Treatment Options for Docetaxel
refractory patients
Winston W Tan MD FACP
Senior Consultant Hematology/Oncology
Genitourinary Oncology
Mayo Clinic College of Medicine
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
S9364: Nadir PSA Level Predicts Survival in
Patients With Metastatic Disease Treated
With Primary ADT
Hussain M, et al. J Clin Oncol. 2006;24:3984-3990; with permission.
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. 2002;20:3001-3015.
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)
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
>Time to progression 5-6 months
>Median survival 20-23 months
Petrylak et al. Semin Onc. 1999; 26(Suppl 17):28-33.
Savarese et al. JCO. 2001;19:2509-2516.
Petrylak et al. Eur Urol Suppl. 2002;1:15-23.
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
SWOG 99-161
N=770
- Mitoxantrone 12 mg/m2; Day 1
- Prednisone 5 mg BID; 21-day cycles
Randomized
- Prednisone 10 mg QD
- Mitoxantrone 12 mg/m2 every 3 wks;
every 21 days up to 10 cycles
TAX-3272
N=1006
- Docetaxel 60 mg/m2 ; Day 2 +
dexamethasone 20 mg TID; Days 1–2
- Estramustine 280 mg TID;
Days 1–5 of 21-day cycles
Randomized
1. Petrylak DP, et al. N Engl J Med. 2004;351:1513-1520.
2. Tannock TF, et al. N Engl J Med. 2004;351:1502-1512.
- Prednisone 10 mg QD
- Docetaxel 30 mg/m2 weekly;
5 wks on, 1 wk off × 6 cycles
- Prednisone 10 mg QD
- Docetaxel 75 mg/m2 every 3 wks
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. 2004;351:1513-1520; with permission.
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
HR: 0.83, P=0.03
Tannock TF, et al. N Engl J Med. 2004;351:1502-1512; with permission.
Management of Metastatic CRPC:
Chemotherapy
• Long-term follow-up of TAX-327:
– 310 additional deaths at 5 years
Median survival
Difference in
survival
Patient survival
>3 years
D3P
D1P
M+P
19.2 months
17.8 months
16.3 months
P=0.004
18.6%
P=0.004
16.8%
13.5%
D3P=docetaxel every 3 weeks; D1P=weekly docetaxel; M+P=mitoxantrone/prednisone therapy.
Berthold DR, et al. J Clin Oncol. 2008;26:242-245.
AR-Targeting Therapies:
Abiraterone Acetate
•
•
Inhibits the CYP 17 (17α-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
Tumor
Response:
Partial
Response
Tumor
Response:
Stable Disease
ECOG PS
Improvement
≥1 level
Patient Population
N
PSA Decline
≥50%
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%), n=32
ECOG PS, Eastern Cooperative Oncology Group Performance Status
1. Ryan C, et al. J Clin Oncol. 2009;27(suppl):245s (abstract 5046).
2. Reid AH, et al. J Clin Oncol. 2009;27(suppl):246s (abstract 5047).
3. Danila DC, et al. J Clin Oncol. 2009;27(suppl):246s (abstract 5048).
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 >50% observed in 43% of CRPC patients
• Phase III trial in the post-docetaxel setting ongoing
Scher HI, et al. Lancet Oncology. 2010;375:1437-1446.
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. 2006;47:Abstract 5345.
2. Clinical Trials.gov. www.clinicaltrials.gov/ct2/show/NCT00326586.
3. Clinical Trials.gov. www.clinicaltrials.gov/ct2/show/NCT00644488.
Management of Metastatic CRPC:
Docetaxel-Refractory 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. 2009;48:1070-1074.
2. Rosenberg JE, et al. Cancer. 2007;110:566-563.
3. Rosenberg JE, et al. J Clin Oncol. 2009;27:2772-2778.
4. Reuter CW, et al. World J Urol. 2010;Mar 14 [Epub ahead of print]
5. Ross RW, et al. Cancer. 2008;112:521-526.
Management of Metastatic CRPC:
Docetaxel-Refractory Patients
• Mitoxantrone or ixabepilone plus prednisone
MP=mitoxantrone/prednisone.
Rosenberg JE, et al. Cancer. 2007;110:566-563; with permission.
Management of Metastatic CRPC:
Docetaxel-Refractory Patients
• Carboplatin/docetaxel therapy
– Recent data suggest that platinum salts may be effective when
combined with taxanes (docetaxel)
Progression-free survival
Ross RW, et al. Cancer. 2008;112:521-526; with permission.
