Advanced Prostate Cancer SAMO Masterclass 4 th March 2016 Aurelius Omlin
Conflicts of interest Advisory Rolle: Astra Zeneca, Astellas, Bayer, Janssen, Pfizer, Sanofi Aventis Research support: TEVA, Janssen Travel support: Astellas, Bayer, Sanofi Aventis
Overview Castration-naive Prostate Cancer (CNPC) Castration-resistant Prostate Cancer (CRPC) Osteoprotective Therapy Staging and Treatment Monitoring
Advanced Prostate Cancer: M1 CNPC Localised Prostate Cancer Castration-naive prostate cancer (CNPC) Castration-resistant prostate cancer (CRPC) ADT M0 M0 CRPC Local Therapy (RT or OP) Salvage RT PSA rise M1 ADT M1 CRPC De Novo M1 ADT: Androgen deprivation therapy M0: No metastases on imaging M1: Metastases documented on imaging
Androgen Deprivation Therapy (ADT) GnRH Agonist Goserelin Leuprorelin GnRH Antagonist Degarelix 10% 90% Orchiectomy
Trials: GETUG 15, CHAARTED, STAMPEDE Men with castration-naïve prostate cancer (mostly metastatic) R A N D O M I Z E ADT ADT + Docetaxel 75mg/m2 Every 21 d x 6/9 cycles GETUG-15 n=385 Accrual: 2004-2008 CHAARTED n=790 Accrual: 2006-2012 STAMPEDE n= 2962 Accrual: 2005-2013 Gravis Lancet Oncol 2013 Sweeney NEJM 2015 James Lancet 2015
Results: GETUG-15, CHAARTED, STAMPEDE GETUG-15 N=385 CHAARTED N=790 STAMPEDE N=1776 ADT ADT+Doc ADT ADT+Doc ADT ADT+Doc Median overall survival (m) 48.6m 62.1m* 44m 57.6m 71m 81m**** High-Volume*** 35.1m 39.8m** 32.2m 49.2m Only M1 pts ***** 45m 60m * Statististically not significant: HR 0.88 (95% CI, 0.68-1.14) ** Statististically not significant: HR 0.78 (95% CI, 0.56-1.09) *** High-volume: 4 Bone metastases and 1 extraaxial or visceral metastases **** Entire patient population: M0 and M1 pts ***** Only M1 pts ADT vs ADT + D (n= 1776) Gravis Lancet Oncol 2013 Gravis Eur Urol 2015 Sweeney NEJM 2015 James Lancet 2015
Effect of the addition of docetaxel on survival in men with M1 disease - Metaanalysis 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 fi t to receive chemotherapy and willing to accept these risks. Vale Lanc Onc 2015
Outlook Other STAMPDE Arms
Overview Castration-naive Prostate Cancer (CNPC) Castration-resistant Prostate Cancer (CRPC) Osteoprotective Therapy Staging and Treatment Monitoring
Castration-Resistant Prostate Cancer (CRPC) PSA Testosteron Death ADT Diagnosis? Time Definitions Androgen deprivation therapy (ADT): GnRH or orchiectomy Castration-resistance (= CRPC): Confirmed PSA rise on ADT in the presence of suppressed testosterone
Advanced Prostate Cancer: M0 CRPC Localised Prostate Cancer Castration-naive prostate cancer (CNPC) Castration-resistant prostate cancer (CRPC) ADT M0 M0 CRPC Local Therapy (RT or OP) Salvage RT PSA rise M1 ADT M1 CRPC De Novo M1 ADT: Androgen deprivation therapy M0: No metastases on imaging M1: Metastases documented on imaging
M0 CRPC: NO Standard therapy Currently open phase III Studies: M0 CRPC SPARTAN ARN-509 vs Placebo, (n=1200) PROSPER Enzalutamide vs Placebo (n=1560) ARAMIS ODM-201 vs Placebo (n=1500) Primary endpoint: Metastasisfree survival l Secondary endpoint: Overall survival Slide: adapted from S. Gillessen
Advanced Prostate Cancer: M1 CRPC Localised Prostate Cancer Castration-naive prostate cancer (CNPC) Castration-resistant prostate cancer (CRPC) ADT M0 M0 CRPC Local Therapy (RT or OP) Salvage RT PSA rise M1 ADT M1 CRPC De Novo M1 ADT: Androgen deprivation therapy M0: No metastases on imaging M1: Metastases documented on imaging
