Initial hormone therapy (and more) for metastatic prostate cancer

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1 Initial hormone therapy (and more) for metastatic prostate cancer Silke Gillessen, MD Medical Oncology Kantonsspital St.Gallen Switzerland

2 Conflicts of interest Speakers Bureau (no honoraria): Amgen, Astellas, Bayer, Janssen Cilag, Sanofi Aventis Consulting activities: AAA International, Astellas, Bayer, Curevac, Dendreon, ESSA, Janssen Cilag, Janssen Diagnostics, Millennium, Novartis, Orion, Pfizer, ProteoMediX, Roche, Sanofi Aventis Pending patent application for a method for biomarker WO A1

3 Some Important Figures Prostate Cancer Breast Cancer New diagnoses 6182 New diagnoses 5861 Median age at diagnosis 69.2y Median age at diagnosis 63.6y Mortality 1340 Mortality 1384 Clinical Trial: Prostate Neoplasms Clinical Trial: "Breast Neoplasms"

Docetaxel M0 1st-line Advanced Prostate Cancer: Castration-resistant 2nd-line ADT: Androgen

4 Localized Prostate Cancer Local Therapy (RT/OP/Active Surveillance) Salvage RT Prostate Cancer Advanced Prostate Cancer: Castration-sensitive/naive PSA Rise De Novo M1 M0 M1 ADT ADT +/- Docetaxel M0 1st-line Advanced Prostate Cancer: Castration-resistant 2nd-line ADT: Androgen Deprivation Therapy M0: By imaging no evidence of metastases M1: Metastases detected by imaging 3rd-line

Metastatic Prostate Cancer Standard-Treatment: Androgen Deprivation Therapy (ADT; Castration) with response rate >90% Charles Huggins (1901-1997) Nobel Prize 1966 I.

5 Metastatic Prostate Cancer Standard-Treatment: Androgen Deprivation Therapy (ADT; Castration) with response rate >90% Charles Huggins ( ) Nobel Prize 1966 I. The Effect of estrogens and androgen injection on serum phosphatases in metastatic carcinoma of the prostate II. Cancer Res., 1941 The effect of castration on advanced carcinoma of the prostate gland Arch. Surg., 1941

6 Androgen Deprivation Therapy (ADT) GnRH Agonist GnRH Antagonist e.g. Goserelin, e.g. Degarelix Leuprorelin 90% 10% Orchiectomy

7 Androgen Deprivation Therapy (ADT) Advantage Rapid Testosterone decline One single procedure Orchiectomy GnRH Agonist GnRH Antagonist Disadvantage Major psychological issue Irreversible Local complications Costs About CHF 5000 one time Easy application Local reactions rare Initial Testosterone flare For 3 years: About CHF 6200 (only drug costs including short term AR antagonist) Rapid Testosterone decline Possibly improved safety profile in men with preexisting cardiovascular disease Local reactions Costs Albertsen PC, Eur Urol For 3 years: About CHF 8400 (only drug costs)

8 Androgen Deprivation Therapy for metastatic disease: Other Forms Intermittent ADT: Not generally recommended Combined (maximal) Androgen Blockade (CAB): Permanent combination of ADT and an earlier generation of AR antagonist (e.g. bicalutamide or flutamide) Not generally recommended Hussain M et al, N Engl J Med 2013 Caubet JF et al, Urology 1997 Prostate Cancer Trialists Collaborative Group Lancet 2000 Samson DJ et al, Cancer 2002

9 ADT: Side Effects Decreased libido and erectile dysfunction Hot flushes Fatigue Anemia Osteoporosis/fractures Obesity Sarcopenia Lipid alterations Insulin resistance

10 ADT: Association with other problems Cardiovascular Disease Diabetes Thromboembolism Colorectal Cancer Depression Dementia Renal failure

Outcome of men with newly diagnosed M1 prostate cancer under ADT 917 patients with de novo M1 PCa (2005-2014)

11 Outcome of men with newly diagnosed M1 prostate cancer under ADT 917 patients with de novo M1 PCa ( ) treated by ADT alone (STAMPEDE randomized trial control arm) Median OS from diagnosis: 42 mo James ND et al, Eur Urol 2015

ADT plus Chemotherapy vs ADT alone Castrationsensitive/naïve men (mostly M1) Randomised GETUG-15 n=385 Accrual: 2004-2008 CHAARTED n=790 Accrual: 2006-2012 STAMPEDE n= 2962

