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Treatment Options for Docetaxel refractory patients

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A multicenter phase II study of abiraterone acetate (AA) in docetaxel pretreated castration-resistant prostate cancer (CRPC) patients (pts) [abstract 5047]. – PowerPoint PPT presentation

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Title: Treatment Options for Docetaxel refractory patients


1
Treatment Options for Docetaxel refractory
patients
  • Winston W Tan MD FACP
  • Senior Consultant Hematology/Oncology
  • Genitourinary Oncology
  • Mayo Clinic College of Medicine

2
Learning Objectives
  • Describe the mechanisms by which androgen
    receptor signaling affects prostate cancer growth
    despite castrate levels of testosterone
  • Summarize therapeutic options for
    castration-resistant prostate cancer (CRPC),
    including the role of chemotherapy, and emerging
    therapies
  • Apply clinical evidence for best treatment
    strategies in CRPC to improve patient care

3
S9364 Nadir PSA Level Predicts Survival in
Patients With Metastatic Disease Treated With
Primary ADT
Hussain M, et al. J Clin Oncol.
2006243984-3990 with permission.
4
CRPC Evolving Paradigm
  • Androgen receptor (AR) signaling is a key factor
    in prostate cancer growth despite castrate serum
    levels of testosterone
  • Caused by a number of different factors
  • Receptor overexpression/amplification
  • AR mutations
  • Increased AR ligand expression
  • AR coactivators
  • Ligand-independent AR activation
  • AR signaling leads to tumor growth and
    proliferation despite castrate androgen levels

Gelmann EP. J Clin Oncol. 2002203001-3015.
5
CRPC Evolving Paradigm
  • CRPC A working definition
  • Evidence of PSA and/or radiographic disease
    progression in the setting of castrate levels of
    testosterone (50 ng/dL)

6
Chemotherapy for AIPC
  • Mitoxantrone combined with prednisone is
    palliative with a median survival of 10-12 months
  • Phase I/II studies show a trend towards improved
    median survival with the combination of
    Estramustine/Docetaxel
  • gtTime to progression 5-6 months
  • gtMedian survival 20-23 months

Petrylak et al. Semin Onc. 1999 26(Suppl
17)28-33. Savarese et al. JCO.
2001192509-2516. Petrylak et al. Eur Urol
Suppl. 2002115-23.
7
Management of Metastatic CRPC Chemotherapy
  • The standard of care for CRPC changed from
    mitoxantrone/prednisone to docetaxel/prednisone
    based on SWOG 99-16 and TAX-327 studies1,2

1. Petrylak DP, et al. N Engl J Med.
20043511513-1520. 2. Tannock TF, et al. N Engl
J Med. 20043511502-1512.
8
Management of Metastatic CRPC Chemotherapy
  • SWOG 99-16
  • Docetaxel/estramustine improved median survival
    by 2 months compared with mitoxantrone/prednisone

HR 0.80
Petrylak DP, et al. N Engl J Med.
20043511513-1520 with permission.
9
Management of Metastatic CRPC Chemotherapy
(TAX-327)
  • Docetaxel therapy led to improved survival and
    rates of response in terms of pain, PSA level,
    and quality of life compared with
    mitoxantrone/prednisone

Tannock TF, et al. N Engl J Med.
20043511502-1512 with permission.
10
Management of Metastatic CRPC Chemotherapy
  • Long-term follow-up of TAX-327
  • 310 additional deaths at 5 years

D3P D1P MP
Median survival 19.2 months 17.8 months 16.3 months
Difference in survival P0.004 P0.004
Patient survival gt3 years 18.6 16.8 13.5
D3Pdocetaxel every 3 weeks D1Pweekly
docetaxel MPmitoxantrone/prednisone therapy.
Berthold DR, et al. J Clin Oncol. 200826242-245.
11
AR-Targeting Therapies Abiraterone Acetate
  • Inhibits the CYP 17 (17a-hydroxylase and
    C17,20-lyase) dual enzyme complex, which is
    principally responsible for androgen synthesis
  • Results in PSA decline, tumor response, and
    improvements in ECOG performance scores

