Castratie Resistent prostaatcarcinoom, Wat is nieuw sedert 2005?
Dr W. Demey, medische oncologie, Zorgprogramma Oncologie Voorkempen
Het landschap in 2005 •
Lokale ziekte : lokale therapie
•
Locoregionale ziekte
(HK/RT/Brachy)
“Palliatieve” HT •
Gemetastaseerde ziekte
2005: “H”RPC •
Estramustine
•
Strontium, Samarium
•
Mitoxantrone
•
Zoledroninezuur
•
Taxotere
•
Ketoconazole
(Serafini, 1998, JCO) palliatie
(Tannock, JCO, 1996, 160 P) palliaitie
survival benefit (tax 327, SWOG) (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, 5 1, 2007 Frontiers in Bioscience 12, 4957-4971, September
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)
Primary endpoint:
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
OS (25% improvement; HR 0.8) de Bono et al. N Engl J Med 2011; 346(21): 1995-2005
Baseline Disease Characteristics (1) AA (n = 797)
Placebo (n = 398)
Extent of disease Bone
89%
90%
Node
45%
41%
Liver
11%
8%
Lung
13%
11%
Other Visceral
6%
5%
Prostate mass
8%
6%
Other tissue
5%
5%
0.1%
0
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
Visceral Metastasis
Viscera, NOS PSA (median, ng/mL)
de Bono et al. N Engl J Med 2011; 346(21): 1995-2005
Baseline Disease Characteristics (2) AA (n = 797)
Placebo (n = 398)
≤7
48.9%
46.0%
≥8
51.1%
54.0%
27 (0.1-16065.9)
35.5 (1.1-7378.0)
Surgery
54%
49%
Radiotherapy
72%
72%
Hormonal
100%
100%
Other*
100%
100%
Gleason score at initial diagnosis
PSA at initial diagnosis (ng/mL) Median (range) Previous cancer therapy
* 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
1
833
0.63
0.51-0.78
2
362
0.74
0.55-0.99
PSA only
363
0.59
0.42-0.82
No. of prior chemo regimens
Type of progression
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
North America
652
0.64
0.51-0.80
Other
543
0.69
0.54-0.90
Region
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)
< 0.001
rPFS (months)
5.6
3.6
0.67 (0.58, 0.78)
< 0.001
Total
38.0%
10.1%
-
< 0.001
Confirmed
29.1%
5.5%
-
< 0.001
Objective response (RECIST)
14.0%
2.8%
-
< 0.001
PSA response rate
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 AA (n = 791)
Placebo (n = 394)
All Grades
Grade 3
Grade 4
All Grades
Grade 3
Grade 4
Fluid retention and edema
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
•
Drie infusies, om de 2 weken,
•
Eindpunt was OS
(CRPC, geen bedreigende ziekte)
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
•
Zeer duur: 7,400 $ per toediening… (in USA)
•
Wellicht plaats voor docetaxel
“should be considered”
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:
•
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:
90 mg IV iedere 3 weken, 2 negatieve trials, 350 P
naar 20 maanden, verder idem
TT first SRE van 17
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:
•
ONJ:
•
IV therapie?
•
Hypocalcemie?
beperkt en goed gekend
Denosumab biedt geen oplossing, incidentie minstens even hoog, langer FU nodig
(duidelijk hoger dan met denosumab: 12,8 vs 5,8%)
MET targeted therapies •
MET:
•
AMG 102: monoclonales antistof Cabozantinib: kleine molecule
• •
receptor tyrosine kinase (oncogenic signaling, angiogenese and metastasis)
Eerste resutaten van Cabozantinib lijken veelbelovend
PSA (ng/ml)
CRPC: verloop Non Metastatic Non-metastatic locally advanced PSA increasing PSA recurrence after local treatment 100 90 80 70 60 PSA 50 recurrence 40 30 Hormone therapy 20 10 0 0 1 2 3 4 5 6 7 8
Metastatic
Metastatic
Symptomatic (bone pain)
Asymptomatic
Symptoms
Metastases
9
Time post diagnosis (years)
10
11
12
13
14
TAX 327: study design Docetaxel 75 mg/m2 q3w Prednisone 5 mg bid
Patients with progressive HRPC
R A N D O M I S E
Docetaxel 30 mg/m2 weekly (5 of 6 weeks) Prednisone 5 mg bid
Mitoxantrone 12 mg/m2 q3w Prednisone 5 mg bid
n=1006
Treatment duration = 30 weeks
TAX 327: results
1.0
Docetaxel 3 wkly
Probability of Surviving
0.9
Docetaxel wkly
0.8
Mitoxantrone
0.7 0.6 0.5 0.4 0.3 Combined: D 3 wkly: D wkly: Mitoxantrone
0.2 0.1
Median survival (mos)
Hazard ratio
P-value
18.2 18.9 17.3 16.4
0.83 0.76 0.91 –
0.03 0.009 0.3 –
Months
0.0 0
6
12
18
24
30
TAX 327: results Docetaxel 75 mg/m² 3 wks
Docetaxel 30 mg/m² 1 wk
Mitoxantrone 12 mg/m² 3 wks
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%
Regimen
Median survival (months)
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 R A N D O M I S E
Patients with metastatic HRPC
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
n=770 Treatment duration:
• 12 cycles of docetaxel and estramustine • 144 mg/m2 mitoxantrone
Docetaxel and mitoxantrone doses could be increased to 70 mg/m2 and 14 mg/m2, respectively, if no grade 3 or 4 toxicities were seen in Cycle 1
SWOG 99-16 100%
D+E M+P
80%
# 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 60% 40% 20% 0% 0
12
Months
24
36
48
TAX 327 Haematologische toxiciteit GIII/GIV Docetaxel 3 wkly
Docetaxel wkly
Mitoxantron e
332
330
335
5.0
5.0
2.0
Neutropenia
32.0
1.5
22.0
Neutropenic infection
3.0
0.0
0.9
Febrile neutropenia
2.7
0.0
1.8
Septic death
0.0
0.3
0.3
Treated (N) Anemia
Rationale to use in asymptomatic M+ patients
TAX 327: survival in subgroups Hazard ratio in favor of: Docetaxel 3qw
Mitoxantrone
ITT 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
•
Alternatief is niet zonder nevenwerkingen
Contra •
Geen verschil symptomatisch vs asymptomatisch
•
Toxiciteit
•
Uitstel is soms afstel: oudere patiënt
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 (Oudard S)
Pijn?
Minim.-No Pain (n:79)
Mild Pain (n:41)
Moderate-Severe Pain (n:25)
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%
Median OS PSA DT ≥ 45 d PSA DT < 45 d
Oudard et al. ASCO 2007. Abstract 5149.
PSADT en Overall Survival in Tax 327
Wanneer Taxotere?
PSA (ng/ml)
Non-metastatic
100 90 80 70 60 50 40 30 20 10 0
Metastatic
Metastatic
PSA increasing:
Asymptomatic
PSADT: Verdere Hormonale R/ vs Docetaxel
Evolutie bot, PSADT Docetaxel?
Symptomatic (bone pain)
Symptoms
Metastases PSA recurrence Hormone therapy
0
1
2
3
4
5
6
7
8
9
Time post diagnosis (years)
10
11
12
13
14
Doelstelling van chemotherapie ? Palliate symptoms
Mitoxantrone + prednisone Radiotherapy Radionucleide
Improve survival
Docetaxel ( EMP)
?
Prevent onset of new lesions
Non-metastatic
Metastatic
PSA increasing
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
