Advanced Prostate Cancer Consensus Conference (APCCC) 2017 in St. Gallen : Defining best Practice in Routine Care

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1 Advanced Prostate Cancer Consensus Conference (APCCC) 2017 in St. Gallen : Defining best Practice in Routine Care Silke Gillessen 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 Why a Consensus Conference? Several topics in prostate cancer with: No evidence Sparse or low-level evidence Conflicting evidence In St.Gallen long tradition for Consensus Conferences NOT Guidelines Recommendations from experts for areas with no or only sparse evidence or conflicting evidence or different interpretation of evidence.

Knowledge translation*: Umbrella term for all of the activities involved in moving research from

4 Knowledge Translation The majority of men with prostate cancer around the globe are not treated in expert centers! Knowledge translation*: Umbrella term for all of the activities involved in moving research from the laboratory, research journals, academic conferences and experts into hands of less experienced people and organizations. Expert centre Community practice *after Wikipedia

5 The first Meeting: APCCC 2015

6 How a consensus process works (modified Delphi process) : Part I Gillessen S, Omlin A et al Ann Oncol 2015

7 How a consensus process works (modified Delphi process) : Part II Gillessen S, Omlin A et al Ann Oncol 2015

8 Editors Choice 2015 Cited > 100x Downloads >15 000x

9 Take home messages from APCCC 2015 DO Measure testosterone before calling someone castration resistant Baseline staging and monitoring examinations including imaging in men with CRPC: PSA alone is insufficient Inform your patients about the possibility to join a clinical trial!

10 Take home messages from APCCC 2015 DO NOT Treat a man with castration-naive metastatic prostate cancer with bisphosphonates or densosumab in the dose for reduction of SREs Treat a man with CRPC and M0 disease with one of the survival prolonging agents outside of a clinical trial Routinely add bicalutamide in a man progressing on ADT if abiraterone or enzalutamide are available Stop a treatment with a life prolonging agent in a man with CRPC based on PSA-rise only

11 Questions without consensus at APCCC may be important topics for clinical research Oligometastatic disease: Diagnosis and Therapy Osteoclast-targeted therapies: Dose, scheduleand duration Novel imaging: How to implement for guiding treatment decisions and for having an impact on outcome

12 10 Areas of controversy for APCCC Management of castration-sensitive/naive prostate cancer 2. Management of castration-resistant prostate cancer (CRPC): sequencing/combination treatment for mcrpc 3. Use ofnovelimagingmodalities 4. Molecular characterization: Tissue and blood based biomarkers in daily clinical practice 5. Germline/somatic mutations 6. Management of high risk and locally advanced prostate cancer 7. Oligometastatic and oligo-progressive prostate cancer 8. Side effects of systemic treatment: Prevention and management 9. Palliative andsupportive/preventive care 10. Global access to prostate cancer drugs and treatment in countries with limited resources

13 N. Clarke UK G.Attard J. De Bono UK UK N.James K. Mastris UK R. Eeles A. Padhani UK UK P.L. KellokumpuLehtinen B. Tombal BE BE H. Beltran US C. Parker UK C. Drake US E. Efstathiou S. Halabi A. Morgans US US US C.Logothetis B. Carver US US F. Feng US W. Oh US M. Rubin US O. Sartor US N. Shore US US H. Scher FL US A. Heidenreich DE S Gillessen CH M. Morris US C. Pritchard US C. Higano T. Wiegel F. Saad DE M. Smith C. Sweeney US US C. Ryan US CA R. Bristow CA G.Daugaard M. Roach US DK H. Soule US G. Kramer AT D. Castellano ES P. Kantoff US T. Beer US M. Sydes UK P. Ost C. Evans US UK A. Sella IL I.Tannock CA M. Gleave H. Suzuki CA JP S. Fanti IT R. Dos Reis K Fizazi C. Sternberg FR IT V. Murthy IN R. Khauli LB R. Valdagni A.Bossi N. Mottet IT Fr FR B H Chung KR M Frydenberg urologist medical oncologist radiation oncologist others AU Panel APCCC17 BR F. Maluf BR I. Davis AU Inspired by Eleni Efstathiou

