Treatment strategies for metastatic prostate cancer

Oliver HakenbergDepartment of Urology, Rostock University

prostate cancer is hormone-dependentprostate cancer is hormone-dependent

LHRH = LHRH = lluteinising hormone releasing hormoneuteinising hormone releasing hormoneLH = LH = lluteinising hormoneuteinising hormoneACTH = ACTH = aadrenocorticotropal drenocorticotropal hhormone ormone

testosterone

pineal gland

cortisole adrenalandrogens

Prostata

testes

prolactine

adrenal glands

hypothalamus

LH

ACTH

LHRHestrogens

orchidectomy

antiandrogens

LHRHanalogues

antiandrogens

0 1 2 3 4 5 6 7 8 90

10

20

30

40

50

Pathologic fractures after orchidektomy

n=235

Daniell et al, J Urol 1997

orchidectomy

no orchidectomy

years

% cumulative incidence of osteoporotic fractures

Immediate androgen ablation

• permanent– advanced metastatic disease M+– locally advanced, if androgen ablation is the

only treatment option

• adjuvant/temporary– radical prostatectomy with positive nodes

(pN+)– adjuvant with radiotherapy in intermediate and

high risk disease

Early or delayed androgen ablation?

Messing et al, Lancet Oncology 2006

RPE pN+early vs observation/delayedrandomizedn= 98

Overall survival

Cancer-specific survival

androgen ablation

• ↓ gonadal testosterone• 10-30% serum androgens from other sources • Adrenal cortex: DHEA + androstendione →

transformed to testosterone in periphery (including prostate)

• progression after xx months → hormone resistant

hormone resistance?

• de novo intratumoral androgen synthesis in progressive CRPC

• → maintenance of intracellular andogen levels • → androgen receptor (AR) stimulation despite

low serume testosterone

• „castration-resistant prostate cancer“ = CRPC

Locke et al, Cancer Res 2008

3 new developments

• autologous vaccine sipuleucel-T (IMPACT)– mCRPC docetaxel-naive (85%)– improved OS vs placebo

• cabazitaxel (TROPIC)– mCRPC doxetaxel-refractory – improved OS vs mitoxantrone

• arbiraterone– hormonal principle in CPRC

Kantoff et al, N Engl J Med 2010De Bono et al, Lancet 2010

Arbirateroneinhibition of testosterone biosynthesis

• arbiraterone acetate inhibits– C17,20 lyase– 17 hydroxylase– Inhibition selective & irreversible

• adrenals, testes, prostate cancer cells • arbiraterone acetate: prodrug• good oral bioavailability• Development of resistance

Sonpavde et al, Eur Urol 2011

Attard et al, Cancer Res 2009

Study data: arbiraterone in CRPC

• phase I– chemotherapy-naive CRPC patients

• phase-II NCT 00474383– progression after docetaxel

• phase-III NCT 00638690– progression after docetaxel

• phase III NCT 00887198– asymptomatic, low metastatic load in

chemotherapy-naive patients

phase I

• n=21

• chemo-naive, CRPC– 12/21 with PSA↓>50% and > 3 months– of which in 6/12 PSA↓ > 90%– PR (RESIST) in 5/8 patients and ↓analgesic

medication– no grade grade 3/4 toxicity

Attard et al, J Clin Oncol 2008

phase II a

• chemotherapy-naive CRPC patients

• PSA↓> 50% in 70-80% of patients

• RESIST response 37.5%

• median time to PSA-rise 225 days

• dexamethasone at progression with arbiraterone: further PSA↓>50% in 33%

Attard et al, J Clin Oncol 2009

phase II b

• n= 47 docetaxele-pretreated CRPC

• PSA↓> 50% in 51% of patients

• 35 with RESIST– PR 17%– SD 66%

• 23% ECOG improvement

Reid et al, J Clin Oncol 2009

Reid et al, J Clin Oncol 2009

Reid et al, J Clin Oncol 2009

Phase II c

• docetaxele-pretreated CRPC

• better efficacy without ketoconazole pretreatment– 53% vs 33% PSA-response without/with– 31% vs 4% PSA↓>90% without/with

ketoconazole– median time to progression 198 vs 99 days

with/without ketoconazole

Danila et al, J Clin Oncol 2009

phase III (COU-AA-301)

• n=1195 docetaxel-refractory CRPC

• arbiraterone vs placebo 2:1 randomisation

• stratification– ECOG 0-1 vs 2– prior chemotherapy schedules 1 vs 2– pain score – type of progression: PSA vs XR

• OS 14.8 vs 10.4 months• TTP 10.2 vs 6.6 months• rPFS 5.6 vs 3.6 months• PSA RR 29.1% vs 5.5%• toxicity