CRPC treatment options until 2010 Docetaxel + P* vs Mitoxantrone + P NEJM 2004 19.2 vs 16.3m CRPC **Zoledronat vs Placebo JNCI 2004; 16 vs 10.5m Slide: adapted from S. Gillessen * Prednisone ** Time to first skeletal related event
CRPC Approved Treatments Switzerland 2016 Docetaxel + P* vs. Mitoxantrone + P NEJM 2004 **19.2 vs 16.3m Cabazitaxel + P* vs Mitoxantrone + P LANCET 2010 **15.1 vs 12.7 CRPC Enzalutamid vs Placebo NEJM 2014 **32.4 vs 30.2 Abiraterone + P* vs Placebo + P NEJM 2013 **34.7 vs 30.3 Radium-223 vs Best standard of care NEJM 2013 **14.9 vs 11.3 Abiraterone + P* vs Placebo + P NEJM 2011 **15.8 vs 11.2 Enzalutamid vs Placebo NEJM 2012 **18.4 vs 13.6 ***Zoledronic acid vs Placebo JNCI 2004; 16 vs 10.5m ***Denosumab vs Zoledronic acid LANCET 2011; 20.7 vs 17.1m Slide: adapted from S. Gillessen *Prednisone **Median overall survival ***Time to first skeletal related event
Abirateron Mechanism of Action I Enzalutamid
Mechanism of Action II Docetaxel Cabazitaxel Radium-223 Weaver Cancer Cell 2005 Taxane treatment Weaver Cancer Cell 2005
CRPC first-line 76 y old patient Rising PSA on ADT Testosterone (<0.35nmol/l) Bone scintigraphy : Multiple bone metastases PSA 85 41 15 22 01.01.20 01.02.20 01.03.20 01.04.20 01.05.20 01.06.20 01.07.20 Which first-line therapy do you recommend? - Clinic - Medical history, histology, duration of response to ADT - CT for evaluation of soft-tissue disease
CRPC first-line: Prospektive Phase III Asymptomatic/minimal symptomatic, no visceral metastases COU-302: Abiraterone + Prednisone (mos 34.7 vs 30.3, HR 0.81) Asymptomatic/minimal symptomatic PREVAIL: Enzalutamid (mos 32.4 vs 30.2, HR 0.71) Symptomatic or asymptomatic TAX327: Docetaxel plus Prednisone (mos 19.2 vs 16.3; HR 0.76) Symptomatic, bone metastases, not fit for chemo or chemo not indicated ALSYMPCA: Radium-223 (mos 16.1 vs 11.5; HR 0.74, subgroup 43%, chemonaive) Ryan NEJM 2012 Beer NEJM 2014 Tannock NEJM 2004 Parker NEJM 2014
How to choose a first-line treatment? Fit for chemotherapy? Yes No Visceral metastases Yes No Visceral metastases Yes No Docetaxel Abiraterone? Enzalutamid Yes Symptomatic No BSC? Steroid? AR Antagonist? Enzalutamid Abiraterone Yes Symptomatic No Docetaxel Radium-223? Yes Time to CRPC <12m No Radium-223 Abiraterone Enzalutamid BSC? Steroid? AR Antagonist? Docetaxel Abiraterone Enzalutamid Abiraterone Enzalutamid CH: not approved in case of visceral metastases
CRPC second-line: Prospektive Phase III Docetaxel Abiraterone + Prednison (COU-301) Abiraterone + Prednison (mos 15.8 vs 11.2; HR 0.74) Enzalutamid (AFFIRM) Enzalutamide (mos 18.4 vs 13.6; HR 0.63) Cabazitaxel + Prednison (TROPIC) Cabazitaxel plus Prednison (mos 15.1 vs 12.7; HR 0.7) Radium-223 (subgroup, ALSYMPCA) Radium-223 (mos 14.4 vs 11.3; HR 0.71, subgroup 57% pts) De Bono NEJM 2011 Scher NEJM 2012 De Bono Lancet 2010 Parker NEJM 2014
CRPC third-line: NO prospektive Phase III Enzalutamide after Abiraterone und Docetaxel N mos PFS 50% PSA decline First-line (PREVAIL) 1717 32.4 NR 78% Second-line (AFFIRM) 1199 18.4 8.3 54% Third-line (10 pooled case series) 536 8.3 3.1 22.9% Cabazitaxel after Docetaxel and Abiraterone or Enzalutamid N mos PFS 50% PSA Abfall Second-line (TROPIC) 755 15.1 2.8 39.2% Third-line case series 1 59 case series 2 79 15.8 10.9 4.6 4.4 39% 35% Scher et al NEJM 2012 Beer et al NEJM 2014 Petrelli Clin Gen Cancer 2014 De Bono Lancet 2010 Pezaro Eur Urol 2014 Al Nakouzi Eur Urol 2014 PSA Waterfall Plot
