First-line Hormone Therapy

Alan HorwichInstitute of Cancer Research and Royal Marsden

Hospital, London, UK

Alan.Horwich@icr.ac.uk

MANAGEMENT OF PROSTATE

CANCERTreatment “windows”

Subclinical

Localised

PSA only recurrence

Asymptomatic metastases

Symptomatic metastases

Castration resistant

Post docetaxel

Palliative care

----------------------------------------------20 years---------------------------------------------

Hormone Therapies for Prostate Cancer

•LHRH agonists…… eg Zoladex, Prostap

•LHRH antagonis…. eg Degarelix

•Antiandrogens………… eg Casodex, Flutamide,

Enzalutamide

•Oestrogens…………… eg Stilboestrol

•Cyp 17 antagonists…. eg Abiraterone, Orteronel

Androgen Ablation in Prostate Cancer

• Loss of libido • Loss of muscle mass

• Erectile dysfunction • Insulin resistance

• Hot flushes • Cardiovascular effects

• Fatigue• Decreased bone

mineral density

Diabetes and cardiovascular disease during androgen deprivation for prostate cancer

Keating JNCI 2010VA Study

N=37443 diagnosis 2001-4 ; 14,597 had ADT. Mean observation 2.6 yrs.

Rate of event/1000 patient years and adjusted Hazard Ratio

Diabetes Incident CHD MI

Sudden

Cardiac

Death

No ADT 87 - 81 - 7.3 - 12 -

LHRHa 160 1.3 144 1.2 12.8 1.3 22 1.3

Orchidectomy 190 1.2 210 1.4 24.3 2.1 23 1.3

Antiandrogen 130 1.0 143 1.1 11.2 1.0 19 1.1

Osteoporosis and duration of LHRHa therapy Stage I-II Ca Prostate with PSA control

Femoral neck bone densitometry

Duration of hormone therapy None 12-36m 36-60m >60m

Incidence of osteoporosis 28% 35% 42% 50%

Relative risk of hip fracture 2.0 2.4 2.9 3.9

Prostatectomy controls (57) Men treated with LHRHa (53)

Morote Eur Urol 2003 44 661

Loss of bone mineral density particularly in first 6–12m (Daniell 2000, Mittan 2002)

Osteoporotic fracture rate increased. 4% 5yr, 20% 10yr (Oefelein 2001)

Issues for Hormone Therapy in

Metastatic Prostate Cancer

① Type of hormone therapy

② Combined androgen blockade?

③ Immediate vs Deferred in asymptomatic patients?

④ Intermittent or continuous?

⑤ Combine with other treatment eg chemotherapy,

bone targeting agents, newer AR targeted drugs,

radiotherapy to the primary site?

⑥ Role with RT to the primary ?

.A randomised comparison of 'Casodex' (bicalutamide) 150 mg monotherapy

versus castration in the treatment of metastatic and locally advanced prostate

cancer.Tyrrell CJ, Kaisary AV, Iversen P, Anderson JB, Baert L, Tammela T, Chamberlain M, Webster A, Blackledge G.

Eur Urol. 1998;33(5):447-56.

•1453 patients with locally advanced or metastatic prostate cancer.

•Less hot flushes and improved physical activity and sexual health on

bicalutamide.

•In M1 disease bicalutamide was less effective (HR for mortality 1.3)

•No difference in the 480 men with locally advanced disease (Iversen et al

2000)

M1

patients

Degarelix CS21 and Extension Trial

bRFS

•Degarelix had better PSA-RFS at 12 months-no OS difference

•No overall difference ? as crossover at 12 months

•Role in emergencies eg impending SCC

•? Role in intermittent therapy

•? More effective at PSA control (possible due to FSH suppression)

•BUT only monthly prep. And more injection site reactions

Crawford et

al 2014

Samson et al 2002

Modest benefit at 5 years

probable outweighed by

increased side-effects

2

.

