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Chemotherapy
In the treatment of prostate
cancer
Helder MansinhoHospital Garcia de Orta
2018
Incidence and mortality
GLOBOCAN 2008
Treatment of metastatic prostate cancer
• 1940 a suppression of testosterone results in tumor
regression1.
• Patients with higher tumor burden have lower survival rates2.3.
Visceral and bone metastases extra axial skeleton.
• Improved survival in metastatic patients resistant to castration.
Docetaxel every 3 weeks.
1-Huggins and Hodges Cancer Res, 1941; 2-Millikan et al J. Clin Oncol,2008; 3-Eisenberger et al. NEJM, 1998; 4-Tannock et al NEJM, 2004; 5-Petrylak et al NEJM 2004.
CRPC
Metastatic
minimally symptomatic
Secondary
hormone
manipulation
Survival benefit Unknown
CRPC Symptomatic
or with poor
prognosis
Docetaxel
3 months
Progression after Docetaxel
Mitoxantrone
Palliative Care
Unknown
2010
CRPC
Metastatic
minimally symptomatic
Secondary
hormone
manipulation
Survival benefitUnknown
CRPC Symptomatic
or with poor
prognosis
Docetaxel
3 months
Progression after Docetaxel
Mitoxantrone
Palliative Care
Unknown
2010
2014 Sipuleucel T
Survival benefit 4 months
Docetaxel
3 months
Abiraterona ou Cabazitaxel
Enzalutamida
Abiraterona
Rad 223
2.2 months
5.2 months
4.6 months
4 months 2.5 months
Enzalutamida
Rad 223
4.8 months
3.1 months
Zoledronic acid or Denosumab in bone metastases
When to use DOCETAXEL ?
• SWOG 99-16 and TAX 327 involved a very heterogeneous group of patients.
• Rapidly progressive or very symptomatic disease.
-Visceral disease
-Short answer to androgenic blockage
• Better sequencing with the new target agents - unknown.
SWOG 99-16
SWOG 99-16
• N= 770
MITOXANTRONA 12 mg/m2
PREDNISOLONA 5 mg bid
Q 21 days
DOCETAXEL 60 mg/m2 d2
ESTRAMUSTINA 280 mg d1-5
DEXAMETASONA 20 mg tid
d1 2
R
A
N
D
O
M
I
Z
A
T
I
O
N
SWOG 99-16
Risk Deaths Medianmonths
D+E 338 217 18
M+P 336 235 16
HR-0,80 (95%CI 0,67,0,97) p=0,01
SWOG 99-16
TAX 327
TAX 327
N=1006
R
A
N
D
O
M
I
Z
A
T
I
O
N
MITOXANTRONA 12 mg/m2
PREDNISOLONA 10 mg q/day
Q 21 days x 10 cycles
DOCETAXEL 30 mg/m2
PREDNISOLONA 10 mg/day
5 weeks on 1 off x 6 cycles
DOCETAXEL 75 mg/m2
PREDNISOLONA 10 mg/day
Q 21 days x 10 cycles
TAX 327
Toxicities
Docetaxel 21/21 dias
Docetaxel semanal
M+P D+E21/21 dias
M+P
32 1.5 22 20 16
3% ANC
0% 2% 5% 2%
32%2.1%
34%4.8%
10%1.2%
20% 5%
30% 24% 7% 7% 2%
10%19%30%
8%12%37%
1%7%
15% 7%
TAX 327 SWOG 9916
Gr 3 ANC
Infection
ToxicityG-I
Diarrhea grade 3
SNP
CV
Edema
Onycholysis
Preclinical dataCABAZITAXEL
• Same efficacy in tumor models sensitive to Docetaxel.
• Superior efficacy over Docetaxel in chemotherapy-resistant tumor models.
• Activity in tubulin polymerization.
• Active in vitro in sensitive and resistant Docetaxel cellular lines.
TROPIC
mCRPC who progressed during or after
treatment with Docetaxel.
