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SOGUG meeting New 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. Currently available secondary hormonal manipulations in CRPC: marginal benefit.

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sogug meeting new drugs after docetaxel chemotherapy in patient with mcrpc
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

currently available secondary hormonal manipulations in crpc marginal benefit
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 (< 4-6 months)

advanced prostate cancer management
Advanced prostate cancer management

Metastatic

hormone-sensitiveprostate cancer

Metastatic

castration-resistant

1st line

LHRH analogues

DOCETAXELTAXOTERE®

Antiandrogens

LHRH antagonist

Survival benefit vs Mitoxantrone

2004

metastatic crpc first line therapy
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 2007;25:1–64Horwich A, et al. Ann Oncol 2009;20(Suppl 4):76–8

advanced prostate cancer management7
Advanced prostate cancer management

Metastatic

hormone-sensitiveprostate cancer

Metastatic

castration-resistant

1st line

Metastatic

Castration-resistant

2nd line

UNMETMEDICAL NEED

LHRH analogues

DOCETAXELTAXOTERE®

Antiandrogens

LHRH antagonist

Survival benefit vs Mitoxantrone

2004

slide8

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

Progression after Docetaxel:

1Eymard JC, Oudard S et al. BJU Int 2010, 2Ansari et al. Oncol reports 2008; 20: 891-896

3Beer TM et al. Cancer. 2008, 112:326-30 ;4Garmey EG et al, Clin Adv Hematol Oncol. 2008; 6(2):118-1132; 5Gernone et al. EAU 2010 (abstract 896)

cabazitaxel jevtana a next generation taxane
Cabazitaxel (Jevtana®): a next generation taxane

Both extracted from needles of the European Yew treeTaxus baccata

Y

X

O

Y

X

Docetaxel

-OH

-OCCH3

Cabazitaxel

-OCH3

-OCH3

99th AACR annual meeting, San Diego, April 2008 (abstract #3227)

cabazitaxel jevtana selected to overcome taxane resistance
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

H

R

Taxane

  • 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

cabazitaxel a next generation taxane
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). 2006;54(2):72-84.²Pivot X, Koralewski P, Hidalgo JL, et al. Ann Oncol. 2008;19(9):1547-1552.

3Mita AC, Denis LJ, Rowinsky EK, de bono JS et al. Clin Can Res. 2009; Jan 15;15(2):723-30.

tropic phase iii registration study 146 sites in 26 countries
TROPIC: Phase III registration study 146 Sites in 26 Countries

mCRPC patients who progressed during and after treatment with a docetaxel-based regimen

(N=755)

Stratification factors

ECOG PS (0, 1 vs. 2) • Measurable vs. non-measurable disease

cabazitaxel 25 mg/m² q 3 wk + prednisone* for 10 cycles

(n=378)

mitoxantrone 12 mg/m² q 3 wk+ prednisone* for 10 cycles

(n=377)

*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, 376:1147-54

patient characteristics
Patient characteristics

ECOG PS: ECOG performance status; PSA: Prostate-specific antigen.

Population with a very advanced disease

De Bono J et al. Lancet, 2010, 376:1147-54

tropic trial pre protocol treatments
TROPIC trial: Pre-protocol treatments

A heavily pretreated population who progressedrapidly after first line docetaxel

De Bono J et al. Lancet, 2010, 376:1147-54

tropic trial overall survival primary endpoint
TROPIC Trial: overall survival (Primary endpoint)

100

80

60

40

Censored

MP

20

CBZP

Combined medianfollow-up: 13.7 months

0

0

6

12

18

24

30

Numberat Risk

MP

CBZP

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, 376:1147-54

tropic trial progression free survival
TROPIC Trial: Progression-free survival

100

80

60

40

Censored

MP

20

CBZP

Combined medianfollow-up: 13.7 months

0

0

3

6

9

12

15

18

21

Time (months)

Numberat Risk

MP

CBZP

PFS composite endpoint: PSA progression, pain progression, tumor progression, symptom deterioration, or death.

Proportion of PFS (%)

377

378

117

168

55

92

30

55

12

18

9

6

6

1

4

1

25% reduction in risk of progression

De Bono J et al. Lancet, 2010, 376:1147-54

17

tropic trial response rate and time to progression
TROPIC Trial: Response rate and time to progression

MP (n=377)

CBZP (n=378)

Hazard ratio(95% CI)

P-value

Tumor assessment

Response rate* (%)

4.4

14.4

0.0005

Median TTP (months)

5.4

8.8

0.61 (0.49–0.76)

<0.0001

PSA assessment

Response rate* (%)

17.8

39.2

0.0002

Median TTP (months)

3.1

6.4

0.75 (0.63–0.90)

0.001

Pain response rate

(N patients)

(168)

(174)

Response rate (%)

7.7

9.2

0.91(0.69-1.19)

0.63

TTP: time to progression ; *50% decrease or more in PSA

De Bono J et al. Lancet, 2010, 376:1147-54

18

treatment exposure on study drug
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, 376:1147-54

most frequent treatment emergent adverse events
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, 376:1147-54

20

slide21
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

conclusion on cabazitaxel study
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 (HR=0.72, P <.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

23

cabazitaxel further development
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?

24

castration resistant prostate cancer new agents in development
Castration-resistant prostate cancer New agents in development

Pre-Docetaxel

Docetaxel

Post-Docetaxel

  • Cabazitaxel
  • Abiraterone
  • MDV3100
  • TAK-700
  • Sunitinib
  • Ipilimumab
slide26

Abiraterone: oral & irreversible inhibitionof CYP17

Low-dose steroid replacement decreases ACTHand minimizes mineralocorticoid-related toxicity

Cholesterol

Desmolase

Pregnenolone

Progesterone

Deoxy-corticosterone

Corticosterone

Aldosterone

CYP1717αhydroxilase

17α-OH-Pregnenolone

ACTH x6reducedby low-dosesteroids

17α-OH-Progesterone

17-Deoxy-corticol

Cortisol

CYP17C17, 20-lyase

5α-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

abiraterone in second line metastatic crpc cou aa 301 study
Abiraterone in second-line metastatic CRPC – COU-AA-301 study

R

A

N

D

O

M

I

Z

E

2:1

Abiraterone: 1000 mg daily

Prednisone 5 mg BIGn=797

Patients

Progressive mCRPC

Failed 1 or 2 chemoregimen, including 1 with docetaxel

Placebo daily

Prednisone 5 mg BIGn=797

  • 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 chemotherapy[1 vs 2]
    • Type of progression [PSA onlyvs 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

mdv3100 an improved ar antagonist
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. Science2009;324:787–90

mdv 3100 phase i ii study psa response
MDV 3100 Phase I-II study PSA response

Chemotherapy-Naïve (n=65)

Post-Chemotherapy (n=75)

PSA Change from

Baseline

62% (40/65)

>50% Decline

51% (38/75)

>50% Decline

Scher HI, et al. Lancet [published on-line april 2010]

slide36

MDV3100 (AFFIRM) - phase III studypost-docetaxel

R

A

N

D

O

M

I

Z

E

MDV3100.- 160 mg QD (n=780)

mCRPCafter up to 2 lines chemo, 1 withdocetaxel

Placebo QD (n=390)

2:1

N=1170 Primary end point: overall survival

*ClinicalTrials.gov identifier: NCT00974311

other antiandrogens in development
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
conclusion
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