Immediate versus deferred treatment for

advanced prostatic cancer:initial results of the Medical Research Council Trial. The Medical

Research Council Prostate Cancer Working Party Investigators Group.

Br J Urol. 1997 Feb;79(2):235-46.

• 948 men with locally-advanced or metastatic prostate cancer

• Randomised to immediate or deferred treatment (orchx or LHRH)

• Deferred patients had more prostate cancer deaths (257 vs 203 (p=0.001)

• Also more TURPs, pathological fractures, spinal cord compressions.

• BUT 1. Pre PSA and 2. 29 deferred patients died from prostate cancer

without having started hormone treatment!

• Deferred treatment remains an option for selected indolent cases

EARLY VERSUS DELAYED ENDOCRINE TREATMENT OF

pN1-3 M0 PROSTATE CANCER---Schroeder et al 2004 for EORTC

234 node positive patients having no local prostate treatment were

randomised to immediate or deferred hormones

Underpowered.

Trend to improved survival with early treatment-HR 1.23 (95%ci 0.88-1.71)

but Delayed Treatment remains an option.

Median survivals:

Early-7.8 yrs

Delayed 6.2 yrs

Phase 3 RCT Intermittent Androgen Suppression vs Continuous

Androgen Deprivation

–patients with PSA progression after local Rx; Crook et al NEJM 2012

BUT in M1 disease Hussain et al 2013 suggests Intermittent Treatment

NOT proven to be non-inferior

4

Intermittent versus Continuous Androgen

Deprivation in M1 Prostate Cancer. Hussain et al 2013 NEJM

Hazard Ratio 1.1 (95% CI 0.99-1.23)

“As CI exceeded 20% detriment, it CANNOT be concluded that

Intermittent therapy is not inferior”

Randomised after

7 months

combined

androgen

blockade IF

PSA≤4

5

STAMPEDE trial of

celecoxib,

Lancet Oncology 2012

Gravis G, Fizazi K et

al 2013.

Lancet Oncol

•385 M1 hormone-naïve: RCT Hormones vs Hormones +Docetaxel: median FU 56 months.

•No difference in overall survival (59 vs 54 months)

•72 SAEs in first 123 men on docetaxel arm including 4 treatment-related deaths

therefore routine G-CSF introduced.

Docetaxel in hormone-naive metastatic prostate cancer.

CHAARTED Trial: Sweeney et al ASCO 2014

Improved Overall Survival by 13 months !!

And improved time to develop CRPC by 6.7 months and TTP (imaging) by 13 months

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

OS (Months)

0 12 24 36 48 60 72 84

Arm ALIVEDEAD MEDIANTOTAL

A 134 19 115 .B 142 26 116 .

Pro

ba

bility

OS by extent of metastatic disease at start of ADT

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

OS (Months)

0 12 24 36 48 60 72 84

Arm ALIVEDEAD MEDIANTOTAL

A 263 82 181 49.2B 251 110 141 32.2

Pro

ba

bility

Presented by: Christopher J. Sweeney,

MBBS

In patients with high volume metastatic disease, there is a 17 month

improvement in median overall survival from 32.2 months to 49.2 months We projected 33 months in ADT alone arm with collaboration of SWOG9346 team

High volume Low volume

p=0.0006

HR=0.60 (0.45-0.81)

Median OS:

ADT + D: 49.2 months

ADT alone: 32.2 months

p=0.1398

HR=0.63 (0.34-1.17)

Median OS:

ADT + D: Not reached

ADT alone: Not reached

ADT + Docetaxel

benefited all

subgroups

Presented by: Christopher J.

