Castratie Resistent prostaatcarcinoom,

Castratie Resistent prostaatcarcinoom, Wat is nieuw sedert 2005? Dr W. Demey, medische oncologie, Zorgprogramma Oncologie Voorkempen

Het landschap in 2005 Lokale ziekte : lokale therapie (HK/RT/Brachy) Locoregionale ziekte Gemetastaseerde ziekte Palliatieve HT

2005: H RPC Estramustine Strontium, Samarium (Serafini, 1998, JCO) palliatie Mitoxantrone (Tannock, JCO, 1996, 160 P) palliaitie Zoledroninezuur Taxotere survival benefit (tax 327, SWOG) Ketoconazole (Small, JCO, 2004, CALGB)

2011: Biologie Prostaatcarcinoom Androgeen receptor is een target Ook bij het H RPC! Activerende mutaties van de receptor: weinig frequent! Overexpressie van de receptor? Prostaatca cellen hebben een eigen paracrine/autocrine functie Prostaatca cellen produceren steroiden, oestrogenen en androgenen Receptor en ligand blijven een target: receptor (MDV 3100, ARN 509) ligand (abiraterone, TAK 700) of alle twee TOK001

LHRH LHRH (ant)agonists LH/FSH orchiectomy Antiandrogens Adapted from J.B. Aragon-Ching, Frontiers in Bioscience 12, 4957-4971, September 5 1, 2007

Mechanisms of escape Adapted from: Pienta et al. Clin Cancer Res 2006;12:1665-1671 6

Definition of CRPC Castrate serum levels of testosterone (testosterone < 50 ng/dl or < 1.7 nmol/l) Normal levels in adult men: 300-1000 ng/dl Three consecutive rises of PSA, 1 week apart, resulting in two 50% increases over the nadir, with a PSA > 2 ng/ml Anti-androgen withdrawal* for at least 4 weeks for flutamide (Eulexin) and for at least 6 weeks for bicalutamide(casodex) PSA progression, despite consecutive hormonal manipulations * Either anti-androgen withdrawal or one secondary hormonal manipulation should have been done in order to fulfill the criteria for CRPC. Progression of osseous lesions: progression or appearance of two or more lesions on bone scan or soft tissue lesions using RECIST (Response Evaluation Criteria in Solid Tumours) and with nodes > 2 cm in diameter. EAU guidelines on prostate cancer, 2011 www.uroweb.org, accessed sept. 24 2011 7

Montgomery, cancer Res 2008

In de Praktijk: Abiraterone In 1990, Dr Potter was asked to find a compound that would inhibit CYP17. Two weeks later he had develop abiraterone (an analogue that showed excellent activity) He continued to develop other similar compounds More than 100 analogues later, Dr Potter discovered that he d had it right all along none worked as well as the first.

What is CYP 17? In steroid and androgen synthesis, several different enzymes play a role CYP17 is part of the family of cytochrome P450 enzymes CYP17 is one enzyme with two distinct functions 17α hydroxylase 17-20 lyase Abiraterone was specifically developed to bind selectively and irreversibly to CYP17 Molina et al. J of Urology 2011; 185, 787-794 Attard et al. Cancer Res 2009; 69: (12) Your Logo

Impact of Abiraterone Adapted from: Attard et al. J Clin Oncol 26:4563-4571

Abiraterone blocks androgen production at all 3 sites Molina et al. J of Urology 2011; 185, 787-794 12

Abiraterone phase 3 trial: COU-AA-301 13

Abiraterone acetate plus low dose prednisone improves overall survival in patients with metastatic castrationresistant prostate cancer (CRPC) who have progressed after docetaxel-based chemotherapy Results of COU-AA-301, a randomized doubleblind placebo-controlled phase 3 study de Bono et al. N Engl J Med 2011; 346(21): 1995-2005

Phase 3, multinational, multicenter, randomized, double-blind, placebocontrolled study (147 sites in 13 countries; USA, Europe, Australia, Canada) 1195 patients with progressive, mcrpc Failed 1 or 2 chemotherapy regimens, one of which contained docetaxel Randomised 2:1 Stratification by: ECOG performance status (0-1 vs. 2) Worst pain over previous 24 hours (BPI short form; 0-3 [absent] vs. 4-10 [present]) Prior chemotherapy (1 vs. 2) Type of progression (PSA only vs. radiographic progression with or without PSA progression) Abiraterone acetate 1000 mg daily Prednisone 5mg twice daily Placebo daily Prednisone 5mg twice daily T R E A T U N T I L P R O G R E S S I O N Primary endpoint: OS (25% improvement; HR 0.8) de Bono et al. N Engl J Med 2011; 346(21): 1995-2005