N=755
Stratification factors
ECOG PS (0,1 vs 2) non-measurable disease
Cabazitaxel 25 mg/m2 every
3 weeks + Prednisona x10
cycles.
N=378
Mitoxantrona 12 mg/m2 every
3 weeks +Prednisona x10
cycles.
N=377
Endpoint primário:Overall survival.
Endpoints secundários: PFS,
Response and safety.
Inclusão:Patients with evaluable
disease that progress –RECIST
criteria; or with new lesions.
PSA progression.
TROPIC
MP CBZ+P
OS (mediana) 12.7 15.1
HR 0.70
95% CI 0.59-0.83
P- value <0001
TROPIC
MP CBZ+P
PFS 1.4 2.8
HR 0.74
TROPIC
TROPIC
TROPIC
TROPIC
TROPIC
Trials with CABAZITAXEL
• AFFINITY
- Cabazitaxel 25 mg/m2 +/- OGX-011
• FIRSTANA
- Docetaxel 75 mg/m2
- Cabazitaxel 25 mg/m2
- Cabazitaxel 20 mg/m2
PROSELICA
- Cabazitaxel 25 mg/m2
- Cabazitaxel 20 mg/m2
CABAZITAXEL-FIRSTANA
ASCO 2016
CABAZITAXEL-PROSELICA
ASCO 2016
CHEMOTHERAPY IN HORMONE-SENSITIVE PATIENTS
• GETUG-15– Gravis G et al. Lancet Oncol 2013; 14:149-58
– Gravis G et al. J Clin Oncol 2015; 33(Suppl 7):abstract 140
– Gravis G et al. Eur Urol. 2015 Nov 21, 2015 [Epub ahead of print]
• CHAARTED– Sweeney C et al. N Engl J Med 2015;373:737-46
• STAMPEDE– James N et al. J Clin Oncol 2015;33 (Suppl 15):abstract 5001
– James N et al. Eur J Cancer 2015;51(S3): abstract 19LBA
– James N et al. Lancet. 2015 Dec 21, 2015
Phases III docetaxel in mHSPC: GETUG 15, Chaarted
HORMONE-SENSITIVE
METASTATIC
PROSTATE CANCER
STRATIFICATION
FACTORS:
Disease extent
ECOG PS
Previous ADT
R
A
N
D
O
M
I
Z
A
T
I
O
N
ARM A:
ADT + docetaxel
75mg/m2/21 d x 6/9
cycles
ARM B:
ADT (androgen
deprivation therapy
alone)
GETUG 15 n=385 Recruitment: 2004-2008
Chaarted n= 790 Recruitment: 2006-2012
Docetaxel in mHSPC: Global survival
Gravis G. Lancet Oncol. 2013;14:149-158; Gravis G. ASCO GU 2015. Abstract LBA2
GETUG 15
ADT + D: 61 monthsADT: 47 monthsHR: 0.9 [0.7–1.2]; P = .44
CHARTEED
The New England Journal of Medicine
Sweeney, L. et al. Aug 2015
CHARTEED
ADT + Docetaxel
improves the OS
versus ADT
PRIMARY
ENDPOINT: OS
Sweeney C., et al. Chemohormonal Therapy in Metast. Aug 2015
CPHSm - Hormone-sensitive metastatic prostate cancer
PRIMARY
ENDPOINT: OS
Hazard Ratio
similar in both
groups.
The group with the
highest tumor
volume had
statistically
significant
differences,
favoring ADT+Doc
Sweeney C., et al. Chemohormonal Therapy in Metast. Aug 2015
CHARTEED
17 meses
• Observable benefit in patients with high
metastatic volume;
• Further follow-up is required in patients with
low metastatic volume.
Sweeney C., et al. Chemohormonal Therapy in Metast. Aug 2015
CHARTEED
Docetaxel no mHSPC: Global survival
Gravis G. Lancet Oncol. 2013;14:149-158; Gravis G. ASCO GU 2015. Abstract LBA2; Sweeney C. ASCO 2014. Abstract 140.
