SOGUG meeting New drugs after docetaxel chemotherapy in patient with mCRPC

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SOGUG meetingNew drugs after docetaxel
chemotherapy in patient with mCRPC
Stéphane OUDARD, MD, PhD Head of the Oncology
department Georges Pompidou Hospital, Paris
France University Rene Descartes, Paris 5
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Currently available secondary hormonal
manipulations in CRPC marginal benefit

• Rationale elevated intratumor androgenlevels
  despite castrate serum levels
• Includes androgen withdrawal, adrenal
  testosterone inhibitors, low doses DES,
  corticosteroids, somatostatin analogues
• Marginal benefit
• PSA response in 10-60 of cases
• Short duration (lt 4-6 months)

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Currently available secondary hormonal
manipulations in CRPC marginal benefit
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Advanced prostate cancer management
Metastatic hormone-sensitiveprostate cancer
Metastatic castration-resistant 1st line
DOCETAXELTAXOTERE
LHRH analogues
Antiandrogens
LHRH antagonist
Survival benefit vs Mitoxantrone
2004
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Metastatic CRPC - First line therapy

• Docetaxel 75 mg/m2 every 3 weeksis the standard
  of carein first-linemetastatic CRPC

1Heidenreich A, et al. (2010 update)
www.uroweb.org 2Mohler J, et al. (2009 update)
www.nccn.org 3Basch EM, et al. J Clin Oncol
200725164Horwich A, et al. Ann Oncol
200920(Suppl 4)768
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Cancer progressionduring or after DocetaxelWhat
are the options?
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Advanced prostate cancer management
Metastatic hormone-sensitiveprostate cancer
Metastatic Castration-resistant 2nd line
Metastatic castration-resistant 1st line
UNMETMEDICAL NEED
DOCETAXELTAXOTERE
LHRH analogues
Antiandrogens
LHRH antagonist
Survival benefit vs Mitoxantrone
2004
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Progression after Docetaxel

• No agent currently approved in patients
  progressing after Docetaxel
• Currently available options provide palliation
  only
• Retreatment with Docetaxel
• Small retrospective studies1-5
• In selected patients good initial
  responders(PSA decrease 50)
• Effect on PSA seems to decrease with rechallenge5

1Eymard JC, Oudard S et al. BJU Int 2010, 2Ansari
et al. Oncol reports 2008 20 891-896 3Beer TM
et al. Cancer. 2008, 112326-30 4Garmey EG et
al, Clin Adv Hematol Oncol. 2008 6(2)118-1132
5Gernone et al. EAU 2010 (abstract 896)
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Cabazitaxel (Jevtana) a next generation taxane
Y
X
O
Y
X
Docetaxel
-OH
-OCCH3
Cabazitaxel
-OCH3
-OCH3

• Both extracted from needles of the European Yew
  treeTaxus baccata

99th AACR annual meeting, San Diego, April 2008
(abstract 3227)
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Cabazitaxel (Jevtana) selected to overcome
taxane resistance

• Some patients do not answer to Docetaxel
  (acquired or constitutional resistance). This may
  be due to various mechanisms
• affinity for multidrug resistant (MDR)
  membrane-associated P-glycoprotein (PgP) efflux
  pump,
• alterations of tubulin, overexpression Bcl-2,
  Aurora-A
• Cabazitaxel
• Poor affinity for the PgP efflux pump
• greater penetration of the blood brain barrier
  compared with docetaxel and paclitaxel
• Active in vitro and in vivo on tumors
  resistant to Docetaxel

• Docetaxel and paclitaxel have a strong affinity
  for the PgP pump
• If the PgP pump is overexpressed, it drives drug
  out of tumor cell

Mita AC et al, Clin Cancer Res. 2009, 15, 723-730
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Cabazitaxel A next-generation taxane

• Preclinical data
• Activity against tumor cells and tumor models
  that are resistant to, or not sensitive
  tocurrently available taxanes¹,²
• As potent as docetaxel against sensitive cell
  lines and tumor models¹,²
• Phase I studies
• Dose-limiting toxicity was neutropenia
• Antitumor activity in mCRPC including
  docetaxel-resistant disease3