Baseline Disease Characteristics (1) Extent of disease AA (n = 797) Placebo (n = 398) Bone 89% 90% Node 45% 41% Liver 11% 8% Visceral Metastasis Lung 13% 11% Other Visceral 6% 5% Prostate mass 8% 6% Other tissue 5% 5% Viscera, NOS 0.1% 0 PSA (median, ng/ml) 128.8 (0.4-9253) 137.7 (0.6-10114) Hemoglobin (median, g/dl) 11.8 11.8 LDH (median, IU/L) 223.0 237.5 de Bono et al. N Engl J Med 2011; 346(21): 1995-2005

Baseline Disease Characteristics (2) Gleason score at initial diagnosis AA (n = 797) Placebo (n = 398) 7 48.9% 46.0% 8 51.1% 54.0% PSA at initial diagnosis (ng/ml) Median (range) 27 (0.1-16065.9) 35.5 (1.1-7378.0) Previous cancer therapy Surgery 54% 49% Radiotherapy 72% 72% Hormonal 100% 100% Other* 100% 100% * Includes chemotherapy de Bono et al. N Engl J Med 2011; 346(21): 1995-2005

Overall Survival Interim Analysis de Bono et al. N Engl J Med 2011; 346(21): 1995-2005

Updated overall survival 19

Survival Benefit Consistently Observed Across Patient Subgroups Variable Subgroup N HR 95% CI All subjects All 1195 0.66 0.56-0.79 Baseline ECOG 0-1 1068 0.64 0.53-0.78 2 127 0.81 0.53-1.24 Baseline BPI < 4 659 0.64 0.50-0.82 4 536 0.68 0.53-0.85 No. of prior chemo regimens 1 833 0.63 0.51-0.78 2 362 0.74 0.55-0.99 Type of progression PSA only 363 0.59 0.42-0.82 Radiographic 832 0.69 0.56-0.84 Baseline PSA above median YES 591 0.65 0.52-0.81 Visceral disease at entry YES 709 0.60 0.48-0.74 Baseline LDH above median YES 581 0.71 0.58-0.88 Baseline ALK-P above median YES 587 0.60 0.48-0.74 Region North America 652 0.64 0.51-0.80 Other 543 0.69 0.54-0.90 BPI; Brief Pain Inventory, ALK-P, alkaline phosphatase Favors AA 0.5 0.75 1 1.5 Favors placebo de Bono et al. N Engl J Med 2011; 346(21): 1995-2005

Secondary End Points AA (n = 797) Placebo (n = 398) HR 95% CI P Value TTPP (months) 10.2 6.6 0.58 (0.46, 0.73) rpfs (months) 5.6 3.6 0.67 (0.58, 0.78) < 0.001 < 0.001 PSA response rate Total 38.0% 10.1% - < 0.001 Confirmed 29.1% 5.5% - < 0.001 Objective response (RECIST) 14.0% 2.8% - < 0.001 de Bono et al. N Engl J Med 2011; 346(21): 1995-2005

Summary of AEs AA (n = 791) Placebo (n = 394) All Grades Grades 3/4 All Grades Grades 3/4 All treatment-emergent AEs 98.9% 54.5% 99.0% 58.4% Serious AEs 37.5% 32.1% 41.4% 35.3% AEs leading to discontinuation 18.7% 10.5% 22.8% 13.5% AEs leading to death 11.6% 14.7% Deaths within 30 days of last dose 10.5% 13.2% Underlying disease 7.5% 9.9% Other specified cause 2.9% 3.3% de Bono et al. Ann Oncol 2010: Abstract LBA5 (Oral presentation at ESMO)

AEs of Special Interest Fluid retention and edema All Grades AA (n = 791) Grade 3 Grade 4 All Grades Placebo (n = 394) Grade 3 Grade 4 31% 2% <1% 22% 1% 0 Hypokalemia 17% 3% <1% 8% 1% 0 Cardiac disorders 13% 3% 1% 11% 2% <1% LFT abnormalities 10% 3% <1% 8% 3% <1% Hypertension 10% 1% 0 8% <1% 0 de Bono et al. N Engl J Med 2011; 346(21): 1995-2005