Overall survival
Management of Metastatic CRPC:
Docetaxel-Refractory Patients
• Cabazitaxel
– Novel taxane that appears to be active in docetaxelresistant 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.
TROPIC: Phase III Registration Study
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.
Inclusion: Patients with measurable
Primary endpoint: OS
Secondary endpoints: Progression-free disease must have progressed by
survival (PFS), response rate, and safety RECIST; otherwise must have had new
lesions or PSA progression
Sartor AO, et al. Presented at the 2010 Genitourinary Cancers Symposium. March 5-7, 2010;
San Francisco, CA.
TROPIC Primary Endpoint: Overall Survival
(Intent-to-Treat Analysis)
Proportion
of OS (%)
MP
12.7
Median OS
(months)
Hazard Ratio
95% CI
P Value
Number
at risk
MP
CBZP
15.1
0.70
0.59–0.83
<.0001
377
300
188
67
11
1
CBZP 378
321
231
90
28
4
Approved by FDA: June 2010
Sartor AO, et al. Presented at the 2010 Genitourinary Cancers Symposium. March 5-7, 2010; San Francisco, CA.
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, P<.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.
Docetaxel in Novel Combination
Regimens for HRPC
•
•
•
•
Docetaxel + Thalidomide
Docetaxel + Calcitriol (Vitamin D)
Docetaxel / Estramustine + Herceptin
Docetaxel + Exisulind
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
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 satraplatintreated patients, respectively).
Antiangiogenic Agents:
Bevacizumab
• CALGB 90401
– Phase III trial comparing docetaxel/prednisone with or without bevacizumab in
hormone-resistant prostate cancer1
- Hormone refractory
prostate cancer
- Metastatic disease
-Testosterone
<50 ng/mL
- No prior chemotherapy
Every 3 weeks:
Docetaxel: 75 mg/m2 IV on Day 1 +
Prednisone: 5 mg BID PO on Days 1-21 +
placebo IV on Day 1
N=1020
Every 3 weeks:
Docetaxel: 75 mg/m2 IV on Day 1 +
Prednisone: 5 mg BID PO on Days 1-21 +
Bevacizumab: 15 mg/kg IV on Day 1
– 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. 2010;28:7s (Abstract LBA4511).
Antiangiogenic Agents: Sunitinib
• Tyrosine kinase inhibitor currently approved for renal cell
carcinoma and gastrointestinal tumors
• Several trials of sunitinib in CRPC:
Author
Patients
Dror Michaelson M, et al. 20091
Sonpavde G, et al.
20102
Outcomes
CRPC
Group A (n=17):
chemotherapy-naïve
Group B (n=17):
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
Metastatic CRPC
(post-docetaxel
progression)
- N=36
- 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. 2009;20:913-920.
2. Sonpavde G, et al. Ann Oncol. 2010;21:319-324.
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
Time to progression
Placebo
(n=107)
ZD4054
10 mg (n=107)
ZD4054
15 mg (n=98)
3.7
4.6
3.8
0.553
0.702
24.5
23.5
0.008
0.052
3.7
2.9
0.743
0.273
P value
Overall survival
17.3
P value
Time to PSA progression
2.8
P value
• Second phase II trial in metastatic CRPC currently underway2
1. James ND, et al. Eur Urol. 2009;55:1112-1123.
2. Clinicaltrials.gov. www.clinicaltrials.gov/ct2/show/NCT01000948.
Bone-Targeting Therapies:
Denosumab
•
•
•
Monoclonal antibody that acts against receptor activator of nuclear
factor-κB 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
New Fracture (%)
Cumulative Incidence of New Vertebral Fracture
6
4
2
3.9
3.3
1.9
0.3
1.0
1.5
Placebo
Denosumab
0
12 months 24 months 36 months
•
Current phase III trial underway in non-metastatic CRPC patients
undergoing ADT2
1. Smith MR, et al. N Engl J Med. 2009;361:745-755.
2. Clinicaltrials.gov. www,clinicaltrials.gov/ct2/show/NCT00838201.
Immunomodulatory Therapies:
Lenalidomide
• 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 >50% in 2 of 7 evaluable patients
– Frequent dose-limiting toxicity
Mathew P, et al. Cancer Chemother Pharmacol. 2010;65:811-815.
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
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
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
Summary
• Metastatic CRPC management will likely evolve
over the next 12–24 months with the
introduction of novel agents, including ARtargeting 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
Thank You