The Role of the Medical Oncologist in
the Treatment of Prostate Cancer
Daniel P. Petrylak, MD
Professor of Medicine
Columbia University Medical Center
When should you see an oncologist?
•
•
•
•
High risk localized disease
Rising PSA after local therapy
Hormone sensitive disease
Endocrine Resistant Disease
Natural History of Metastatic Prostate Cancer
Castration
Chemo Rx
Tumor Volume
and Activity
Secondary
Hormonal Rx
Time
Ligand activated androgen receptor
signaling remains a ‘driver’ in CRPC
• Hypothesis:
• Hormone-refractory prostate cancer
(HRPC) frequently remains driven by a
ligand-activated androgen receptor (AR).
• This disease is not truly hormone
refractory
Biological evidence for a continued
hormone ‘driver’ in CRPC
• High intratumoral androgens despite castration
• Castration resistance:
– AR amplification/ mutations in CRPC increase AR
activity
– ↑ AR mRNA expression alone → resistance in
isogenic lines
– Aberrant activation of the androgen receptor
Abiraterone: Response
Response Parameter Untreated Prior Docetaxel
PSA >50%:
38/54 (70%)
18/34(47%)
>30%:
TTP PSA
RECIST
43/54 (80%)
231 days
15/29(60%)
22/34 (65%)
161 days
NR
Abiraterone Clinical Trials
• Abiraterone vs placbo in patients with
CRPC prior to docetaxel
• Abiraterone/prednisone vs
placebo/prednisone in CPRC patients post
chemotherapy. Close to accrual
Waterfall Plot of Best Percent PSA
Change from Baseline
Chemotherapy-Naïve (N=65)
62% (40/65)
>50% Decline
Post-Chemotherapy (N=75)
51% (38/75)
>50% Decline
AFFIRM
Phase 3 Registration Trial of MDV3100 in
Post-Chemotherapy CRPC Patients
2
MDV3100 – 240 mg QD
R
1
Primary Endpoint:
Sample size:
Statistics:
Biomarkers:
Placebo QD
25% survival increase (12 to 15 months)
~1170 (780 and 390)
85% Power; p=0.05, two-sided
CTC enumeration and profiling with outcome
Scher, H. (North America) and De Bono, J. Co-PI, Medivation
When is chemotherapy initiated?
• At first PSA rise in non metastatic patients
• At PSA rise in an asymptomatic patient
• At PSA rise and scan progression in an
asymptomatic patient
• In a patient with symptomatic bone pain
Docetaxel HRPC Trials
Mitoxantrone 12 mg/m2
Prednisone 10 mg q day
Q 21 days up to 10 cycles
N=1006
Randomize
TAX 3271
N=770
*Warfarin and aspirin
Randomize
SWOG 99162
Docetaxel 30 mg/m2/wk
Prednisone 10 mg q day
5 on; 1 off x 6 cycles
Docetaxel 75 mg/m2
Prednisone 10 mg q day
Q 21 days up to 10 cycles
Mitoxantrone 12 mg/m2
Prednisone 5 mg bid
Q 21 days
Docetaxel 60 mg/m2 d 2
Estramustine 280 mg d1-5*
Dexamethasone 20 mg, tid d 1 & 2
1. Tannock et al. N Engl J Med 2004:351;1502-1512. 2. Petrylak et al. N Engl J Med 2004;351:1513-1520.
Overall Survival
100%
D+E
M+P
80%
# at
Risk
338
336
# of
Median
Deaths in Months
217
18
235
16
HR: 0.80 (95% CI 0.67, 0.97), p = 0.01
60%
40%
20%
0%
0
12
Months
24
36
48
Petrylak et NEJM 2004
Overall Survival — TAX 327
1.0
Docetaxel 3 wkly
Probability of Surviving
0.9
Docetaxel wkly
0.8
Mitoxantrone
0.7
0.6
0.5
0.4
Median
survival
(mos)
Hazard
ratio
18.2
18.9
17.3
16.4
0.83
0.76
0.91
–
P-value
0.3
0.2
0.1
0.0
Combined:
D 3 wkly:
D wkly:
Mitoxantrone
0
6
12
0.03
0.009
0.3
–
18
Months
Tannock et al. N Engl J Med 2004:351;1502-1512.