Abiraterone: conclusie Bij castratieresistent prostaatca na docetaxel: bewezen survival benefit bij hormoongevoelig prostaatca: te testen Prechemotherapie: studies zijn gesloten. Andere drugs komen eraan

Schematic of the various androgen-receptor (AR) signaling aberrancies that may drive progressive prostate cancer. Ryan C J, Tindall D J JCO 2011;29:3651-3658 2011 by American Society of Clinical Oncology

Immunotherapie voor prostaatcarcinoom Historisch niet gezien als immuun responsief Recent duidelijk OS (sipuleucel-t, nejm, FDA-approved) Andere op komst!? PROSTAVAC-VF Beide gebaseerd op stimulatie van het immuunsysteem door prostaatca-eiwitten Studies tonen een OS echter geen winst in PFS: gebrek aan biomarkers.

Overview of tumor-specific immune response and components targeted by individual immunotherapies. Cha E, Fong L JCO 2011;29:3677-3685 2011 by American Society of Clinical Oncology

Sipuleucel-T, nejm, 2010 Autologue perifeer bloed monocyten (met APC) Ex vivo activatie door een fusie eiwit (PA, zuur fosfatase en GM-CSF), Randomisatie 2:1 van 512 P (CRPC, geen bedreigende ziekte) Drie infusies, om de 2 weken, Eindpunt was OS

Reductie op overlijden van 22% OS winst: 4,1 mnd

Sipuleucel-T: Geen verschil in PFS: laattijdig effect? Goede tolerantie (cytokine release) Kost: 98.000 $ PROSTAVAC-VF: 8,5 mnd OS in fase II, fase III is lopende

Ipulimumab? Cha E, Fong L JCO 2011;29:3677-3685 2011 by American Society of Clinical Oncology

Chemotherapie voor CRPC: TROPIC Mitoxantrone Docetaxel Klassiek probleem bij prostaatca is het kleine aantal cellen dat actief aan het delen is, Proliferatie neemt toe tijdens ziekteproces Resistentie op docetaxel door P-glycoproteine Veranderde expressie van tubuline isotypes Defect in apoptose pathways

P-glycoproteine

Tropic: design 755 P; progressing during of after docetaxel, Cabazitaxel vs mitoxatrone OS eindpunt HR: 0,72, OS winst: 2,5 maand, p<0,001

Cabazitaxel: OS benefit (de Bono, Lancet 2010)

Tropic bespreking Grotere toxiciteit dan mitoxantrone (diarree en neutropenie) Weinig neuropathie Metabolisatie gebeurd in de lever. Primare profylaxe met G-CSF should be considered Zeer duur: 7,400 $ per toediening (in USA) Wellicht plaats voor docetaxel

Skeletal morbidity 1. meest frequente plaats van metastasering Axiaal skelet Pijn Hypocalcemie Pathologische frakturen Myelumcompressie 2. Treatment-related osteoporosis Indeukingsfrakturen

The role of the receptor activator of nuclear factor kappa B (RANK) and RANK ligand (RANKL) in normal bone physiology. Saylor P J et al. JCO 2011;29:3705-3714 2011 by American Society of Clinical Oncology

Bone-Targeted therapies Bisphosphonaten: structureel lijkend op pyrofosfaat, incorporatie in de matrix door binding aan de hydroxyapatite kristallen. Het vormt een barrière op de resorptie door osteoclasten. Zoledroninezuur is het krachtigste bisfosfonaat. Denosumab: SC toegediend antistof met binding op de RANKL, halfwaardetijd van meer dan 30 dagen, inhibitie op bone turnover van zeker 6 maanden Radiopharmaceuticals: Samarium, als pijntherapie

Preventie van castratie geïnduceerde osteoporose Klassiek veel lagere dosis/frekwentie dan bij metastasen Voor de bisfosfonaten: onvoldoende trials in deze specifieke populatie Denosumab: 1468 patiënten, ADT, hoog risico op #, Denosumab vs placebo, nejm, 2009, BMD= slechte predictor van problmenen bij mannen

Mean Percent Changes from Baseline Bone Mineral Density (BMD) Values during the Study Period, According to Skeletal Site and Study Group. Smith MR et al. N Engl J Med 2009;361:745-755.

