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