14 10 Areas of controversy for APCCC Management of castration-sensitive/naive prostate cancer 2. Management of castration-resistant prostate cancer (CRPC): sequencing/combination treatment for mcrpc 3. Use ofnovelimagingmodalities 4. Molecular characterization: Tissue and blood based biomarkers in daily clinical practice 5. Germline/somatic mutations 6. Management of high risk and locally advanced prostate cancer 7. Oligometastatic and oligo-progressive prostate cancer 8. Side effects of systemic treatment: Prevention and management 9. Palliative and supportive/preventive care 10. Global access to prostate cancer drugs and treatment in countries with limited resources

Management of high-risk and locally-advanced M0 prostate cancer www.apccc.

15 Management of high-risk and locally-advanced M0 prostate cancer Do you recommend lymph node dissection in men with cn0 cm0 high-risk prostate cancer undergoing prostatectomy? 1 - Yes, in the majority of patients 5 % 2 % 2 - In a minority of selected patients 9 % 3 - No 4 - Abstain 5 - Unqualified to answer 84 % Option 1 Option 2 Option 3 Option 4 0 Published open access in European Urology.

Adjuvant radiation therapy for localised prostate cancer www.apccc.

undetectable postoperative PSA and who have recovered urinary continence, do you recommend

patients 4 % 2 - Only if multifocal or extensive margins 3 - No 21 % 48 % Option 1 Option 2 Option

16 Adjuvant radiation therapy for localised prostate cancer In men post-prostatectomy without lymph node involvement on surgical pathology (pn0), with undetectable postoperative PSA and who have recovered urinary continence, do you recommend adjuvant radiation therapy in in case of: Positive surgical margins 1 - Yes, in the majority of patients 4 % 2 - Only if multifocal or extensive margins 3 - No 21 % 48 % Option 1 Option 2 Option Abstain 27 % Option Unqualified to answer 0 Published open access in European Urology.

17 Adjuvant radiation therapy for localised prostate cancer If you recommend adjuvant radiation therapy in men with high-risk pn0 disease postprostatectomy, what field of radiation therapy do you recommend in the majority of men? 1 - Prostatic bed only 2 - Prostatic bed plus whole pelvis 8 % 3 - I do not recommend adjuvant radiation therapy 4 - Abstain 5 - Unqualified to answer 51 % 41 % Option 1 Option 2 Option 3 Option 4 0 Published open access in European Urology.

Adjuvant radiation therapy for localised prostate cancer www.apccc.org If you recommend adjuvant radiation therapy in men with high-risk pn0 disease postprostatectomy, do you recommend adding ADT?

18 Adjuvant radiation therapy for localised prostate cancer If you recommend adjuvant radiation therapy in men with high-risk pn0 disease postprostatectomy, do you recommend adding ADT? 1 - Yes, in the majority of patients 2 - In a minority of selected patients 3 - No 4 - Abstain (I do not recommend adjuvant radiation therapy) 32 % 36 % Option 1 Option 2 Option 3 32 % 5 - Unqualified to answer 0 Published open access in European Urology.

19 Adjuvant radiation therapy for localised prostate cancer If you recommend adjuvant radiation therapy in men with pn1 disease (adequate sampling) post-prostatectomy, what field of radiation therapy do you recommend in the majority of men? 1 - Prostatic bed only 2 - Prostatic bed plus whole pelvis 3 % 3 - Other field definition 4 - Abstain (including I do not recommend adjuvant radiation therapy) 5 - Unqualified to answer 97 % Option 1 Option 2 Option 3 0 Published open access in European Urology.