Cumulative Incidence of New Vertebral Fracture at 12, 24, and 36 Months, According to Study Group. Smith MR et al. N Engl J Med 2009;361:745-755.

Metastase preventie? Eerste trials met zoledroninezuur zijn om methodologische redenen mislukt, ZEUS trial is nog lopende Denosumab lijkt de tijd tot vaststellen van botmetastasen wel te kunnen verlengne (4,2 mnd)

Als therapie bij het botgemetastaseerd prostaatcarcinoom Pamidronaat: 90 mg IV iedere 3 weken, 2 negatieve trials, 350 P Zoledroninezuur: 643 P, TT first SRE van 321 naar 488 dagen, incidentie van 44,2% naar 33,2% op 15 mnd. Trend van verbeterde overleving. Probleem met nefrotoxiciteit en ONJ. Denosumab: Denosumab vs zoledroninezuur: TT first SRE van 17 naar 20 maanden, verder idem

Primary analysis of the Denosumab 103 trial. Saylor P J et al. JCO 2011;29:3705-3714 2011 by American Society of Clinical Oncology

Nevenwerkingen van skelet gerichte therapie Nierfunctie: beperkt en goed gekend ONJ: Denosumab biedt geen oplossing, incidentie minstens even hoog, langer FU nodig IV therapie? Hypocalcemie? (duidelijk hoger dan met denosumab: 12,8 vs 5,8%)

MET targeted therapies MET: receptor tyrosine kinase (oncogenic signaling, angiogenese and metastasis) AMG 102: monoclonales antistof Cabozantinib: kleine molecule Eerste resutaten van Cabozantinib lijken veelbelovend

CRPC: verloop PSA (ng/ml) Non Metastatic locally advanced PSA recurrence after local treatment 100 90 80 70 60 50 40 30 20 10 0 Hormone therapy Non-metastatic PSA increasing PSA recurrence 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Time post diagnosis (years) Metastatic Asymptomatic Metastases Metastatic Symptomatic (bone pain) Symptoms

TAX 327: study design Patients with progressive HRPC R A N D O M I S E n=1006 Docetaxel 75 mg/m 2 q3w Prednisone 5 mg bid Docetaxel 30 mg/m 2 weekly (5 of 6 weeks) Prednisone 5 mg bid Mitoxantrone 12 mg/m 2 q3w Prednisone 5 mg bid Treatment duration = 30 weeks

Probability of Surviving 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 TAX 327: results Median survival Hazard (mos) ratio P-value Docetaxel 3 wkly Docetaxel wkly Mitoxantrone Combined: 18.2 0.83 0.03 D 3 wkly: 18.9 0.76 0.009 D wkly: 17.3 0.91 0.3 Mitoxantrone 16.4 Months 0 6 12 18 24 30

TAX 327: results Regimen Docetaxel 75 mg/m² 3 wks Docetaxel 30 mg/m² 1 wk Mitoxantrone 12 mg/m² 3 wks Median survival (months) 18.9 p: 0.009 17.3 p: 0.3 16.4 Pain response 35% p:0.01 31% p:0.07 22% PSA response 45% p:0.0005 48% p:0.0001 32% Tannock IF et al., TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N. Engl J Med. 2004 Oct 7;351(15):1502-12.

SWOG 9916: study design Patients with metastatic HRPC R A N D O M I S E Docetaxel 60 mg/m2 q3w, Day 2 Estramustine 280 mg tid, Days 1 5 Premedication: dexamethasone 20 mg tid, Day 1 Mitoxantrone 12 mg/m2 q3w, Day 1 Prednisone 5 mg bid Treatment duration: n=770 12 cycles of docetaxel and estramustine 144 mg/m 2 mitoxantrone Docetaxel and mitoxantrone doses could be increased to 70 mg/m 2 and 14 mg/m 2, respectively, if no grade 3 or 4 toxicities were seen in Cycle 1

100% 80% 60% SWOG 99-16 D+E M+P # at Risk 338 336 # of Deaths 217 235 Median in Months 18 16 HR: 0.80 (95% CI 0.67, 0.97), p = 0.01 40% 20% 0% 0 12 24 36 48 Months

TAX 327 Haematologische toxiciteit GIII/GIV Docetaxel 3 wkly Docetaxel wkly Mitoxantron e Treated (N) 332 330 335 Anemia 5.0 5.0 2.0 Neutropenia 32.0 1.5 22.0 Neutropenic infection Febrile neutropenia 3.0 0.0 0.9 2.7 0.0 1.8 Septic death 0.0 0.3 0.3