24
30
Evidence for Angiongenis as a Target
for Prostate Cancersis
• Microvessel density correlates with
prognosis in radical prostatetectomy
specimens
• Elevated levels of VEGF correlate with
prognosis in CRPCa
• bFGF expresse in epithelial and stromal
cells
CALGB Study
• Primary endpoint of improvement in
median survival from 19 in docetaxel arm
to 23 months in docetaxel/bevizcuzimab
arm not met
Press Release Roche 2010
CALGB 9040: Randomized Double Blinded Placebo
controlled Phase III Trial Comparing Docetaxel +
Prednisone with or without Bevacizumab in men with
HRPC
•Metastatic PC
•T <50 ng/ml
•No prior chemo
•Adequate hem, renal
& liver function
Stratification
RANDOMIZE
Eligibility
Halabi
nomogram
N = 1020 patients
CALGB, ECOG, NCIC
Arm A
Dexamethasone
Docetaxel
Prednisone
Placebo*
Arm B
Dexamethasone
Docetaxel
Prednisone
Bevacizumab*
8 mg po x 3 doses
75 mg/m2 on d1 q21d
10 mg po daily
IV on day 1 q 21 days
8 mg po x 3 doses
75 mg/m2 on d1 q 21d
10 mg po daily
15 mg/kg IV on day 1q 21d
Structure of Thalidomide
and the 2nd-Generation IMiDs
Best response by % change in PSA
100
90
80
70
60
50
40
30
20
10
0
-10
-20
-30
-40
-50
-60
-70
-80
-90
-100
No prior chemotherapy
Prior chemotherapy
MAINSAIL TRIAL
Screening
•Metastatic
CRPC
•Chemo-naïve
•Disease
Progression
CRPC
Patients
N= 1,015
Randomize
1:1
Docetaxel/Prednisone +
Lenalidomide Until Progression
or Toxicity
N ~ 500
Docetaxel/Prednisone +
Placebo
Until Progression or Toxicity
N ~ 500
Follow-Up:
•For Survival
•For Other
Treatments
•Up to five
years
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: OS
Secondary endpoints: Progression-free
survival (PFS), response rate, and safety
Inclusion: Patients with measurable
disease must have progressed by RECIST;
otherwise must have had new lesions or
PSA progression
2
Pre-Protocol Treatments
Total prior docetaxel dose (mg/m²)
Median
Months from last docetaxel dose to progression
Median
Number of patients progressed (%)
During last docetaxel treatment
<3 months since last docetaxel dose
≥3 months since last docetaxel dose
Radiation (%)
Curative
Palliative
Chemotherapy (%)
1 regimen
2 regimens
≥3 regimens
MP (n=377)
CBZP (n=378)
529.2
576.6
0.70
0.80
27.6
48.0
24.0
30.4
41.8
27.0
29.7
29.2
25.9
35.4
71.1
21.0
8.0
68.8
24.9
6.3
2
Primary Endpoint: Overall Survival
(ITT Analysis)
Proportion 100
of OS (%)
80
Median OS (months)
Hazard Ratio
60
MP
CBZP
12.7
15.1
95% CI
0.70
0.59–0.83
P-value
<.0001
40
20
0
0 months
Number
at risk
MP
CBZP
377
378
6 months
12 months
18 months
24 months
30 months
300
321
188
231
67
90
11
28
1
4
2
On-Study Laboratory Abnormalities
Safety Population
MP (n=371)
All Grades (%) Grade ≥3 (%)
Hematology
Anemia
Leukopenia
Neutropenia
Thrombocytopenia
Biochemistry
Alkaline Phosphatase
ALAT
ASAT
Hyperbilirubinemia
Creatinine
CBZP (n=371)
All Grades (%) Grade ≥3 (%)
81.4
92.5
87.6
43.1
4.9
42.3
58.0
1.6
97.3
95.7
93.5
47.4
10.5
68.2
81.7
4.0
57.7
18.9
28.0
4.6
