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New Trends in the Management of Metastatic Prostate Cancer
1. William K. Oh, M.D.
Chief, Hematology/Medical Oncology
Tisch Cancer Institute
Mount Sinai School of Medicine
New York, NY
New Trends in the
Management of Metastatic
Prostate Cancer
2. Clinical States of Prostate Cancer
Clinically
localized
“Rising PSA”
state
Non-metastatic,
hormone-
sensitive
Metastatic,
hormone-sensitive
Non-metastatic
CRPC
Metastatic
CRPC
10-15 years +
Death from other causes
Death from prostate cancer
3. Clinical States of Prostate Cancer
Clinically
localized
“Rising PSA”
state
Non-metastatic,
hormone-
sensitive
Metastatic,
hormone-sensitive
Non-metastatic
CRPC
Metastatic
CRPC
10-15 years +
Death from other causes
Death from prostate cancer
4. Patient Case
● 85 yo practicing lawyer with hypertension,
plays tennis
● 15 lb weight loss, decreased energy, LUTS
● PSA 1146 ng/ml
● Bone scan with extensive mets
● Starts ADT, PSA drops after 6 weeks to 203
ng/ml and pain improves
Should he receive chemotherapy?
5. Patient Case
● He completes 6 cycles of docetaxel
● Tolerates well
– Fatigue, but works every day
– Mild LE edema
● PSA down to 0.10
● Repeat bone scan shows significant
improvement in bone lesions
● Working, traveling, has started hitting tennis
balls again
6. What Is The Role Of Chemotherapy
For Newly Diagnosed Metastatic
Prostate Cancer?
7. E3805 – CHAARTED Treatment
STRATIFICATION
Extent of Mets
-High vs Low
Age
≥70 vs < 70yo
ECOG PS
- 0-1 vs 2
CAB> 30 days
-Yes vs No
SRE Prevention
-Yes vs No
Prior Adjuvant ADT
≤12 vs > 12 months
R
A
N
D
O
M
I
Z
E
ARM A:
ADT + Docetaxel
75mg/m2 every 21
days for maximum
6 cycles
ARM B:
ADT (androgen
deprivation therapy
alone)
Evaluate
every 3 weeks
while
receiving
docetaxel and
at week 24
then every 12
weeks
Evaluate
every 12
weeks
Follow for time
to progression
and overall
survival
Chemotherapy
at investigator’s
discretion at
progression
Presented by: Christopher J. Sweeney, MBBS
• ADT allowed up to 120 days prior to randomization.
• Intermittent ADT dosing was not allowed
• Standard dexamethasone premedication but no daily prednisone
8. Primary endpoint: Overall survival
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
O S (M onths)
0 12 24 36 48 60 72 84
A rm A LIV ED E A D M E D IA NT O T A L
A 397 101 296 57.6
Probability
HR=0.61 (0.47-0.80) p=0.0003
Median OS:
ADT + D: 57.6 months
ADT alone: 44.0 months
Presented by: Christopher J. Sweeney, MBBS
10. Docetaxel: Survival – M1 Patients
SOC 343 deaths
SOC+Doc 134 deaths
HR (95%CI) 0.73 (0.59, 0.89)
P-value 0.002
Non-PH p-value 0.23
Median OS (95% CI)
SOC 43m (24, 88m)
SOC+Doc 65m (27, NR)
Restricted mean OS time
SOC 49.3m
SOC+Doc 56.1m
Diff (95%CI) 6.8m (2.8, 11.0m)
11. How does disease volume,
symptoms, age factor into chemo
decision in mHSPC?
• Low vs high volume is a consideration
• Symptoms are a negative prognostic factor
and will push me more towards chemo
• Age has to be consideration
– No absolute upper limit for chemo tolerance
– Dose adjust or add G-CSF, as needed
12. Tolerability of ADT + Docetaxel
GETUG 15 CHAARTED STAMPEDE
Patients 385 790 2962
Febrile neutropenia,
grade ≥3
7.5%* 6% 12%
* 4 deaths prior to addition of G-CSF
13. Lower PSA Nadir Strongly Predicts
Better Outcome With ADT
Hussain M, et al. J Clin Oncol, 2006;24(24):3984-3990
Docetaxel?
