First-line Hormone Therapy

(1)

First-line Hormone Therapy

Alan Horwich

Institute of Cancer Research and Royal Marsden

Hospital, London, UK

(2)

MANAGEMENT OF PROSTATE

CANCER

Treatment “windows”

Subclinical

Localised

PSA only recurrence

Asymptomatic metastases

Symptomatic metastases

Castration resistant

Post docetaxel

Palliative care

---20 years---

(3)

Hormone Therapies for Prostate Cancer

•LHRH agonists………….

eg Zoladex,

Prostap

•LHRH antagonists……

eg Degarelix

•Androgen Receptor targeted..

eg Casodex,

Flutamide,

Enzalutamide

•Steroids………..

eg Prednisone,

Dexamethasone

•Oestrogens………

eg Stilboestrol

(4)

James et al Eur Urol 2014

• 917 men with M1 disease treated 2005-2014 in the control arm (Androgen Deprivation)

• Median FFS 11.2 months (IQR 5.1-28.8 months)

• Median overall survival 42.1 months (IQR 22.7-90.7 months)

Androgen Deprivation in M1

Disease

(5)

Androgen Ablation in Prostate Cancer

• Loss of libido

• Loss of muscle mass

• Erectile dysfunction • Insulin resistance

• Hot flushes

• Cardiovascular effects

• Fatigue

• Decreased bone

(6)

Diabetes and cardiovascular disease during androgen deprivation for

prostate cancer

Keating JNCI 2010 VA 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

(7)

Efsathiou JCO 2009 2792-99

No. = 945 FU 8.1 yrs CVD = 117

At 9 yrs CVD 8% vs 11% In favour of LHRHa group

(8)

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)

(9)

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?

(10)

1. A randomised comparison of 'Casodex' (bicalutamide) 150

mg monotherapy versus castration in the treatment of

metastatic and locally advanced prostate cancer.

.

•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 2000_M1 patients

Tyrrell et al 1998

Casodex less effective

than androgen ablation

(11)

(12)

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

(13)

Samson et al 2002

Modest benefit at 5 years probable outweighed by increased side-effects

(14)

3. 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 29 deferred patients died from prostate cancer without having started hormone treatment!

(15)

3. 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

(16)

3. Immediate vs deferred hormone therapy

in 985 men with M0 prostate cancer who had refused or were unsuitable for

radical treatment. RESULT HR 1.25 for OS favours immediate treatment.

BUT Prostate cancer deaths Other cause

deaths-no difference Time to hormone therapy in deferred patients EORTC 30891 Studer et al 2006 JCO 24; 1868-76

(17)

4. Intermittent Androgen Suppression vs Continuous Androgen

Deprivation

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

(18)

4. BUT

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”.

Therefore Intermittent Hormones NOT standard in M1 disease.

Randomised after 7 months combined androgen blockade IF PSA≤4

(19)

5. Adding treatments to androgen deprivation.

STAMPEDE trial of celecoxib,

(20)

Gravis G,

Fizazi K et al 2013.

Lancet Oncol •385 M1 hormone-naïve: randomised 2004-2008 (median FU 50 months).

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

PSA- PFS OS

Median 23 v 13 months p=0.005

(21)

Docetaxel in hormone-naive metastatic prostate cancer.

CHAARTED Trial: Sweeney et al ASCO 2014

Improved Overall Survival by 13 months !! Significant in High Volume subgroup.

(22)

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 P r o b a b ilit y

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 P r o b a b ilit y

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

Presented by: Christopher J. Sweeney, MBBS

(23)

OVERALL SURVIVAL HIGH VOLUME METASTASES

MedSubgroup Analysis of « High Volume » ian follow-up: 84.0 months [82.9-84.0

Median OS ADT alone: 35.1 [29.9- 44.2] ADT + D: 39 [ 28- 52.6] HR: 0.8 [0.6-1.2] p=0.35 Median OS ADT alone: 35.1 [29.9- 44.2] ADT + D: 39 [28- 52.6] HR: 0.8 [0.6-1.2] p=0.35

Fizazi GU ASCO 2015—median FU 83 months

Subgroup analysis of those with “High-Volume” metastases. GETUG-15 update

(24)

5. CHAARTED and GETUG-15:

differences

Ack: David Dearnaley

Presenting 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 59m vs 54m

( median FFS 21m vs 15m 23m vs 13m )

Time from failure to death 37m vs 29m 36m vs 41m

Surprising that in CHAARTED there was shorter survival after failure in the patients who had not yet had Docetaxel

(25)

5. Reasons why Overall Survival

conclusion might differ in

GETUG vs CHAARTED

•Trial populations? – CHAARTED had a high proportion of

poor risk patients.

•Chance?—the OS hazard ratio in GETUG included within

the 95%confidence intervals a possible 36% benefit

•Additional effective post-docetaxel therapies in

CHAARTED trial?– Possibility that more abiraterone,

enzalutamide, cabazitaxel were given in the docetaxel

arm?

(26)

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

(27)

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.

(28)

(29)

ADT

+ Abiraterone 1000mg

Prednisone 5mg BID _{Co-primary endpoints:}

OS and PFS (HR: 075) ADT + Local radiotherapy R A N D O M I Z E D •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