Management of CRPC

1. Dr Rohan Sharma
Urology Resident
MPUH
NADIAD

2. Prostate Cancer Clinical
States Model
Scher H I et al. JCO 2008;26:1148-1159

3. CRPC - definition
 On ADT
 S.Testosterone < 50 ng/dl
 Disease progression, either PSA or other metastatic disease

4. Development of Castrate-Resistant Prostate Cancer
Alternative
Splicing
Aberrant
Modification
•GF, cytokines
•Src
Sumo
AC
P
Co-Factor
Perturbation
•CoAct gain
•CoR loss/dismissal
CoACT
Intracrine
Androgen
Synthesis
T
Mutation
•Gain of function
AR
Selective Pressure
Adaptation
CRPC
RESTORED AR ACTIVITY
(rising PSA)
RECURRENT TUMOR DEVELOPMENT
Hormone Therapy
AR
DEREGULATION
•amplification
•overexpression
>30%CRPC
Knudsen KE, et al. Trends Endocrinol Metab. 2010;21(5):315-324.

5. CRPC
 M0 – only rise of PSA
 M1

6. CRPC – M0
 PSADT
 >10 months
 <10 months

7. CRPC – M0, PSADT > 10 months
 Observation
 Other secondary hormonal therapy
 Ketoconazole
 Bicalutamide, Flutamide
 Corticosteroids
 Estrogen
 Antiandrogen withdrawal

8. CRPC – M0, PSADT < 10 months
 2nd generation antiandrogens
 Enzalutamide (Prosper trial)
 Apalutamide (Spartan trial)
 Other secondary hormonal therapy

13. CRPC – M1 – first line
 Docetaxel
 Abiraterone
 Enzalutamide
 Sipuleucel-T
 Radium-223
 Mitoxantrone

14. Docetaxel – Pivotal trials
 Tax 327 - Docetaxel vs Mitoxantrone
 SWOG 9916
 First chemotherapy drug demonstrated OS benefit.

15. Abiraterone Acetate: Androgen Biosynthesis
Inhibitor
Pregnenolone
Testosterone DHT
17OH-
Pregnenolone
Cortisol
Aldosterone
Cholesterol
Abiraterone
Abiraterone
DHEA Androstenedione
Androgens
DHEA, dehydroepiandrosterone/didehydroepiandrosterone; DHT, dihydrotestosterone
Knudsen KE, et al. Trends Endocrinol Metab. 2010;21(5):315-324.

16. COU 302: Abiraterone Acetate Phase III Trial in
Chemo-naïve mCRPC
• Phase III multicenter, randomized, double-blind, placebo-
controlled study conducted at 151 sites in 12 countries; United
States, Europe, Australia, Canada
• Stratification by ECOG performance status 0 vs 1
1:1
N = 1088
• Progressive chemo-
naïve mCRPC patients
• Asymptomatic or
mildly symptomatic
Abiraterone acetate 1000 mg daily
Prednisone 5 mg bid
n = 546
Placebo daily
Prednisone 5 mg bid
n = 542
Primary Endpoints:
Saad F, et al. J Urol. 2013;189(4): Abstract 713.
• Radiographic
progression-free survival
(rPFS) by central review
• Overall survival
Secondary Endpoints:
• Time to opiate use
(cancer-related pain)
• Time to initiation of
chemotherapy
• Time to ECOG PS
deterioration
• Time to PSA progression
ECOG PS, Eastern Cooperative Oncology Group Performance Status

17. Statistically Significant Improvement Over Placebo
in rPFS and all Secondary Endpoints
Saad F, et al. J Urol. 2013;189(4): Abstract 713.
Patient reported outcomes favored AA + prednisone vs placebo + prednisone
Full data to be reported
*Prespecified alpha level 0.0035
Note: All secondary endpoints remain significant after adjusting for multiplicity testing
Outcome
AA + Prednisone
Median, Months
Placebo + Prednisone
Median, Months HR (95% CI) P Value
rPFS 16.5 8.3 0.53 (0.45, 0.62) <.0001
OS 35.3 30.1 0.79 (0.66, 0.96) .0151*
Time to opiate use
(cancer related pain)
Not reached 23.7 0.71 (0.59, 0.85) .0002
Time to chemotherapy
initiation
26.5 16.8 0.61 (0.51, 0.72) <.0001
Time to ECOG PS
deterioration
12.3 10.9 0.83 (0.72, 0.94) .0052
Time to PSAprogression 11.1 5.6 0.50 (0.43, 0.58) <.0001
AA, abiraterone acetate; HR, hazard ratio

