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.
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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.
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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.
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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).

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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.
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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.
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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.
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Management of Metastatic CRPC Docetaxel-Refractor
y Patients

• Mitoxantrone or ixabepilone plus prednisone

MPmitoxantrone/prednisone. Rosenberg JE, et al.
Cancer. 2007110566-563 with permission.
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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.
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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.
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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.
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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.
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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.
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Docetaxel in Novel Combination Regimens for HRPC

• Docetaxel Thalidomide
• Docetaxel Calcitriol (Vitamin D)
• Docetaxel / Estramustine Herceptin
• Docetaxel Exisulind

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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

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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).

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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).
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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.
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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.
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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.
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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.
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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

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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

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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

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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

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Thank You