– hyperhydration 2.3% vs 1.0%– hypokalaemia 3.8% vs 0.8%– hypertension 1.3% vs 0.3%– cardiopulmonary 4.1% vs 2.3%

phase III (COU-AA-301) 1.interim analysis 2010

De Bono et al, ESMO 2010

arbiraterone

• n=1195 docetaxel resistant

• 2:1 randomisation– arbiraterone 1000 mg + 5 mg prednisone

vs

– placebo + 5 mg prednisone

• overall survival– arbiraterone 14.8 months

– placebo 10.9 months

de Bono et al, N Engl J Med 2011

treatment options for metastatic prostate cancer

• hormonal – androgen ablation

• orchidectomy• LHRH-antagonists or –agonists• androgen blockers

– androgen conversion blocker• arbiraterone

• chemotherapy– docetaxel– cabazitaxel

• bisphosphonates• pain treatment• nuclear medical tretament: samarium, strontium• best supportive care

Prognosis of metastatic prostate cancer

• initial response to androgen ablation > 80%

• progression in 50-60% of patients within 2 years

• after that median survival 23-37 months

• 5 year survival rate with M+oss 20%

androgen antagonists

• steroidal– cyproterone acetate

• non-steroidal– bicalutamide– flutamide– nilutamide

pro

po

rtio

n w

ith

ou

t ev

ent

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 6 12 18 24 30 36 42 48 60time (months)

bicalutamide 150 mg + standard carePlacebo + standard care

54

reduction of the risk of PSA progression by 59 %

Kaplan-Meier curve of time to PSA progression

HR 0.41; 95% CI 0.38, 0.45; p<<0.0001

Early Prostate Cancer Program

natural course of prostate cancer after radical prostatectomy and PSA recurrence (n= 311)

150 5 10years

PSA recurrencedistant metastases

death of prostate cancer

Pound et al., JAMA 1999

Hormone-independent prostate cancer

hormone independent

hormonesensitive

hormone dependent

hormone withdrawal

hormone naive hormone independent

definition of castration-resistant prostate hormone-refractory prostate cancer (HRPC)

• serume testosteron at castration level

• secondary hormonal treatment without effect• ketoconazole

• estrogens

• rising PSA at 3 consecutive measurements at intervals of 1 week at leastt• with continued LHRH – blockade and after witrhdrawal of androgen blocker

• lowest PSA limit: 0.4 ng/ml

Chemotherapy for prostate cancer?

Reviews response rates

1985: (17 Studien) 6,5 % M. Eisenberger, J Clin Oncol 1985

1992: (26 Studien) 8,7 % Yagoda & Petrylak, Cancer 1993

P.Walsh 1995:„This is going to be an extremely short discussion. Not only does it fail to cure the cancer, it doesn’t even prolong survival to any significant degree, and its side effects only add to the unpleasantness of having prostate cancer.“

• phase III: mitoxantrone (12mg/m²) + prednisone (10mg/d) vs. prednisone (10mg/d)

– 161 patients. (80 M+P; 81 P)

• phase III: mitoxantrone (14mg/m²) + hydrocortisone (40mg/d) vs. hydrocortisone (40mg/d)

– 242 patients

results– improvement in pain– improvement in quality of life– duration of response 5-7 months– no influence on survival

chemotherapy for prostate cancer – mitoxantrone for HRPC?

Tannock et al. 1996Kantoff et al. 1999

mitoxantrone approved by FDA

as standard chemotherapy in

HRPC

docetaxel

• TAX 327

• SWOG 9916

• both studies showed overall survival advantage for docetaxel

Petrylak, N Engl J Med 2004Tannock, N Engl J Med 2004

20%

40%

60%

80%

100%

0 12 24 36 48months

D + EM + P

no. at

Risk

338 336

217235

median survival(months)

1816

HR: 0.80 (95% CI 0.67, 0.97), p = 0.01med. F/U: 1 J

docetaxel chemotherapyoverall survival SWOG 9916

no (n)died

Petrylak et al, N Engl J Med 2004

SWOG 99-16

Petrylak J NCI 2006

Survival in subgroupsdocetaxel 3 weekly vs mitoxantrone

0.2 0.4 0.6 0.8 1 1.2 1.4

Intent to Treat

age < 65

age ≥ 65

age ≥ 75

pain no

pain yes

KPS ≥ 80

KPS ≤ 70

hazard ratio in favour of

docetaxel mitoxantrone

Tannock et al, N Engl J Med 2004

Cochrane Reviewchemotherapy of HRPC

• n=6929 patients; 47 studies• investigated substances:

– EMP

– docetaxel

– 5-FU

– cyclophosphamide

– doxorubicine

– mitoxantrone

– vinorelbine

Shelley M, Harrison C et al. Cochrane Database Syst Rev 2006

Cochrane Review

• PSA response (>50%):– EMP 48%– docetaxel 52%– 5-FU 20%– cyclophosphamide n.d.– doxorubicine 50% (CAVE: only 1

study!)