Patient Population N PSA Decline 50 Tumor Response Partial Response Tumor Response Stable Disease ECOG PS Improvement 1 level
CRPC, chemotherapy naive1 33 24 (73) 9 (27) 19 (58) 8 (61.5)
CRPC, prior docetaxel2 47 24 (51) 6 (13) 25 (53) 11 (35)
CRPC, prior docetaxel3 58 45 39 (64) 16 (50), n32
ECOG PS, Eastern Cooperative Oncology Group
Performance Status
  • Ryan C, et al. J Clin Oncol. 200927(suppl)245s
    (abstract 5046).
  • Reid AH, et al. J Clin Oncol. 200927(suppl)246s
    (abstract 5047).
  • 3. Danila DC, et al. J Clin Oncol.
    200927(suppl)246s (abstract 5048).

12
AR-Targeting Therapies MDV3100
  • Novel small-molecule AR antagonist
  • Binds the AR with greater relative affinity than
    the clinically used antiandrogen bicalutamide
  • Reduces the efficiency of its nuclear
    translocation and impairs both DNA binding to
    androgen response elements and recruitment of
    coactivators
  • Results of recent phase I/II study
  • PSA declines of gt50 observed in 43 of CRPC
    patients
  • Phase III trial in the post-docetaxel setting
    ongoing

Scher HI, et al. Lancet Oncology.
20103751437-1446.
13
AR-Targeting Therapies BMS-641988
  • Hypothesized to slow growth of prostate cancer by
    blocking action of androgens
  • Found to have superior potency and efficacy
    compared with bicalutamide1
  • Found to promote an expression profile more
    similar to castration than bicalutamide1
  • Awaiting data from 2 completed Phase I trials for
    CRPC
  • Randomized multicenter dose-escalation study
    (United States)2
  • Nonrandomized multicenter, open-label study
    (Japan)3

1. Attar RM, et al. Proc Amer Assoc Cancer Res.
200647Abstract 5345.2. Clinical Trials.gov.
www.clinicaltrials.gov/ct2/show/NCT00326586.3.
Clinical Trials.gov. www.clinicaltrials.gov/ct2/sh
ow/NCT00644488.
14
Management of Metastatic CRPC Docetaxel-Refracto
ry Patients
  • No standard of care
  • Salvage chemotherapeutic regimens include
  • Mitoxantrone and/or ixabepilone plus
    prednisone1-3
  • Carboplatin plus docetaxel4,5

1. Thomas C, et al. Urologe A. 2009481070-1074.
2. Rosenberg JE, et al. Cancer.
2007110566-563. 3. Rosenberg JE, et al. J Clin
Oncol. 2009272772-2778. 4. Reuter CW, et al.
World J Urol. 2010Mar 14 Epub ahead of
print 5. Ross RW, et al. Cancer.
2008112521-526.
15
Management of Metastatic CRPC Docetaxel-Refractor
y Patients
  • Mitoxantrone or ixabepilone plus prednisone

MPmitoxantrone/prednisone. Rosenberg JE, et al.
Cancer. 2007110566-563 with permission.
16
Management of Metastatic CRPC Docetaxel-Refractor
y Patients
  • Carboplatin/docetaxel therapy
  • Recent data suggest that platinum salts may be
    effective when combined with taxanes (docetaxel)

Progression-free survival
Overall survival
Ross RW, et al. Cancer. 2008112521-526 with
permission.
17
Management of Metastatic CRPC Docetaxel-Refractor
y Patients
  • Cabazitaxel
  • Novel taxane that appears to be active in
    docetaxel-resistant tumor cell lines
  • Evaluated in the phase III TROPIC study
  • Median survival cabazitaxel treatment group vs
    mitoxantrone treatment group
  • Improved progression-free survival and tumor
    response rates