11.6
9.7
0.3
0.5
0.8
0.5
53.6
25.9
27.8
3.8
15.6
7.3
1.1
0.8
0.5
1.3
2
Total Deaths During Study
Safety Population
MP (n=371)
CBZP (n=371)
Total deaths during study
275 (74.1%)
227 (61.2%)
Due to progression
253 (68.2%)
197 (53.1%)
Due to AEs
7 (1.9%)
18 (4.9%)
Due to other reasons
15 (4.0%)
12 (3.2%)
2
Zometa 039: Skeletal-Related
Event (SRE) Prevention Study
Bone metastases with progressive disease after ADT
(N=639)
Randomize
Standard Care +
ZOMETA
Endpoint: SRE
Standard Care +
Placebo
Skeletal-Related Events
• Pathologic fracture
• Spinal cord compression/vertebral
body collapse
• Radiation or surgery to bone
• Change in antineoplastic therapy
Proportion of Patients With SRE
(-HCM) at Month 15 by Treatment
(Intent-to-Treat Patients)
0.8
0.7
0.6
Proportion
of Patients
With SRE
0.5
38%
0.4
*
45%
34%
0.3
0.2
0.1
0
*P<.05 vs placebo
ZOMETA 8/4 mg
ZOMETA 4 mg
Placebo
Time to First SRE (–HCM)
by Treatment
% Patients
Without the
Event
ZOMETA 4 mg
Placebo
110
100
90
80
70
60
50
40
30
20
10
0
0
50
100
150
200
250
300
350
Median Time, Days*
NR
321
400
Time After the Start of Study Drug (Days)
*P=.011 ZOMETA 4 mg vs placebo
450
500
550
Study Design: International, Randomized, DoubleBlind, Active-Controlled Study
Key Inclusion
• Hormone-refractory
(castration resistant)
prostate cancer and bone
metastases
Key Exclusion
• Current or prior IV
bisphosphonate treatment
Denosumab 120 mg SC and
Placebo IV* every 4 weeks (N = 950)
Zoledronic acid 4 mg IV* and
Placebo SC every 4 weeks (N = 951)
• Calcium and Vitamin D supplemented in both treatment groups
• Accrual period from May 2006 to December 2008
• Analysis cut-off date October 2009
*Per protocol and Zometa® label, IV product dose adjusted for baseline creatinine
clearance and subsequent dose intervals determined by serum creatinine.
No SC dose adjustments made due to increased serum creatinine.
Proportion of Subjects Without SRE
Time to First On-Study SRE
HR 0.82 (95% CI: 0.71, 0.95)
P = 0.0002 (Non-inferiority)
P = 0.008 (Superiority)
1.00
Risk
18% Reduction
0.75
0.50
KM Estimate of
Median Months
0.25
Denosumab
Zoledronic acid
20.7
17.1
0
0
3
6
9
12
15
18
21
24
27
Study Month
Subjects at risk:
Zoledronic Acid
951
733
544
407
299
207
140
93
64
47
Denosumab
950
758
582
472
361
259
168
115
70
39
Conclusions
• Standard of care for CRPCA is
docetaxel/prednisone
• Novel phase IIII studies are combining
docetaxel with novel targeted agents
• Carbazitaxel is approved as a second line
therapy for castration resistant prostate
cancer
• New biological approaches are being
evaluated in the second line setting
Questions
• Prostate cancer after hormone ablation is
A)
B)
C)
D)
Still hormone responsive
Does not respond to chemotherapy
Spreads to the bone in 90% of pateints
A and C
Question 2
• A significant complication of treatments
targeting bone (bisphosphophonates and
denosamab) is
A)
B)
C)
D)
Osteonecrosis of the jaw
Hand foot syndrome
Rash
Diarrhea