Treatment options for mCRPC in 2015 Guidelines? Treatment Median follow-up of 12.8 months 3.9-month

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Transcript of Treatment options for mCRPC in 2015 Guidelines? Treatment Median follow-up of 12.8 months 3.9-month

  • Treatment options for

    mCRPC in 2015

    Guidelines?

    Treatment Algorithm?

    Christos N. Papandreou, M.D., Ph.D. University of Thessaly

    School of Μedicine

    March 2015

  • DISCLOSURES

    • Invited speaker / Advisory boards / Grants

    – Amgen

    – Astellas

    – Bayer

    – Bristol

    – Janssen

    – Novartis

    – Roche

    – Sanofi

  • Prostate cancer disease continuum

    Tumour volume

    Time

    Castration

    Docetaxel/chemotherapy

    Local therapy*

    Metastatic

    Symptoms

    Castration-resistant

    Non-metastatic

    Asymptomatic

    Hormone-sensitive

    2nd-line hormonal therapies

    Bicalutamide Flutamide Nilutamide

    Death

    Abiraterone Cabazitaxel Enzalutamide Alpharadine

    *e.g. Radiotherapy

    Continued AR signalling

    Kohli & Tindall. Mayo Clin Proc 2010;85:77–86. AR, androgen receptor

    Abiraterone

  • CRPC – Definition

    European Association of Urology (EAU)

    Castrate-resistant prostate cancer

    Serum castration levels of testosterone

  • Cytokines, RTKs,

    Microtubule binding Steroids

     AR gene located on

    X chromosome

     AR protein has 3 main

    regions:

     N-terminal domain

    (NTD) which contains

    the activation function

     Central DNA binding

    domain (DBD)

     C-terminal ligand binding

    domain (LBD) where

    testosterone and DHT

    bind

    The human AR gene, transcript and protein

    Hu R et al. Expert Rev Endocrinol Metab. 2010 Sep;5(5):753-76

    (CAG repeats)

  • Pienta KJ et al. Clin Cancer Res 2006;12:1665-1671; Debes JD NEJM 2004; 351: 1488-90

    1. T prod - Amplification AR

    2. Mutations AR – AR SVR

    3. Outlow pathway

    4. Bypass pathway

    5. Co-activiators

    6. Stem cell regeneration

    Mechanisms of disease progression in CRPC

    Bcl

    Bcl BclBcl

    Bcl

    Bcl

    4

    Bcl-2 overexpression

    Androgen

    production

    ARSV

    bicalutamide resistance

  •  High concentrations of androgens in tumour (both primary1-2 & mets3) microenvironment

     Origin: adrenal gland & prostate cancer cells1-3

     Genetic polymorphisms in androgen conversion and transportation4

     DHT synthesis may bypass testosterone in driving CRPC5

    1Nishiyama et al. Clin Cancer Res 2004; 10: 7121-26 2Titus MA et al. Clin Cancer Res 2005; 11: 4653-57

    3Montgomery RB et al. Cancer Res 2008;68:4447-54 4Yang M et al.J Clin Oncol 2011; 29:2565-73

    5Chang K-H et al. PNAS 2011;108: 13728–33

    Persistent androgens in tumours (1)

  • AR splice variants (ARv)

     Ligand binding domain is lacking

     Not expected to associate with cytoplasmic chaperones

     May contribute to development of CRPC

     ARv isoforms are constitutively active, promoting tumor cell growth independent of ligand

     May contribute to resistance to Enz and Abi

    Dehm SM et al. Cancer Res 2008; 68: 5469–77 Hu R et al. Cancer Res 2009; 69:16-22

    Watson et al. PNAS 2010; 107: 16759-65 Ryan CJ & Tindall DJ; J Clin Oncol 2011; 29: 3651-58

  • Therapeutic strategies targeting

    AR signaling pathway

  • Docetaxel inhibits PSA expression in human prostate tumors

    Control Docetaxel treatment

    Control Docetaxel

    Significant reduction

    in PSA expression

    in prostate tumors

    of patients treated

    with docetaxel 0

    20

    40

    60

    80

    100

    120

    140

    P SA

    E xp

    re ss

    io n

    *

    *p < 0.01

    Zhu et al. Cancer Res, 70:7992,2010

  • Abiraterone: CYP17 blockade inhibits

    androgen synthesis

    Fizazi. ECCO-ESMO 2009; Teaching Lecture

    abiraterone

  • Abiraterone acetate

    Phase III post-chemo study design

     Phase 3 multicenter, randomized, double-blind, placebo-controlled study (147 sites in 13 countries; USA, Europe, Australia, Canada)

    Abiraterone 1000mg daily

    Prednisone 5mg BID

    n=797

    Primary end point:

    • OS (25% improvement;

    HR 0.8)

    Secondary end points:

    • TTPP

    • rPFS

    • PSA response

    Efficacy end points (ITT)