¹Attard G, Greystoke A, Kaye S, De Bono J. Pathol
Biol (Paris). 200654(2)72-84.²Pivot X,
Koralewski P, Hidalgo JL, et al. Ann Oncol.
200819(9)1547-1552. 3Mita AC, Denis LJ,
Rowinsky EK, de bono JS et al. Clin Can Res.
2009 Jan 1515(2)723-30.
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De Bono J et al. Lancet, 2010, 3761147-54
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TROPIC Phase III registration study 146 Sites
in 26 Countries
mCRPC patients who progressed during and after
treatment with a docetaxel-based regimen (N755)
Stratification factors ECOG PS (0, 1 vs. 2)
Measurable vs. non-measurable disease
cabazitaxel 25 mg/m² q 3 wk prednisone for 10
cycles (n378)
mitoxantrone 12 mg/m² q 3 wk prednisone for 10
cycles (n377)
Oral prednisone/prednisolone 10 mg daily.
Primary endpoint Overall Survival Secondary
endpoints Progression-freesurvival (PFS),
response rate, and safety
Inclusion Patients with measurable disease must
have progressed by RECIST otherwise must have
had new lesions or PSA progression
De Bono J et al. Lancet, 2010, 3761147-54
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Patient characteristics
ECOG PS ECOG performance status PSA
Prostate-specific antigen.
Population with a very advanced disease
De Bono J et al. Lancet, 2010, 3761147-54
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TROPIC trial Pre-protocol treatments
A heavily pretreated population who
progressedrapidly after first line docetaxel
De Bono J et al. Lancet, 2010, 3761147-54
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TROPIC Trial overall survival (Primary endpoint)
Proportion of OS ()
Time (months)
377 378
299 321
195 241
94 137
31 60
9 19
28 reduction in the risk of death
De Bono J et al. Lancet, 2010, 3761147-54
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TROPIC Trial Progression-free survival
Proportion of PFS ()
PFS composite endpoint PSA progression, pain
progression, tumor progression, symptom
deterioration, or death.
377 378
55 92
12 18
6 1
4 1
117 168
30 55
9 6
25 reduction in risk of progression
De Bono J et al. Lancet, 2010, 3761147-54
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TROPIC Trial Response rate and time to
progression
TTP time to progression 50 decrease or more
in PSA
De Bono J et al. Lancet, 2010, 3761147-54
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Treatment exposure on study drug
as percentage of total number of treatment cycles
An excellent dose intensitywith few dose
reductions or treatment delays
De Bono J et al. Lancet, 2010, 3761147-54
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Most Frequent Treatment-EmergentAdverse Events
Sorted by 2 incidence rate for grade 3 events
in the cabazitaxel arm.
Low rate of grade 3-4 peripheral neuropathy (1
in each group)
De Bono J et al. Lancet, 2010, 3761147-54
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Comparison of Cabazitaxel and docetaxeland
mitoxantrone hematotoxicity according to the line
of treatment
Tax327 study docetaxel and mitoxantrone given in
first-line setting Tropic study cabazitaxel and
mitoxantrone given in second-line setting
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TROPIC Trial Fatal Events
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Conclusion on Cabazitaxel study

• Cabazitaxel demonstrated a statistically and
  clinically significant survival improvement
  compared with mitoxantrone in study population
• 15.1 months vs 12.7 months
• 28 reduced risk of death (HR0.72, P lt.0001)
• Survival benefit consistent across subgroups
• Secondary endpoints of PFS, RR, and TTP also
  significantly improved
• Safety profile was manageable
• Proactive management of side effects recommended
  (neutropenia/diarrhea)
• Cabazitaxel is the first treatment to show a
  survival benefit in patients with mCRPC after
  failure of docetaxel-based therapy

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Cabazitaxel Further development

• Which dose of cabazitaxel to use 25 or 20
  mg/m2?
• Is cabazitaxel as effective as docetaxel in
  first-line setting?
• Is cabazitaxel more or less hematotoxic than
  docetaxel?
• Will cabazitaxel be evaluated in early stages?