Sartor AO, et al. Abstract No. 9. 2010
Genitourinary Cancers Symposium San Francisco,
CA.
18
TROPIC Phase III Registration Study
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.
Inclusion Patients with measurable disease must
have progressed by RECIST otherwise must have
had new lesions or PSA progression
Primary endpoint OS Secondary endpoints
Progression-freesurvival (PFS), response rate,
and safety
Sartor AO, et al. Presented at the 2010
Genitourinary Cancers Symposium. March 5-7, 2010
San Francisco, CA.
19
TROPIC Primary Endpoint Overall Survival
(Intent-to-Treat Analysis)
Proportionof OS ()
Numberat risk
Approved by FDA June 2010
Sartor AO, et al. Presented at the 2010
Genitourinary Cancers Symposium. March 5-7, 2010
San Francisco, CA.
20
Management of CRPC Docetaxel-Refractory Patients
  • Conclusions from the TROPIC trial
  • Cabazitaxel demonstrated a statistically and
    clinically significant overall survival
    improvement compared with mitoxantrone
  • 30 risk reduction of death (HR 0.70, Plt.0001)
  • Median overall survival improvement in favor of
    cabazitaxel
  • Benefit was consistent across subgroups
  • Progression-free survival, relative risk, and
    time to progression were also significantly
    improved
  • Safety profile was predictable and manageable
  • Neutropenia, diarrhea, fatigue and asthenia were
    the most common adverse events

Sartor AO, et al. Presented at the 2010
Genitourinary Cancers Symposium. March 5-7, 2010
San Francisco, CA.
21
Docetaxel in Novel Combination Regimens for HRPC
  • Docetaxel Thalidomide
  • Docetaxel Calcitriol (Vitamin D)
  • Docetaxel / Estramustine Herceptin
  • Docetaxel Exisulind

22
Satraplatin
  • Second line
  • 950 patients
  • Satraplatin/prednisone vs prednisone
  • 40 decrease in TTP
  • 9.7 vs 11 weeks TTP
  • Petrylak et al ASCO (prostate) 2007

23
Satraplatin
  • Satraplatin is an orally active platinum compound
    that has significant activity in
    cisplatin-resistant tumor models. Activity in
    prostate cancer was suggested in early clinical
    studies .
  • Satraplatin was evaluated more extensively in a
    phase III trial, in which 950 men who had
    progressed after first-line chemotherapy for
    castrate-resistant prostate cancer (51 percent of
    whom had been treated with docetaxel) were
    randomly assigned to prednisone plus either
    satraplatin (80 mg/m2 for five days every five
    weeks) or placebo . Final results of this trial
    were presented at the American Society of
    Clinical Oncology (ASCO) meetings in 2008.
  • Progression-free survival (PFS) was significantly
    increased in patients assigned to satraplatin
    compared to placebo (one-year PFS rate 17 versus
    7 percent, median PFS 11.1 versus 9.7 weeks,
    hazard ratio HR 0.67, 95 CI 0.57-0.77).
  • There was no difference in overall survival (61
    weeks on both treatment arms, HR 0.95, 95 CI
    0.84-1.15).
  • Treatment was generally well tolerated, with
    myelosuppression being the major cause of grade 3
    or 4 adverse events (neutropenia,
    thrombocytopenia, and anemia in 22, 23, and 12
    percent of satraplatin-treated patients,
    respectively).

24
Antiangiogenic Agents Bevacizumab
  • CALGB 90401
  • Phase III trial comparing docetaxel/prednisone
    with or without bevacizumab in hormone-resistant
    prostate cancer1
  • Preliminary data suggest that this trial did not
    reach its primary endpoint of overall survival2
  • Data to be presented at the 2010 American Society
    of Clinical Oncology (ASCO) annual meeting, June
    4 to 8, 2010.

