Osbourne et al (1990) compared the use of ‘Zoladex’ (goserelin) 3.6 mg with CPA (100 mg orally three times daily) and the synthetic oestrogen analogue DES (1 mg orally three times daily) in patients with advanced prostate cancer (T3 or greater, M0/M1). The trial comprised 2 arms. In Arm A, patients were randomised to the 3 treatments in a 2:1 ratio. Patients in whom DES was contraindicated or not appropriate were enrolled into Arm B and randomised to treatment in a 2:1 ratio. More patients were randomized to 'Zoladex' as when the trial was designed a control database on the drug was required. A total of 360 patients were randomised into two different treatment arms: Arm A: 69 patients were given ‘Zoladex’ (goserelin), 33 DES and 35 CPA Arm B: 152 patients were given ‘Zoladex’ (goserelin) and 71 CPA. The patients were followed up for 2 years. In Arm A, the median survival was in excess of 194 weeks for ‘Zoladex’ (goserelin) and 143 weeks for DES and 64 weeks for CPA (p=0.004 'Zoladex' [goserelin] vs CPA). In Arm B, there was no significant difference in median survival: 132 weeks for ‘Zoladex’ (goserelin) and 130 weeks for CPA. The difference in median survival between 'Zoladex' (goserelin) and CPA patients in Arms A and B were not be explained by differences in baseline characteristics. Adjusted survival analysis suggested the survival advantage for 'Zoladex' (goserelin) may be due to more patients of M1 status, with worse performance status and higher median alkaline phosphatase levels being enrolled into the 'Zoladex' group at trial entry. Reference: Osbourne DR et al. Recent Advances in Urological Cancers Diagnosis and Treatment, Paris 1990: 53-55. CPA-cyproteron acetát, DES-diethylstilbestrol,NS-statisticky nevýznamný Osbourne et al 1990

LHRH (goserelin) vs CPA účinnější než cyproteron acetát (CPA) v parametru doba do progrese (TTP) (p=0.016) Účinnější než CPA v parametru celkové přežívání (193 vs. 143 týdnů) Randomised comparative studies have proven that in advanced prostate cancer, compared with CPA, 'Zoladex' (goserelin) is more effective in delaying time to progression (p=0.016) and is as effective in improving survival (Thorpe et al 1996; Osbourne et al 1990). No comparative clinical data are available to demonstrate the clinical effects of leuprolide (depot formulation) compared with CPA. References: Osbourne DR et al. Recent Advances in Urological Cancers Diagnosis and Treatment, Paris 1990: 53-55. Thorpe SC et al. Eur Urol 1996; 29: 47-54. Thorpe et al 1996; Osbourne et al 1990

LHRH (goserelin) A/ V léčbě lokálně pokročilého karcinomu prostaty (LPKP) AA/ Neoadjuvance AAA/ K radioterapii (RT) AAB/ K radikální prostatektomii (RP) AB/ Adjuvance ABA/ K radioterapii (RT) ABB/ K radikální prostatektomii (RP) B/ V léčbě metastatického karcinomu prostaty BA/ v monoterapii BB/ v kombinaci s antiandrogenem (CAB)

EORTC 30853: celkové přežití (OS) Zoladex v kombinaci s flutamidem ve srovnání se samotnou orchiektomií významně prodlužuje celkové přežití Žijící pacienti (%) 100 ‘Zoladex’ (goserelin) 3.6 mg + flutamid (n=155) 90 80 orchiektomie (n=155) 70 60 50 p=0.04; HR 0.77; 95% CI 0.60, 0.99 Median follow-up 7.2 let 40 30 20 This slide shows the Kaplan-Meier estimate of overall survival. The median follow-up was 7.2 years. In patients with metastatic (M1) prostate cancer, ‘Zoladex’ (goserelin) combination therapy, significantly improved overall survival compared with orchiectomy alone (p=0.04). The median duration of overall survival was 27 months on orchiectomy and 34 months on combination therapy. Reference: Denis LJ et al. Eur Urol 1998; 33: 144-151. 10 2 4 6 8 10 Čas (roky) Denis et al 1998

Nežádoucí účinky hormonální léčby LHRH / OE Ztráta libida Erektilní dysfunkce Hot flushes Osteoporóza Obezita Metabolický syndrom Snížení kognitivních funkcí

Hormonální léčba - shrnutí V léčbě lokálně pokročilého karcinomu prostaty (LPKP) Neoadjuvance K radioterapii (RT) LHRH Adjuvance K radioterapii (RT) Antiandrogeny , LHRH K radikální prostatektomii (RP) Antiandrogeny , LHRH V léčbě metastatického karcinomu prostaty v monoterapii LHRH , Orchiektomie v kombinaci LHRH , Orchiektomie + antiandrogenem (CAB)

karcinom prostaty kurativní léčba Lokálně pokročilý PIN N+ Orgánově ohraničený M+ Objem, mL 1 4 25 100 1000 PSA, ng/mL 3 10 20 200 700 300 Rozmezí vyléčitelnosti PIN, prostatic intraepithelial neoplasia 43

karcinom prostaty adjuvance antiandrogeny / OE Lokálně pokročilý PIN N+ Orgánově ohraničený M+ Objem, mL 1 4 25 100 1000 PSA, ng/mL 3 10 20 200 700 300 Rozmezí vyléčitelnosti PIN, prostatic intraepithelial neoplasia 44

karcinom prostaty LHRH anebo OE Lokálně pokročilý PIN N+ Orgánově ohraničený M+ Objem, mL 1 4 25 100 1000 PSA, ng/mL 3 10 20 200 700 300 Rozmezí vyléčitelnosti PIN, prostatic intraepithelial neoplasia 45

karcinom prostaty hormonálně rezistentní Lokálně pokročilý PIN N+ Orgánově ohraničený M+ Objem, mL 1 4 25 100 1000 PSA, ng/mL 3 10 20 200 700 300 Rozmezí vyléčitelnosti PIN, prostatic intraepithelial neoplasia 46

Hormonálně rezistentní karcinom Testosteron < 1,7 nmol/l Opakovaná elevace PSA po RRP 1,2 ng/ml jinak 2,0 až 5,0 ng/nl

Léčba HRPC Docetaxel 75mg/m2 / 3 týdny symptomatický pacient Výrazné nežádoucí účinky (febrilní leukopenie, trombocytopenie apod.

Léčba HRPC Biologická léčba – klinické studie Sunitinib ZD 4054 Lenalidomid

Bicalutamid 150 mg – zachovává kostní denzitu Bicalutamid (‘Casodex’) 150 mg LHRH analog Změna kostní denzity z původní hodnoty % 3.0 2.0 1.0 0.0 -1.0 -2.0 -3.0 -4.0 Reference Sieber PR et al. Bone mineral density is maintained during bicalutamide ('Casodex') treatment. Proc Am Soc Clin Oncol 2002; 21: 196a (abstr 783). -5.0 -6.0 24 48* 72* 96* Follow-up (týdny) *Statisticky signifikantní rozdíl mezi oběma skupinami p<0.0001 Studie US0004: Sieber et al 2002