Overview Castration-naive Prostate Cancer Castration-resistant Prostate Cancer Osteoprotective Therapy Staging and Treatment Monitoring
Prevention of the risk of Skelettal Complications Gartrell Nat Rev Clin Onc 2014
Effect of approved drugs on SRE/SSE in CRPC Drug SRE/SSE HR (95% CI) Zoledronic acid vs Placebo 16 vs 10.6m 0.64 (0.49-0.85) Denosumab vs Zoledronic acid SRE: 20.7 vs 17.1m SSE: NR vs 24.2m 0.82 (0.71 0.95) Abiraterone + P vs Prednisone Post-chemo: 25 vs 20.3m 0.62 (0.48 0.79) Pre-chemo: NA Enzalutamide vs Placebo Post-chemo: 16.7 vs 13.3m 0.69, P = 0.0001 NA Pre-chemo, Pat without SRE after 12 Months: 84% vs 73% Radium-223 vs Best standard of care SSE: 15.6 vs 9.8m SSE Pat on Zoledronate: 19.6 vs 10.2m Docetaxel/Cabazitaxel and NA 0.72 (0.61-0.84) 0.66 (0.52 0.83) 0 49 (0 33 0 74) SRE = Skeletal related event SSE = Symptomatic skeletal event Saad JNCI 2002 Fizazi Lancet 2011 De Bono NEJM 2011 Scher NEJM 2012 Beer NEJM 2014 Parker NEJM 2014
Osteoprotective Therapy 2016 Situation Castration-naive prostate cancer, bone metastases and ADT CRPC, no bone metastases CRPC and bone metastases Recommendation Ca and Vitamin D substitution For osteoporosis or increased risk of fractures: Bisphosphonate: for osteoporosis (e.g. Zoledronic acid 5mg/year) Denosumab (60mg, 6-monthly) Ca and Vitamin D substitution For osteoporosis or increased risk of fractures: Bisphosphonate: for osteoporosis (e.g. Zoledronic acid 5mg/year) Denosumab (60mg, 6-monthly) Calcium and Vitamin D substitution Consider if no contra-indications: Dental check before starting bone targeting agents Denosumab (120mg, 4 w) Zoledronic acid (4mg, 4 w), cave: creatinine clearance! SAKK 96/12 Trial Saylor European Urology 2012
Overview Castration-naive Prostate Cancer Castration-resistant Prostate Cancer Osteoprotective Therapy Staging and Treatment Monitoring
Staging and Treatment Monitoring Assessment of disease status o Bone only vs visceral disease o «oligometastatic» vs extensive metastatic disease Monitoring of antitumour activity o Dynamics of disease evolution o CRPC drugs are expensive! Prevention of complications o E.g. epidural disease and spinal cord compression o Development of visceral metastases o Urinary retention o
Staging and Treatment Monitoring on Clinical Trials In daily clinical practice: Staging: Before starting a new therapy: always! Monitoring: Risk adapted (see APCCC recommendations Annals 2015) Scher JCO 2008
Summary Advanced Prostate Cancer 2016 M1 castrationnaive ADT CNPC +/- Docetaxel PSA rise on ADT, M0 Clinical Trials Asymptomatic Abiraterone (NO visceral metastases) Enzalutamid Docetaxel First-line CRPC Symptomatic Docetaxel Radium-223 (bone metastases, no visceral or bulky lymph node metastases, unfit for chemotherapy or chemotherapy not indicated) 2 nd -line after Docetaxel Cabazitaxel Abiraterone Enzalutamid Radium-223 Third-line Options for patients in good PS: Cabazitaxel Abiraterone Enzalutamid Radium-223 Docetaxel Re- Challenge Clinical Trials!
Advanced Prostate Cancer Consensus Conference (APCCC) APCCC 9-11 March 2017 www.apccc.org Thank you for our attention! aurelius.omlin@kssg.ch