18. Final Overall Survival Analysis of COU-AA-302: A RandomizedPhase III Study of
Abiraterone Acetate in Metastatic Castration-Resistant Prostate Cancer Without
Prior Chemotherapy
• Median follow-up of 49.2 months
• Abiraterone treatment effect more pronounced when adjusting for 44% of prednisone
patients who received subsequent abiraterone (HR = 0.74)
100
80
OverallSurvival,%
Time to Death, Months
HR (95% CI): 0.81 (0.70-0.93)
P = .0033
Abiraterone, 34.7 months
60
40
Prednisone, 30.3 months
20
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60
Abiraterone 546 538 525 504 483 453 422 394 359 330 296 273 235 218 202 189 118 59 15 0 0
Prednisone 542 534 509 493 466 438 401 363 322 292 261 227 201 176 148 132 84 42 10 1 0
Ryan CJ, et al. Lancet Oncol. 2015;16(2):152-160.

19. Low dose Abiraterone
 Phase II trial
 N=72
 1000 mg fasting vs 250 mg low fat diet
 PSA response at 12 weeks (> 50% reduction)
 50% vs 58%
Szmulewitz RZ, et al. J Clin Oncol. 2018

20. Enzalutamide
• Oral drug rationally
designed to target AR
signaling, impacting
multiple steps in AR
signaling pathway
• No demonstrated
agonist effects in
preclinical models
T
Nucleus
Enzalutamide
Inhibits binding of
androgens to AR
Inhibits nuclear
translocation of AR
Inhibits association
of AR with DNA
Tumor death
CytoplasmT
X
AR
X
AR
X
Tran C, et al. Science. 2009;324(5928):787-790.

21. Primary endpoint: OS and PFS
Enzalutamide 160 mg QD
Placebo QD
PREVAIL Phase III Trial of Enzalutamide in Asymptomatic
or Mildly Symptomatic mCRPC Prechemotherapy
R
A
N
D
O
M
I
Z
E
1:1
mCRPC
Asymptomatic or
mildly symptomatic
patients
<4 BPI
(N = 1680)
Fully accrued
BPI, brief pain inventory; PFS, progression-free survival
Available at https://clinicaltrials.gov/ct2/show/NCT01212991. Accessed May 2, 2016. Beer TM, et al. N Engl J Med. 2014;371(5):424-433.

22. PREVAIL Phase III Trial of Enzalutamide in
Asymptomatic or Mildly Symptomatic mCRPC
Prechemotherapy Preliminary Results
Beer TM, et al. N Engl J Med. 2014;371(5):424-433.
• Overall Survival: 30% reduction in the risk of death
(HR = 0.70; 95% confidence interval, 0.59-0.83)
• Progression-Free Survival: 81% reduction in risk of
radiographic progression or death compared with placebo
(HR = 0.19; 95% confidence interval, 0.15-0.23)

23. PREVAIL: Overall Survival
Placebo
Enzalutamide
HR: 0.71 (95% CI: 0.60, 0.84)
P<.0001
Survival,%
100
90
80
70
60
50
40
30
20
10
0
9630 36333012 15 18 21 24 27
Duration of Overall Survival, Months
Patients Still Alive at
Data Cut Off Median OS
Enzalutamide 72% 32.4 months
Placebo 63% 30.2 months
Beer TM, et al. J Clin Oncol. 2014;32(suppl 4). Abstract LBA1. Beer TM, Et al. N Engl J Med. 2014;371(5):424-433.
Enzalutamide: 29% reduced risk of death

