1. WHEN IS CHEMOTHERAPY INDICATED FOR HORMONE-NAÏVE PROSTATE CANCER
FERRY SAFRIADI
Department of Urology
AMC Hasan Sadikin Hospital/Padjadjaran University
39TH ASMIUA, Surabaya 7-10 Nov 2016

2. Epidemiology
Prostate cancer is the second leading cause of cancer deaths among North American men, with an estimated 29,720 deaths in 2013 in the United States and 3,900 deaths in Canada.
American Cancer Society: Cancer Facts and Figures 2011
Advisory Committee on Cancer Statistics: Canadian Cancer Statistics 2013.
In Asian countries: incidence of Pca is increasing rapidly due to a more westernized lifestyle.
In Japan; mortality rate projected to increase by 2.8 times in 2020.
Namiki M, et al. Jpn J Clin Oncol 2010

3. Incidence: Indonesia
6,6%
13663

4. Mortality: Indonesia
6,3%
9191

5. CRPC Patients Characteristic In 3 Indonesian University HospitalN
158/1097 (14.4%)
Median age
69 years old
Median PSA
193.5 ng/ml
Mode Gleason Score 8
Chemotherapy and Estramustine were given to patients with CRPC (5.7%) of 14.4%.
Safriadi F, et al. in press

7. For men with androgen-sensitive metastatic disease, continuous ADT is the current standard of care.
Loblaw DA, et al:.J Clin Oncol 2007
ADT is capable of achieving castrate levels of testosterone (≤50 ng/dL), and most patients with metastatic hormone naive prostate cancer initially respond to this treatment.
Feldman BJ, et al. Nat Rev Cancer 2001
The majority of patients will develop resistance to these traditional hormonal approaches and the median time to progression is about months.
Denis LJ, et al..Eur Urol 1998.

8. TAX 327
2000-2, mHRCP: 1006 men
Doce 3 weekly vs. 1 weekly vs. mitoxantrone 3 weekly.
HR for death:
Doce 3 weekly: 0.76
Doce weekly: 0.91
Median Survival:
Mitoxantrone: 16.6 mo
Doce 3 weekly: 18.9 mo
Doce weekly: 17.4 mo
Tannock IF, et al. NEJM 2004

9. PREVAIL STUDY Chemonaive setting.
872 in the enzalutamide group and 845 in the placebo group.
rPFS 12 months:
65% vs.14%.
Risk reduction of death: 29%.
Delayed the initiation of chemotherapy.
Beer TM, et al. NEJM 2014

10. CO-AA-302 mCRPC: chemonaive 1008 men: - abi 1000mg daily vs. plac
Median rPFS:
abi 16.5 mo vs.plac 8.3 mo
HR 0.53 p < 0.001
Ryan CJ, et al. NEJM 2013

11. The M0 Challenge HR localized PCa Docetaxel ± 7-15 years (3-5) SRE
ESMO2014 Tombal final
The M0 Challenge
Docetaxel
± 7-15 years (3-5)
HR localized PCa
SRE
PAIN
Local therapies
PSA Prog.
RX progr.
ADT
MO CRPC space
Time to chemotherapy
(months)
Active
arm
Control Δ HR
(95%CI) p
COU-AA-302 (Prednisone)
26.5
16.8
9.5
0.61
≤ 0.001
PREVAIL (placebo)
28.0
10.8
17.2
0.35
< 0.001
Eur Urol Nov;66(5):
Beer TM, N Engl J Med Jul 31;371(5):

12. ESMO2014 Tombal final
The M0 Challenge
Docetaxel
± 7-15 years
HR localized PCa
SRE
PAIN
Local therapies
PSA Prog.
RX progr.
ADT
MO CRPC space
PREVAIL and COU-AA-302 have induced a shift toward treatment of ± 1 year.
Once approved widely, abiraterone and/or enzalutamide will be given at early entry in mCRPC
Joniau S for EmPACT, Eur Urol. 2014, Widmark A, SPCG-7, Lancet
Warde P, SPCG-7, Lancet

13. EAU Guidelines of Prostate Cancer 2015

14. Panduan Penatalaksanaan CRPC di Indonesia
Indeks Pasien
Gejala
Metastatik
Kemoterapi
Status Performa
Penatalaksanaan 1 -
Baik
Rekomendasi: dilakukan observasi serta tetap diteruskan pemberian terapi ADT 2
-/minimal +
Standard: (A) Abiraterone + prednisone, (B) docetaxel 3
Standard : Docetaxel.
Rekomendasi: Abiraterone + prednisone 4
Buruk
Pilihan: dengan Abiraterone + prednisone, atau Ketoconazole + steroid, atau terapi radionuklida 5
Standard: Abiraterone acetate + prednisone, atau Cabazitaxel 6
Pendapat ahli: terapi paliatif abiraterone + prednisone, atau ketoconazole + steroid, atau terapi radionuklida

15. The impact of PREVAIL and COU-AA-302 in the modern CRPC landscape
Enzalutamide
Symptoms
Abiraterone
Chemo-based treatment
Enzalutamide
Cabazitaxel
Abiraterone
Radiographic progression
Bone targeted therapies, including RA223 M0
CRPC survival
Ryan et al. Lancet Oncol Beer C et al. N Engl J Med 2014; Tannock IF et al. N Eng J Med 2004;

16. ESMO2014 Tombal final
The M0 Challenge
Docetaxel
± 7-15 years (3-5)
HR localized PCa
SRE
PAIN
Local therapies
PSA Prog.
RX progr.
ADT
MO CRPC space
As a consequence trials in that setting will be a very early experimental drug versus an early abiraterone or enzalutamide
HN PC: hormone naïve PCa; CRPC: Castration-Resistant Prostate Cancer; M0, non-metastatic; RX progression: radiological progression; SRE skeletal related events
Joniau S for EmPACT, Eur Urol. 2014, Widmark A, SPCG-7, Lancet
Warde P, SPCG-7, Lancet