14. Conclusions: Docetaxel in mHSPC
• Docetaxel x 6 cycles is a new standard of
care for mHSPC
– No prednisone (but premed dex, as usual)
• All mHSPC patients should be offered
chemo
• Risk-benefit discussion: age, toxicity
15. Clinical States of Prostate Cancer
Clinically
localized
“Rising PSA”
state
Non-metastatic,
hormone-
sensitive
Metastatic,
hormone-sensitive
Non-metastatic
CRPC
Metastatic
CRPC
10-15 years +
Death from other causes
Death from prostate cancer
16. Recent Trials in mCRPC: OS
Therapy Prior Docetaxel Comparator
Hazard
Ratio
P value
Sipuleucel-T Mostly No Placebo 0.775 0.032
Docetaxel No Mitoxantrone 0.76 0.009
Cabazitaxel Yes Mitoxantrone 0.70 <0.0001
Abiraterone/
Prednisone
No Prednisone 0.81 0.0033
Yes Prednisone 0.646 <0.0001
Enzalutamide No Placebo 0.706 <0.001
Yes Placebo 0.631 <0.001
Radium-223 Mostly Yes Placebo 0.70 0.002
20. Androgen Signaling Remains a Key
Driver In CRPC
• AR is highly expressed on prostate
cancer cells and stimulates growth
• Over 90% of advanced prostate cancers
respond to ADT initially
• Even after progression to CRPC,
androgen signaling remains a critical
driver of cancer
21. Abiraterone and Enzalutamide:
Four Positive Studies!
PREVAIL
COU-AA-301
Co-Primary
Endpoints:
OS, rPFS
Primary
Endpoint:
OS
AFFIRM
COU-AA-302
mCRPC
Pre-chemotherapy
mCRPC
1st Line
Chemotherapy
mCRPC
Post-chemotherapy
24. Enzalutamide
• Oral investigational
drug rationally
designed to target AR
signaling, impacting
multiple steps in AR
signaling pathway.
• No demonstrated
agonist effects in pre-
clinical models.
Enzalutamide
1
T
AR
T
Cell nucleus
Inhibits Binding of
Androgens to AR
Inhibits Nuclear
Translocation of AR
Inhibits Association
Of AR with DNA
AR
Cell cytoplasm
Tran et al. Science 2009;324:787–90.
Charles Sawyers & Michael Jung
2
3
26. Targeting Androgen Signaling in CRPC
• Targeting androgen signaling is associated
with a significant survival benefit
• Use of abiraterone and enzalutamide is
effective both before or after chemotherapy
– In general, the default has become prechemo
• Toxicity is generally acceptable
– Abiraterone: LFTs, prednisone-related
– Enzalutamide: falls, fatigue, weakness
28. PSA Responses Diminish With
Second-Line AR Therapy
ENZA ABI ABI ENZA
First Line Second Line First Line Second Line
≥50% PSA
Decline
55-60% 4-8% 38-46% 13-29%
32. Androgen Receptor Splice Variant 7 and Efficacy of Taxane Chemotherapy in
Patients With Metastatic Castration-Resistant Prostate Cancer
Antonarakis, JAMA Oncol. ,2015
34. So What Is The Optimal Use Of
Chemotherapy for mCRPC?
35. First-Line Chemotherapy
• With ABI and ENZA available, are there
any patients who should receive cytotoxic
chemotherapy up front?
– Biomarkers (AR-V7+)
– Histologic subtypes
• Neuroendocrine differentiation
• Small cell carcinoma
– Clinical/predictive factors
• Rapid progression on primary ADT?
• Poor prognosis Halabi score?
37. • Next gen semi-synthetic taxane
• Preclinical data
– More cytotoxic in vitro than docetaxel in
multidrug-resistant gene 1–expressing tumors
– Active in tumor models resistant to docetaxel
• Phase I trial DLT neutropenia
Cabazitaxel
Mita Clin Can Res 2009
38. TROPIC
Primary endpoint: OS
Secondary endpoints: Progression-free
survival (PFS), responserate, and safety
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.
Stratification factors
ECOG PS (0, 1 vs. 2) • Measurablevs. non-measurable disease
mCRPC patients who progressed during and
after treatment with a docetaxel-based regimen
(N=755)
39. Overall Survival (ITT)
MP 377 300 188 67 11 1
CBZP 378 321 231 90 28 4
Number
at risk
Proportion
of OS (%)
80
60
40
20
0
100
0months 6months 12months 18months 24months 30months
15.112.7
0.59–0.8395% CI
<.0001P-value
0.70Hazard Ratio
CBZPMP
Median OS (mo)
45. Conclusions
• Therapeutic targeting of tubulins is
clinically relevant
– Docetaxel, cabazitaxel
• Cabazitaxel is equivalent to docetaxel in
first line mCRPC
• Unknown in sequencing is how
CHAARTED/STAMPEDE will influence
use of first line chemo for mCRPC