Sweeney, MBBS

Meta-analysis of trials: Matt Sydes MRC

CHAARTED and GETUG-15: similarities

Presenting features CHAARTED GETUG-15

Age 64yrs 64yrs

Metastases at presentation 73% 71%

Docetaxel: Courses (% dose reductions) 6 (26%) 8 (11%)

Outcomes

Deaths 237 176

Median OS ADT+Docetaxel group 57.6m 58.9m

Improved PSA/clinical PFS 20.7m vs 14.7mH.R 0.56 (0.44-0.70)

22.9m vs 12.9mHR 0.72 (0.57-0.91)

CHAARTED and GETUG-15: differencesPresenting features CHAARTED GETUG-15

Geography N.America France/Belgium

Recruitment period 2006-2012 2004-2008

Number 790 385

Follow-up 29 months 50 months

Risk groups: High 66% 22%

PSA at entry 53ng/ml 26ng/ml

Outcomes

OS ADT+D vs ADT 58m vs 44m HR 0.61 59m vs 54m HR 1.01

( Time to PSA/clinical failure 21m vs 15m HR 0.56 23m vs 13m HR 0.72)

Time from failure to death 37m vs 34m 36m vs 41m

Surprising that in CHAARTED there was shorter survival after

failure in the patients who had not yet had Docetaxel

CHAARTED and GETUG-15: treatment after clinical failure

CHAARTED CHAARTED GETUG-15 GETUG-15

ADT+D ADT ADT+D ADT

No. failed 145 174 Est.70% Est.75%

Docetaxel 35% 74% 40% est 83% est

Carbazitaxel 30% 17% 3% est 2% est

Abiraterone/enzalutamide

63% 45% 21%* est RCT only

20%* estRCT only

Comments:

•GETUG-15: similar and low incidence of effective

additional treatments – trial approximates more closely

comparison of immediate or deferred docetaxel.

•CHAARTED: interpretation complicated by high and

unbalanced use of effective additional treatments.

Interpretation of Difference; GETUG vs CHAARTED

•Different trial populations? – but no obvious intra-trial

heterogeneity

•Chance?

•Opportunity for additional post-docetaxel effective

therapies in CHAARTED trial:

Did delay in failure lead to more availability of treatments

or more opportunity to give more effective treatments?

•Does early docetaxel treatment sensitise to subsequent

abiraterone/enzalutamide ?

Role of radiotherapy to the

primary in patients

with metastases?

Mouse models of metastasis.

Factors secreted by the primary tumors (e.g., VEGF-A, PlGF, PSAP) are thought to mobilize

bone marrow–derived cells that are subsequently attracted to premetastatic sites. The cells of

this “premetastatic niche” then release factors that can attract disseminating tumor cells

6

PSA recurrence Death from CaP

24% vs 12%

RR 0.44 p<0.0001

75% vs 26% RR 0.16 p<0.0001

WIDMARK Lancet 2009 373 301-8

Result supported by Warde et al for NCIC/MRC 2011 Lancet. n=1205.

Survival benefit in a similar trial.

Also by STAMPEDE non-randomised result in either N0 or N1 patients (ESMO 2014)

MRC STAMPEDE TRIAL: MAMS design

ADT

+ Abiraterone 1000mg

Prednisone 5mg BID Co-primary endpoints:

OS and PFS (HR: 075)ADT

+ Local radiotherapy

RANDOMIZED

•Patients with

newly

diagnosed

metastatic

prostate cancer

PEACE-1: European Phase III Trial of Abiraterone

Acetate in patients with newly diagnosed (hormone-

naïve) metastatic prostate cancer

Courtesy of K Fizazi

2x2 design

Study sponsor: Unicancer

Androgen deprivation

therapy (ADT)

ADT

+ Local radiotherapy

+ Abiraterone 1000 mg

Prednisone 5mg BID

n= 916 planned patients

Conclusions

•Hormone therapy is a highly effective initial

systemic treatment for prostate cancer.

•It is a low toxicity treatment but there are

impacts on quality of life.

•Single modality androgen deprivation is the

standard of care.

•Variations such as deferred or intermittent

treatment or combination with Docetaxel are

options to discuss with your patients.