    Placebo daily

    Prednisone 5mg BID

    n=398

    R A N D O M I Z E D

    2:1

    • 1195 patients with

    progressive mCRPC

    • Failed 1 or 2

    chemotherapy regimens,

    1 of which contained

    docetaxel

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

    COU-AA-301

  • 14.8 months vs 10.9 months

    Hazard ratio, 0.65;

    95% CI, 0.54 to 0.77; P

  • N Engl J Med 2011;364:1995-2005

  • N Engl J Med 2011;364:1995-2005

  • French ATU: Poor response to abiraterone

    in patients with high Gleason score

     Abiraterone French ATU program

    (post-docetaxel setting)

     408 mCRPC patients enrolled in 19 centers

     Gleason 8-10: 51.2% at diagnosis

     Independent predictive factors of poor

    response to Abiraterone:

    Gleason score 8-10

    Number of chemotherapy lines (>1)

    Azria D et al. J Clin Oncol 2012;30 (Suppl 5):abstract 149

  • Ph III trial of Abiraterone in asymptomatic or mildly

    symptomatic mCRPC Pre-chemotherapy

    Abiraterone acetate

    1000 mg daily

    Placebo daily

    50% improvement in radiologic progression-free survival and 25%

    improvement in overall survival Primary endpoint:

    • 1000 patients with

    asymptomatic or

    mildly symptomatic

    metastatic CRPC

    • Chemotherapy naïve

    • Randomized 1:1

    • Stratified by: ECOG

    performance status

    (0 vs. 1)

    T

    R

    E

    A

    T

    U

    N

    T

    I

    L

    P

    R

    O

    G

    R

    E

    S

    S

    I

    O

    N

    Prednisone 5mg twice daily

    Prednisone 5mg twice daily

    COU-AA-302

    No visceral mets

  • EPI-001

     Inhibits transactivation of the N-terminal domain

     Differs from anti- androgens which target C-terminal ligand binding domain

     Can potentially escape several mechanisms of castration resistance

     Not yet clinically tested

    Andersen RJ. Cancer cell 2010; Cancer Cell 17, 535–546

    DHT

    NUCLEUSCYTOPLASM

    T DHEA

    AR

    EPI-001

  • MDV3100 (Enzalutamide)

    Affects multiple steps in androgen signaling  Inhibits binding of androgens to AR C-terminal

    domain

     Inhibits nuclear translocation of AR

     Inhibits association of AR with DNA

    Chen, et al. Lancet 2009, 10: 981–91

    Scher H et al. ASCO GU 2012: J Clin Oncol 2012, 30;(suppl 5): abstr LBA1

  •  Eplerenone activates mutant AR

     Exogenous corticoids activate mutant AR in CRPC patients treated with abiraterone

     Spironolactone binds and activates wild-type and mutant AR

     Mutant AR activation by eplerenone inhibited by abiraterone or bicalutamide, but most effectively by Enzalutamide (MDV3100)

    Richards J et al. Cancer Res 2012; 72; 2176–82

  • 31

    Study design  AFFIRM is a Phase 3, randomised, double-blind, placebo-controlled trial

     Recruitment in 156 centres from 15 countries between September 2009 and November 2010

     The AFFIRM trial design incorporated the recommendations of the Prostate Cancer Clinical Trials Working Group 2

    Exclusion criteria included: Severe concurrent disease, infection or comorbidity, brain metastases, history of another malignancy

    within previous 5 years, treatment with androgen receptor antagonists, 5-alpha reductase inhibitors, oestrogens or

    chemotherapy, within 4 weeks of enrolment. Corticosteroids were not required but allowed.

    CRPC=castration-resistant prostate cancer; OS=overall survival.

    Scher HI, et al. N Eng J Med 2012;367:1187–97.

    R A N D O M I S E D

    2:1

    Patients:

    • 1199 patients with

    progressive CRPC

    • 1–2 prior chemotherapy

    regimens (≥1 docetaxel)

    Primary endpoint:

    • OS

    Enzalutamide

    160 mg daily

    n=800

    Placebo

    n=399

  • Scher et al. NEJM Aug 15. [Epub ahead of print] (2012).

    AFFIRM: Overall survival

    3 6 9 18 21 2415

    100

    80

    60

    40

    20

    0

    0

    Su rv

    iv al

    ( %

    )

    Duration of overall survival (months)

    12

    775 701 627 72 7 0211800 400Enzalutamide, n =

    376 317 263 33 3 081399 167Placebo, n =

    Placebo: 13.6 months (95% CI: 11.3–15.8)

    Enzalutamide: 18.4 months (95% CI: 17.3–NYR)

    HR = 0.63 (95%CI: 0.53–0.75); p

  • {27%}

  • AFFIRM: Enzalutamide improved outcomes in patients with liver and

    lung metastases compared with placebo

    Efficacy outcome

    Li