24. Timing and Selection of Secondary
AR-Directed Therapies
 Choice of abiraterone vs enzalutamide cannot be dictated
based on differences in efficacy
 Similar OS, PFS from cross-trial comparisons
 Enzalutamide has been evaluated in men with visceral metastases in
the chemo-naive setting
 Both are category 1 recommendations in NCCN guidelines
 Therefore choice is based on differential toxicity
 Abiraterone acetate for seizure-prone men and those more frail,
elderly (> 75 years old) men at high risk for falls
 Enzalutamide for men with significant CV risk factors,
contraindications to prednisone, brittle diabetes, and metabolic
syndrome
 Significant cross-resistance, so initial choice is likely most important

26. AR-V7
Androgen receptor variant-7 (AR-V7) is a truncated
form of the AR that lacks the LBD, the target of
abiraterone and enzalutamide, but remains
constitutively active as a transcription factor
AR-FL AR-V7

27. AR-V7 and Resistance to Enzalutamide and
Abiraterone in Prostate Cancer
Antonarakis ES, et al. N Engl J Med. 2014;371(11):1028-1038.
Outcome AR-V7[–] → AR-V7[–] (n = 36) AR-V7[–] → AR-V7[+] (n = 6) AR-V7[+] → AR-V7[+] (n = 16)
PSAResponse
68%
(95% CI, 52%-81%)
17%
(95% CI, 4%-58%)
0%
(95% CI, 0%-19%)
PSA Progression-FreeSurvival 6.1 months
(95% CI, 5.9 months-NR)
3.0 months
(95% CI, 2.3 months-NR)
1.4 months
(95% CI, 0.9 months-2.6 months)
Progression-Free Survival 6.5 months
(95% CI, 6.1 months-NR)
3.2 months
(95% CI, 3.1 months-NR)
2.1 months
(95% CI, 1.9 months-3.1 months)
AR-V7, the most important AR transcriptional
variant, is expressed at detectable levels in CTCs
in a significant proportion of CRPC patients
CTCs, circulating tumor cells

28. Interpretation of AR-V7 Data
• Detection of AR-V7 in CTCs from men with mCRPC is associated with
primary resistance to abiraterone and enzalutamide
• AR-V7–positive patients may retain sensitivity to taxanes
• In AR-V7–positive men:
– Taxanes may be more efficacious than AR-directed therapies
• In AR-V7–negativemen:
– Taxanes may have comparable efficacy to AR-directed agents
• AR-V7 may be a treatment-selection marker in mCRPC

29. Radium 223
 Alpha emitter
 As first line
 Only bone mets
 Alsympca trial – OS benefit

32. 2nd line treatment for metastatic CRPC
 Docetaxel
 Abiraterone
 Enzalutamide
 Cabazitaxel
 Pembrolizumab

33. COU 301: Overall Survival Placebo
Abiraterone
Acetate
Median OS, months 10.9 14.8
Hazard Ratio 0.65
95% CI 0.54-0.77
P
value
<.001
0 100 200 300 400 500 600 700
0
20
80
60
40
100
OverallSurvival,%
Days from Randomization
• 2 prior chemotherapy regimens OS: 14.0 months abiraterone acetate vs 10.3 months placebo1
• 1 prior chemotherapy regimen OS: 15.4 months abiraterone acetate vs 11.5 months placebo1
• Updated results: 4.6 month difference in median OS with abiraterone acetate2
Placebo
Abiraterone acetate
Median OS Δ: 3.9 months
35.4% reduction in risk of death
OS, overallsurvival
1. de Bono JS, et al. N Engl J Med. 2011;364(21):1995-2005. 2. Fizazi K, et al. Eur J Cancer. 2011;47(Suppl 2): Abstract 7000.

37. Pembrolizumab
 Keynote 028 trial
 For MSI high patients only
 Durable response for few heavily pre-treated patients

38. Bone health
 Zoledronic acid – 3 weekly to 3 monthly
 Denosumab – 4 weekly
 Denosumab comparatively better than zoledronic acid.

39. Genetic analysis
 Olaparib for BRCA positive patients
 Not approved yet

40. Conclusion
 M0 – PSADT
 M1 – heavy burden disease – docetaxel
 Low burden disease – Abiraterone/Enzalutamide
 MSI
 Bone health