12 ADT plus Chemotherapy vs ADT alone Castrationsensitive/naïve men (mostly M1) Randomised GETUG-15 n=385 Accrual: CHAARTED n=790 Accrual: STAMPEDE n= 2962 Accrual: ADT ADT + Docetaxel 75mg/m2 Every 21d x 6/9 Zyklen Gravis G et al. Lancet Oncol, 2013; Sweeney C et al. New Engl J Med, 2015; James N et al. Lancet, 2015

13 Addition of Docetaxel on OS in CHAARTED Mo HR 0.61 Sweeney C et al. N Engl J Med 2015

14 Effect of addition of Docetaxel to ADT: Meta-Analysis Docetaxel combined with androgen deprivation therapy should be considered a new standard of care for men with metastatic disease starting on long-term androgen deprivation therapy for the first time who are fit to receive chemotherapy and willing to accept the risks. Vale C et al. Lancet Oncol 2015

15 Heavily discussed² 1. Parker C et al. Ann Oncol 2015;26(Suppl 5):v69-v77; 2. Tannock IF, Sternberg CN. Ann Oncol 2016;27:545-6

16 EAU-ESTRO-SIOG guidelines Mottet N et al. EAU guidelines on prostate cancer NCCN guidelines

17 Future: Ongoing randomized mcspc trials Control Arm Experimental Arm Acronyms Sponsor ADT + NSAA (+/- Doc) ADT + Enza (+/- Doc) EnzaMet ARCHES ANZUP Astellas ADT (No Doc) Control + TAK700 SWOG ADT (PEACE-1: strat by docetaxel use, amended) ADT (strat by doc in last few) ADT + (+/- Doc) ADT + Doce ADT (strat by Doc) Control + Abiraterone PEACE1 Latitude STAMPEDE Arm G ADT + Abi + Enza STAMPEDE Arm J MRC ADT + Apalutamide (+/-Doc) ADT + Darolutamide +Doc TITAN ARASENS Unicancer/EORTC Janssen MRC Janssen Bayer ADT + Metformin STAMPEDE Arm K MRC ADT+Doc ADT+Doc+Radium Proposals only MRC Alliance

18 Future: Ongoing randomized de novo mcspc trials: role of local therapy Control Arm Experimental Arm Acronyms Sponsor ADT ADT +/- abi (strat docet) ADT + Prostate rads ADT + Prostate rad +/- abi (strat docet) STAMPEDE Arm H PEACE 1 MRC Unicancer Best systemic therapy BST + RP or RT MDACC (Fox Chase/UCSF) ADT ADT + Prostate Rads HORRAD Netherlands Best systemic Rx BST+ local Rx (some limited to oligomets only) TROMBONE RAMPP UK German GETUG (planned) SWOG (planned) EORTC (planned)

19 STAMPEDE Trial MAMS design Practise changing! Expected soon! +?

STAMPEDE Addition of Zoledronic acid: Skeletal events (Newly-diagnosed w/bone metastases) HR=0.94 SOC (95% CI: 0.76-1.

20 STAMPEDE Addition of Zoledronic acid: Skeletal events (Newly-diagnosed w/bone metastases) HR=0.94 SOC (95% CI: ) P=0.564 SOC + ZA No Excluding ONJ SOC 0 reports SOC + ZA 2 reports No effect on survival James ND et al, Lancet 2016

21 Smith M, et al. J Clin Oncol 2014

22 Take home messages ADT mainstay in metastatic castration sensitive prostate cancer: Efficient, but be aware of the side effects Addition of docetaxel has overall survival benefit (in some men) Bisphosphonates (in dose/schedule to reduce incidence of SRE/SSEs) have no survival improvement and no reduction of SRE/SSEs in metastatic castration sensitive disease Castration-naive metastatic prostate cancer is a rapidly evolving field: Stay tuned!

23 Thank you very much for your attention!

Chemohormonal Therapy For Prostate Cancer. What is old, is new again!

Chemohormonal Therapy For Prostate Cancer What is old, is new again! Mount Tremblant January 20, 2017 Kala S. Sridhar MD, MSc, FRCPC Medical Oncologist, Princess Margaret Hospital Head, GU Medical Oncology