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Castration-resistant prostate cancer New agents
in development
Pre-Docetaxel
Docetaxel
Post-Docetaxel

• Cabazitaxel
• Abiraterone
• MDV3100
• TAK-700
• Sunitinib
• Ipilimumab

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Abiraterone oral irreversible inhibitionof
CYP17
Low-dose steroid replacement decreases ACTHand
minimizes mineralocorticoid-related toxicity
Cholesterol
Desmolase
Pregnenolone
Progesterone
Deoxy-corticosterone
Corticosterone
Aldosterone
CYP1717ahydroxilase

17a-OH-Pregnenolone
17-Deoxy-corticol
Cortisol
17a-OH-Progesterone
ACTH x6reducedby low-dosesteroids
CYP17C17, 20-lyase
5a-reductase
DHEA
Androstenedione
Testosterone
DHT
CYP19 aromatase
Estradiol
Inhibits testosterone productionin testis,
adrenal glands and prostate
Attard et al. J. Clin. Oncol. 2008, 26 4563-71
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Abiraterone in second-line metastatic CRPC
COU-AA-301 study
R A N D O M I Z E 21

• Abiraterone 1000 mg daily
• Prednisone 5 mg BIGn797

Patients Progressive mCRPC Failed 1 or 2
chemoregimen, including 1 with docetaxel

• Placebo daily
• Prednisone 5 mg BIGn797

• Stratification factors
• ECOG PS 0-1 versus 2
• Worst pain over previous 24 hours (BPI short
  form 0-3 absent vs 4-10 present
• Prior chemotherapy1 vs 2
• Type of progression PSA only vs radiographic
  progression

147 sites in 13 countries(US, Europe, Australia,
Canada)
Primary endpoint Overall SurvivalSecondary end
points TTPP, rPFS, PSA response
De Bono J et al. ESMO 2010
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Comparison of Cabazitaxel and Abiraterone phase
III studies in mCRPC
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MDV3100 an improved AR antagonist?

• Higher affinity for the androgen receptor than
  bicalutamide
• Prevents nuclear translocation and co-activator
  recruitment of the ligand-receptor complex
• Induces tumour cell apoptosis
• No AR agonist activity in castrate-resistant
  setting
• Induces tumour responses in CRPC patients who
  have failed other hormone therapies

AR Antiandrogen Receptor
Tran C, et al. Science 200932478790
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MDV 3100 Phase I-II study PSA response
Chemotherapy-Naïve (n65)
Post-Chemotherapy (n75)
PSA Change from Baseline
62 (40/65) gt50 Decline
51 (38/75) gt50 Decline
Scher HI, et al. Lancet published on-line april
2010
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MDV3100 (AFFIRM) - phase III studypost-docetaxel
R A N D O M I Z E
MDV3100.- 160 mg QD (n780)
mCRPCafter up to 2 lines chemo, 1 withdocetaxel
Placebo QD (n390)
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N1170 Primary end point overall survival
ClinicalTrials.gov identifier NCT00974311
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Other antiandrogens in development

• TAK-700 (Orteronel) (phase III post-docetaxel)
• TOK-001, CYP17 inhibitor (phase I/II)
• SARDS
• ARN-509 (phase II)
• HDAC Inhibitors
• Steroid sulfatase inhibitors
• Co-factor antagonists

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Conclusion

• Management of CRPC is rapidly evolving
• Clinical trial data with abiraterone and MDV-3100
  confirm continued AR addiction in patients with
  mCRPC
• Highlights continued importance of the AR axis,
  even in advanced disease
• Docetaxel is the standard in first-line mCRPC
• Progression after Docetaxel is no more an unmet
  need
• Cabazitaxel shows a significant survival
  advantagecompared to the active agent
  mitoxantrone/prednisone
• Abiraterone also provides survival advantage
  versus placebo
• The most appropriate sequencing of Abiraterone
  and Cabazitaxel remains to be determined