GETUG 15 (1/2 high risk )
ADT + D: 57.6 monthsADT alone: 44 monthsHR = 0.61 (0.47–0.80) P = .0003
CHAARTED (2/3 high risk)
ADT + D: 58.9 monthsADT: 54.2 monthsHR: 0.9 [0.7–1.2]; P = .44
STAMPEDE
Presented at ECCO 2015 by the Prof Nicholas James
STAMPEDE
James N., et al. Addition of
docetaxel. Dec 2015
2962
STAMPEDE
James N., et al. Addition of docetaxel. Dec 2015
Docetaxel:failure free
Survival
Median OS (95% CI)SOC 71 mo SOC + Doc 81 mo
STAMPEDE: Docetaxel – Survival, M1 Patients
SOC 343 deathsSOC + Doc 134 deaths
HR (95% CI) 0.73 (0.59, 0.89)P value 0.002
Median OS (95% CI)SOC 43 mo (24, 88 mo)SOC + Doc 65 mo (27, NR)
James N. ASCO 2015. Abstract 5001.
Lancet Oncol 2016; 17: 243–56
M1 docetaxel: Survival
Results based on 2992 men / 1271 deaths
9% of absolute gain in 4-year-survival rate
Trial name
OverallSTAMPEDE (SOC+ZA +/- Doc)STAMPEDE (SOC +/- Doc)GETUG15CHAARTED
HR=0.77 (0.68, 0.87) p<0.0001
.5 1 2
Heterogeneity:2=4.80, df=3, p=0.187, I2 = 37.5%
Favours SOC + docetaxel Favours SOC
Vale C, Lancet Oncol 2015
LATITUDE ASCO-2017
ABIRATERONE-STAMPEDE
N. James-ASCO 2017
mCNPC and high metastatic burden
48
OSADT + DOC ADT
Mediana (meses) Mediana (meses) HR (95% CI) P Value
GETUG-15 62.1 48.6 0.88 (0.68-1.14) 0.3
CHAARTED2 57.6 47.2 0.73 (0.59-0.89) 0.0018
STAMPEDE3 60 45 0.76 (0.62-0.92) 0.005
LATITUDE ADT + AA Vs ADT NR 34,7 0.62 (0.51-0.76) ˂0.001
Stampede ADT + AA Vs ADT +/ -RT
NR NR 0.63 (0.52-0.76) 0.00000115
Fizazi K. et al. (2017) Presented at ASCO 2017. 1. Gravis G, et al. Eur Urol. 2016:70:256-262. 2. Sweeney C, et al. N Engl J Med. 2015;373:737-746; Sweeney C, et al. Ann Oncol.2016;27(Suppl 6):243-265. 3. James N, et al. Lancet. 2016;387:1163-1177. and Vale C, et al. Lancet Oncol 2016;17:243-256.
49
STAMPEDE
50
Nicholas James ESMO 2017
ADT +
Abiraterona 1000 mgPrednisona 5 mg BID
+/- docetaxelPrimary Endpoints : SG
e SLP (HR: 0.75)ADT +
Local Radiotherapy +/- docetaxel
RANDOMIZATION
• Patients with de novo diagnosis (hormone-naïve) CaP metastatic
• 916 planned patients
PEACE-1: European Study, phase III in Metastatic Prostate Cancer de novo
Sponsor: Unicancer
T. Androgenic deprivation(ADT)
+/- docetaxel
ADT +
Local Radiotherapy +Abiraterona-Pred
+/- docetaxel
ClinicalTrials.gov. Identifier: NCT01957436.
T. Helleday*
Annals of Oncology 27: 755–757, 2016
CONCLUSIONS
• Docetaxel + Prednisone is the 1st lineoption for patients with aggressivemetastatic disease resistant to castration.
• Docetaxel should be considered for high-risk volume hormone-sensitive patients.
CONCLUSIONS• The therapeutic algorithm in metastatic
CPRC is not established.
• Cabazitaxel is approved by FDA in 2ndline chemotherapy.
• PARP inhibition has anti-tumor activity inCRPC and is associated to DNA repairdefects.
Obrigado