17. Proportion of patients with bone metastases
Denosumab and bone-metastasis-free survival in men with CRPC
1.0
0.8
Key eligibility criteria
CRPC with:
PSA  8 ng/ml or
PSA DT  10 months
No bone metastases
No prior IV bisphosphonate use
HR = 0.85 (95% CI, 0.730.98)
P = 0.028
0.6
Proportion of patients with bone metastases
0.4
Median:
Events:
0.2
Placebo (n = 716)
25.2 months
370
Denosumab (n = 716)
29.5 months
335
0.0 3 6 9 12 15 18 21 24 27 30 33 36 39 42
Study month
Smith, et al. Lancet. 2012

18. BTT risk reduction 25%
Saad F, et al. Eur Urol 2015

19. GETUG-AFU15 Controversial results: # of docetaxel cycles Sample size
Length of follow up
Proportion of high-vol disease
HR 0.88 ( ), p= 0.3
Gravis G et al. Lancet Oncol 2013

20. CHAARTED STUDY High volume Low volume
ESMO2014 Sweeney final
CHAARTED STUDY
High volume
Low volume
Hazard Ratio 0.60
(95% CI ) P=0.0006
ADT + DOC
Not reached
ADT alone
Not reached
ADT + DOC
49.2 mths
ADT alone
32.2 mths
Hazard Ratio 0.63
(95% CI ) P=1398
high volume: >4 bone lesions and >1 lesion in any bony structure beyond the spine/pelvis or visceral disease
17-month benefit in median OS (from 32.2 to 49.2 months) for high volume
Sweeney C et al. J Clin Oncol mg/m2 plus prednisone

21. STAMPEDE : Survival – M1 Patients
SOC+Doc
SOC
SOC 343 deaths
SOC + Doc 134 deaths
HR (95%CI) 0.73 (0.59, 0.89)
P-value
Median OS (95% CI)
SOC 43m (24, 88m)
SOC+Doc 65m (27, NR)
James ND et al. Lancet

22. Docetaxel : Failure-free survival
SOC 750 FFS events
SOC+Doc 371 FFS events
HR (95%CI) 0.62 (0.54, 0.70)
P-value < *
SOC+Doc
Median FFS (95% CI)
SOC 21m (18, 24m)
SOC+Doc 37m (33, 42m)
SOC
James ND et al. Lancet

23. The impact of PREVAIL and COU-AA-302 in the modern CRPC landscape
Enzalutamide1
Chemo-based treatment3 ?
Abiraterone2
Radiographic progression M0
CRPC survival
Ryan et al. Lancet Oncol Beer C et al. N Engl J Med 2014; Tannock IF et al. N Eng J Med 2004;

24. FIRSTANA: randomized, open-label phase 3 trial of CABA 25 mg/m2 and 20 mg/m2 vs DOC in chemo-naive mCRPC pts
CABA 25 mg/m² every 3 wks + prednisone 10 mg/d
N=388
159 centers worldwide R A N D O M I Z E
mCRPC patients who have not previously received chemotherapy
N=1,168
CABA 20 mg/m² every 3 wks + prednisone 10 mg/d
N=389
DOC 75 mg/m² every 3 wks
+ prednisone 10 mg/d
N=391
Primary endpoint: OS
Secondary endpoints: Safety, PFS, tumor response (if measurable disease), PSA response, pain response, time to SREs, QoL, pharmacokinetics, pharmacogenomics
Exploratory: cDNA
Prophylactic G-CSF NOT allowed at cycle 1
Statistics: OS superiority of CABA over DOC (HR 0.75)
Sartor AO et al. J Clin Oncol 2016;34(suppl):abstract ClinicalTrials.gov NCT

25. FIRSTANA OS (primary endpoint) PFS (composite)*
Median PFS, months (95% CI)
DOC + P ( )
CABA 20 + P 4.4 ( )
CABA 25 + P 5.1 ( )
CABA 20 vs DOC
HR=1.009 ( )
P=0.9967
CABA 25 vs DOC
HR=0.97 ( ) P=0.7574
CABA 20 vs DOC
HR=1.063 ( )
P=0.4218
CABA 25 vs DOC
HR=0.989 ( )
P=0.8035
Median OS, months (95% CI)
DOC + P ( )
CABA 20 + P ( )
CABA 25 + P ( )
Sartor AO et al. J Clin Oncol 2016;34(suppl):abstract

26. Effect of the addition of docetaxel on survival in men with M1 disease
Addition of docetaxel to standard of care translates into
an absolute improvement in 4-year OS of 9% (95% CI 5-14).
an absolute 4-year failure rates of 16% (95% CI 12-19)
Vale CL et al. Lancet Oncol. 2016

27. The advanced PCa landscape
Abiraterone
Enzalutamide
Docetaxel
Cabazitaxel
PSA progr.
RX progr.
SRE
PAIN
ADT
M1 HNPC
Bone targeted therapies
± 2-4 years
± 7-15 years
High-risk localized PCa
SRE
PAIN
Local therapies
RX progr.
ADT
MO CRPC space
PSA progr.
ADT: androgen deprivation therapy; HNPC: hormone-naïve prostate cancer; PCa: prostate cancer;
PSA: prostate-specific antigen; RX progr.: radiological progression; SRE: skeletal-related events
Mottet N et al. EAU guidelines on prostate cancer, update 2015; (accessed March 2016)
Vale CL et al. Lancet Oncol 2016;17:243-46

28. Newly diagnosed Fit enough

29. THANK YOU