First-line Hormone Therapy

Transcription

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 years

3 Hormone Therapies for Prostate Cancer LHRH agonists. Prostap LHRH antagonists Androgen Receptor targeted.. Flutamide, Enzalutamide Steroids.. Oestrogens Cyp 17 inhibitors. eg Zoladex, eg Degarelix eg Casodex, eg Prednisone, Dexamethasone eg Stilboestrol eg Abiraterone,

4 Androgen Deprivation in M1 Disease James et al Eur Urol men with M1 disease treated in the control arm (Androgen Deprivation) Median FFS 11.2 months (IQR months) Median overall survival 42.1 months (IQR months)

5 Androgen Ablation in Prostate Cancer Loss of libido Loss of muscle mass Erectile dysfunction Insulin resistance Hot flushes Fatigue Cardiovascular effects Decreased bone mineral density

6 Diabetes and cardiovascular disease during androgen deprivation for prostate cancer Keating JNCI 2010 VA Study N=37443 diagnosis ; 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 LHRHa Orchidectomy Antiandrogen

7 Efsathiou JCO 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 Morote Eur Urol Prostatectomy controls (57) Men treated with LHRHa (53) 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 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? 6 Role with RT to the primary?

10 1. A randomised comparison of 'Casodex' (bicalutamide) 150 mg monotherapy versus castration in the treatment of metastatic and locally advanced prostate cancer 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 Casodex less effective than androgen ablation Tyrrell et al 1998

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12 Degarelix CS21 and Extension Trial Crawford et al 2014 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

13 2. COMBINED ANDROGEN BLOCKADE 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 Feb;79(2): 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! Deferred treatment remains an option for selected indolent cases

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 Median survivals: Early-7.8 yrs Delayed 6.2 yrs Underpowered. Trend to improved survival with early treatment-hr 1.23 (95%ci ) but Delayed Treatment remains an option.

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 deaths-no difference Other cause Time to hormone therapy in deferred patients EORTC Studer et al 2006 JCO 24;

17 4. Intermittent Androgen Suppression vs Continuous Androgen Deprivation PSA progression after local Rx; 2012 Crook et al NEJM Equivalent efficacy and Intermittent Hormones had improved Quality of Life

18 4. BUT Intermittent versus Continuous Androgen Deprivation in M1 Prostate Cancer. Hussain et al 2013 NEJM Randomised after 7 months combined androgen blockade IF PSA 4 Hazard Ratio 1.1 (95% CI ) As CI exceeded 20% detriment, it CANNOT be concluded that Intermittent therapy is not inferior. Therefore Intermittent Hormones NOT standard in M1 disease.

19 5. Adding treatments to androgen deprivation. STAMPEDE trial of celecoxib, Lancet Oncology 2012

20 Gravis G, Fizazi K et al Lancet Oncol 385 M1 hormone-naïve: randomised (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. And improved time to develop CRPC by 6.7 months and TTP (imaging) by 13 months

22 OS by extent of metastatic disease at start of ADT High volume Low volume Probability p= HR=0.60 ( ) Median OS: ADT + D: 49.2 months ADT alone: 32.2 months Probability p= HR=0.63 ( ) Median OS: ADT + D: Not reached ADT alone: Not reached OS (Months) OS (Months) 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 Presented by: Christopher J. Sweeney, MBBS

23 OVERALL SURVIVAL HIGH VOLUME METASTASES GETUG-15 update MedSubgroup Analysis of «High Volume» ian follow-up: 84.0 months [ Median OS ADT alone: 35.1 [ ] ADT + D: 39 [ ] HR: 0.8 [ ] Median p=0.35 OS ADT alone: 35.1 [ ] ADT + D: 39 [ ] HR: 0.8 [ ] p=0.35 Fizazi GU ASCO 2015 median FU 83 months Subgroup analysis of those with High-Volume metastases.

24 5. CHAARTED and GETUG-15: differences Ack: David Dearnaley Presenting features CHAARTED GETUG-15 Geography N.America France/Belgium Recruitment period Number 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? STAMPEDE result due ASCO 2015

26 6 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 WIDMARK Lancet Death from CaP 24% vs 12% RR 0.44 p< % vs 26% RR 0.16 p< 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)

28 6. STAMPEDE FROM 2014

29 PEACE-1: European Phase III Trial of Abiraterone Acetate in patients with newly diagnosed (hormonenaïve) metastatic prostate cancer Androgen deprivation therapy (ADT) Patients with newly diagnosed metastatic prostate cancer R A N D O M I Z E D ADT + Abiraterone 1000mg Prednisone 5mg BID ADT + Local radiotherapy Co-primary endpoints: OS and PFS (HR: 075) n= 916 planned patients ADT + Local radiotherapy + Abiraterone 1000 mg Prednisone 5mg BID 2x2 design Study sponsor: Unicancer Courtesy of K Fizazi

30 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 for initial Rx of M1 disease. Variations such as deferred or intermittent treatment or combination with Docetaxel are options to discuss with your patients.