Rationale to use in asymptomatic M+ patients TAX 327: survival in subgroups ITT Hazard ratio in favor of: Docetaxel 3qw Mitoxantrone Age < 65 Age 65 Age 75 Pain no Pain yes KPS 80 KPS 70 0.2 0.4 0.6 0.8 1 1.2 1.4 Presented at ESMO, 2004 by R de Wit

Docetaxel : conclusies uit fase III trials Docetaxel q3w ± EMP versus mitoxantrone-prednisone: 20 24% reductie van het risico op overlijden verhoogt PSA respons veerbeterde QoL Al bij al goed verdragen: voorspelbare toxiciteit

Bovendien Docetaxel was niet versus placebo maar versus Mitoxantrone, een actief product Crossover had plaats signficante winst

Starten bij asymptomatische patiënt Pro Weinig ziekte-load Prima KI Eenmaal symptomen: snelle progressie Onethisch wachten: survival benefit Contra Geen verschil symptomatisch vs asymptomatisch Toxiciteit Uitstel is soms afstel: oudere patiënt Alternatief is niet zonder nevenwerkingen

Wanneer starten met chemotherapie? Dilemma bij de asymptomatische patient met een chronische maligniteit Beslissing bemoeilijkt door het mislukken van studies die chemotherapie vergelijken met een tweede hormonale manipulatie Geen enkele studie omtrent timing van chemotherapie In de docetaxel studies werden zowel symptomatische als asymptomatische patienten behandeld

Nomogram uit de TAX 327 (Armstrong, de Wit, Tannock, Eisenberger) Aanwezigheid viscerale metastasen (lever) Aantal metastatische localisaties Pijn Karnofsky Meetbare ziekte PSA PSA DT Gleason Alkalische fosfatasen Hemoglobine

Retrospective study: 145 pts treated in 1 single centre in France Pijn? (Oudard S) Minim.-No Pain (n:79) Mild Pain (n:41) Moderate-Severe Pain (n:25) Median OS PSA DT 45 d PSA DT < 45 d 21.4 mo [16-26.8] 32.4 mo 16.5 mo 15.0 mo [8.2-21.8] 18.4 mo 11.2 mo 13.1 mo [9.8-16.5] 16.1 mo 8.3 mo 1-yr OS 75% 56% 52% 2-yr OS 43% 20% 20% 3-yr OS 29% 11% 4% Oudard et al. ASCO 2007. Abstract 5149.

PSADT en Overall Survival in Tax 327

Wanneer Taxotere? Non-metastatic PSA increasing: Metastatic Asymptomatic Metastatic Symptomatic (bone pain) PSA (ng/ml) 100 90 80 70 60 50 40 30 20 10 0 Hormone therapy PSADT: Verdere Hormonale R/ vs Docetaxel PSA recurrence 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Time post diagnosis (years) Evolutie bot, PSADT Docetaxel? Metastases Symptoms

Doelstelling van chemotherapie? Palliate symptoms Mitoxantrone + prednisone Radiotherapy Improve survival Radionucleide Docetaxel ( EMP) Prevent onset of new lesions? Non-metastatic PSA increasing Metastatic Asymptomatic Metastatic Symptomatic (bone pain)

Toekomst? Timing docetaxel afhankelijk van effectieve tweedelijns (chemo)-therapie? Hormoon-refractair prostaatcarcinoom?

When Should Chemotherapy be Started? Men with HRPC have a variety of symptoms that lead to reduced QoL (fatigue and effects of hormonal therapy and supportive treatments) Both QoL and pain can be improved by chemotherapy Men with minimal symptoms had prolonged survival -? chemotherapy Some had decreased QoL after chemotherapy - weekly Berthold DR, et al. ASCO Prostate 2007; abstract # 147

Docetaxel : more questions Do we have to wait until symptoms appear to treat the patients, knowing that the benefit in survival appears to be equivalent?

Disease Burden Median Survival Chemotherapy Indicated Rising PSA only ~4 years? No Asymptomatic metastases (limited) ~18 to 24 months Individualize Asymptomatic metastases (extensive) ~18 months Yes Symptomatic metastases ~9 to 16 months Yes Beer T, modified