1. Clinicaltrials.gov. www.clinicaltrials.gov/ct2/
show/NCT00110214. 2. Kelly WK, et al. J Clin
Oncol. 2010287s (Abstract LBA4511).
25
Antiangiogenic Agents Sunitinib
  • Tyrosine kinase inhibitor currently approved for
    renal cell carcinoma and gastrointestinal tumors
  • Several trials of sunitinib in CRPC

Author Patients Outcomes
Dror Michaelson M, et al. 20091 CRPC Group A (n17) chemotherapy-naïve Group B (n17) docetaxel-resistant 1 confirmed PSA response in each group 8 and 7 men had stable PSA (week 12) in groups A and B, respectively Improvements on radiographic imaging in the absence of post-treatment PSA declines
Sonpavde G, et al. 20102 Metastatic CRPC (post-docetaxel progression) N36 12.1 had 50 decline in PSA 21.2 had 30 decline in PSA 44 demonstrated improvements on imaging 13.6 reported declines in pain scores 2 points
1. Dror Michaelson M, et al. Ann Oncol.
200920913-920. 2. Sonpavde G, et al. Ann Oncol.
201021319-324.
26
Bone-Targeting Therapies ZD4054
  • Endothelin-A receptor antagonist
  • Recent multinational phase II trial in metastatic
    CRPC1
  • Primary endpoint of time to progression not
    achieved
  • Improvement in overall survival observed in both
    treatment arms
  • Second phase II trial in metastatic CRPC
    currently underway2

Placebo (n107) ZD4054 10 mg (n107) ZD405415 mg (n98)
Time to progression 3.7 4.6 3.8
P value 0.553 0.702
Overall survival 17.3 24.5 23.5
P value 0.008 0.052
Time to PSA progression 2.8 3.7 2.9
P value 0.743 0.273
1. James ND, et al. Eur Urol. 2009551112-1123. 2
. Clinicaltrials.gov. www.clinicaltrials.gov/ct2/s
how/NCT01000948.
27
Bone-Targeting TherapiesDenosumab
  • Monoclonal antibody that acts against receptor
    activator of nuclear factor-?B ligand to improve
    bone mineral density and fractures
  • Useful in CRPC, as ADT is associated with bone
    loss and increased risk for fracture
  • Recent study in men receiving ADT for prostate
    cancer1
  • Current phase III trial underway in
    non-metastatic CRPC patients undergoing ADT2

1. Smith MR, et al. N Engl J Med.
2009361745-755. 2. Clinicaltrials.gov.
www,clinicaltrials.gov/ct2/show/NCT00838201.
28
Immunomodulatory TherapiesLenalidomide
  • Highly potent immunomodulatory derivative of
    thalidomide
  • Potentiates the action of paclitaxel in vitro
    against prostate cancer cell lines in co-culture
    with mononuclear cells
  • Phase I study in metastatic CRPC patients
  • Combined with weekly paclitaxel
  • PSA declines by gt50 in 2 of 7 evaluable patients
  • Frequent dose-limiting toxicity

Mathew P, et al. Cancer Chemother Pharmacol.
201065811-815.
29
Management of Metastatic CRPC Integrating Novel
Therapeutics
  • Current therapeutic paradigm
  • Second-line hormonal therapy
  • Docetaxel-based chemotherapy
  • Retreatment with docetaxel, mitoxantrone,
    investigational therapy, supportive care

30
Custersin studies
  • Phase III of docetaxel vs docetaxel plus custerin
    docetaxel after initial response and then on
    progression is randomized in patient with
    castrate resistant prostate cancer with
    metastasis with symptomatic pain
  • Phase III first line same arms

31
MDV Phase III studies
  • Phase III AFFIRM study MDV 3100 vs placebo in
    patients who have progressed on docetaxel
  • Phase III study on chemotherapy naïve patients
    also being studied

32
Summary
  • Metastatic CRPC management will likely evolve
    over the next 1224 months with the introduction
    of novel agents, including AR-targeting agents
    and new chemotherapies
  • Introduction of new agents will challenge the
    clinical research community to design and conduct
    studies that bring some clarity into optimal
    use/sequence of these agents

33
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