– mitoxantrone 33%– vinorelbine n.d.

Shelley M, Harrison C et al. Cochrane Database Syst Rev 2006

• only DOC => overall survival ↑ (<2.5 months)

• pain ↓ DOC > Mit + Pred• quality of life ↑ DOC > Mit + Pred

results

authors‘ conclusion:

„At the present time this* probably represents the best chemotherapeutic regime available for men with HRPC“

*- docetaxel q3w

Shelley M, Harrison C et al. Cochrane Database Syst Rev 2006

secondary hormone manipulation or chemotherapy?

secondary hormone manipulation

chemotherapy

CALGB9583 SWOG 9916 TAX-327

AAW + Ketokonazol

EMP docetaxel

vs MP

DP q3w

vs DP q1w vs MP

n 260 770 1006

overall survival in better arm

16.7 months 17.5 months 18.9 months

overall survival in worse arm

15.3 months 15.6 months 16.5 months

Bellmunt, Eur Urol Suppl 2009

open questions

• when to start with chemotherapy?• should asymptomatic M+ patients be treated?• how long to continue treatment?• secondary treatment?• intermittent chemotherapy?• re-exposition?

Early vs late chemotherapy?• for

– benefit established for other entities (breast cancer, colorectal cancer)

– lower tumour mass– treatment prolongs survival

• against– toxicity vs unreliable response– early induction of chemotherapy-refractory state– outcome is not influenced since no difference in

survival between symptomatic vs asymptomatic patients (TAX327)

forms of HRPCindications for starting with chemotherapy

• only rising PSA

• asymptomatic, low metastatic load

• asymptomatic, large metastatic load

• symptomatic metastases

no indication PSA doubling time?

individual decisioninclusion in study?

yes

yes

Estimating the prognosis in CPRCPSA doubling time

• günstig– TAX 327: PSA-DT > 55 Tage – Oudard et al: PSA-DT > 45 Tage

Armstrong et al, Clin Cancer Res 2007Oudard et al, Ann Oncol 2007

Armstrong, A. J. et al. Clin Cancer Res 2007;13:6396-6403

nomographic estimation

rising PSA under chemotherapy…

• often initiial PSA flare-up

• no negative influence on survival, unless there are signs of clinical progression

=> minimum of 8 weeks treatment before deciding to discontinue !

Olbert Anticancer Drugs 2006

Copyright restrictions may apply.Thuret et al, Ann Oncol 2008

PSA-Flare with chemotherapy in patients with subsequent PSA response or stable disease

PSA values normalized to a starting point of 100 ng/ml

Chemotherapy until…

• best number of cycles unknown

• TAX 327: mean of 8 cycles

• but: chronic toxicity increases with no of cycles

• intermittend chemotherapy?

When to discontinue chemotherapy…?

• definite worsening of physical state• PSA doubling time < 3 Monate• slow PSA increase:

- discontinue if clinically progressive

Miller et al. Akt Urol 2006

First line chemotherapydocetaxel Mono (75mg/m² KO d1, q21d)

Second line chemotherapyoptions:

– docetaxel (M D) PR: 44-85%

– docetaxel weekly PR: 72%

– mitoxantrone (D M) PR: 6-15%

– satraplatin (SPARC)

– cabazitaxel

Cabazitaxel second lineoverall survival

de Bono et al, Lancet 2010

open label, randomized, n= 755CPRC patients with progression on docetaxelcabazitaxel 25 mg/m2 q3w + prednisone 10 mg p.o. dailyvsmitoxantrone 12 mg/m2 q3w i.v.+ prednisone 10 mg p.o. daily

mean survival overallCABA 15.1 monthsMITO 12.7 months

Cabazitaxel second lineprogression-free survival

de Bono et al, Lancet 2010

ketoconazole• 200 or 400 mg tid p.o. ketoconazole

• + hydrocortisone replacement doses 30-0-10 mg p.o.

• n= 114

• response depends on disease burden

Keizman et al, Prostate 2010

Beltran et al, Eur Urol 2011

Hypothetical calculationFuture prognosis of metastatic prostate cancer?

• initial response to androgen ablation > 80%• progression in 50-60% of patients within 2 years • after that median survival 23-37 months• + 4 months with docetaxel• + 4 months with cabazitaxel• + 4 months with arbiraterone

„This will buy you three months“

Rostock