20 Summary Management of high risk and locally advanced prostate cancer Consensus for lymphnode dissection including regions to sample and pathology reporting No consensus for the role of adjuvant versus early salvage radiotherapy Phase 3 trials running

21 10 Areas of controversy for APCCC Management of castration-sensitive/naive prostate cancer 2. Management of castration-resistant prostate cancer (CRPC): sequencing/combination treatment for mcrpc 3. Use ofnovelimagingmodalities 4. Molecular characterization: Tissue and blood based biomarkers in daily clinical practice 5. Germline/somatic mutations 6. Management of high risk and locally advanced prostate cancer 7. Oligometastatic and oligo-progressive prostate cancer 8. Side effects of systemic treatment: Prevention and management 9. Palliative and supportive/preventive care 10. Global access to prostate cancer drugs and treatment in countries with limited resources

22 Management of castration-sensitive/naïve prostate cancer: ADT +/- Docetaxel GETUG-15 N=385 ECOG-ACRIN Group CHAARTED N=790 STAMPEDE N=1776 ADT ADT+Doc ADT ADT+Doc ADT ADT+Doc Median overall survival (mos) in M1 48.6m 62.1m* 44m 57.6m 45m 60m mos in High Volume*** 35.1m 39.8m** 32.2m**** 49.2m NA NA mos in M0 + M1 pts NA NA NA NA 71m 81m * Statististically not significant: HR 0.88 (95% CI, ) ** GETUG-15: 47% high-volume, statististically not significant: HR 0.78 (95% CI, ) *** High-volume: Visceral metastases and/or 4 bone lesions with 1 beyond the vertebral bodies and pelvis **** In CHAARTED: 64% high-volume Gravis Lancet Oncol 2013 Gravis Eur Urol 2016 Sweeney NEJM 2015 James Lancet 2015

23 ADT + Docetaxel Metaanalysis M1 pts M0 pts Vale Lanc Onc 2015

24 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

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

For men who are suitable for chemotherapy: Do you recommend Docetaxel in addition to ADT in men with de novo metastatic castration-sensitive/naive prostate cancer and high volume disease as defined

26 For men who are suitable for chemotherapy: Do you recommend Docetaxel in addition to ADT in men with de novo metastatic castration-sensitive/naive prostate cancer and high volume disease as defined by CHAARTED (visceral metastases and/or 4 bone lesions with 1 beyond vertebral bodies and pelvis)? 1 - Yes, in the majority of patients 4 % 2 - In a minority of selected patients 3 - No 4 - Abstain 96 % Option 1 Option 2 Option 3 Option Unqualified to answer 0 Published open access in European Urology.

disease as per CHAARTED (no visceral metastases and <4 bone lesions and only confined to axial skeleton)?

27 Do you recommend Docetaxel in addition to ADT in men with de novo metastatic castration-sensitive/naive and low-volume disease as per CHAARTED (no visceral metastases and <4 bone lesions and only confined to axial skeleton)? 1 - Yes, in the majority of patients 6 % 2 - In a minority of selected patients 3 - No 4 - Abstain 65 % 29 % Option 1 Option 2 Option 3 Option Unqualified to answer 0 Published open access in European Urology.

28 Eligibility for Docetaxel Published open access in European Urology.

29 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) Control + Abiraterone PEACE1 Latitude STAMPEDE Arm G Unicancer/EORTC Janssen MRC ADT (strat by doc in last few) ADT + (+/- Doc) ADT + Doce ADT (strat by Doc) ADT + Abi + Enza STAMPEDE Arm J MRC ADT + Apalutamide (+/-Doc) ADT + Darolutamide +Doc TITAN ARASENS Janssen Bayer ADT + Metformin STAMPEDE Arm K MRC ADT+Doc ADT+Doc+Radium Proposals only MRC Alliance

30 Addition of Abiraterone to ADT in CSPC Trials New questions for APCCC 2019 A, ADT group; AA, abiraterone acetate; G, combination group; P, prednisone; SOC, standard of care.

31 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)

prostate cancer, who are not symptomatic from the primary, do you recommend

1 - Yes, in the majority of patients 10 % 2 - In a minority of selected patients

32 In men with de novo metastatic castration-sensitive/naive high-volume prostate cancer, who are not symptomatic from the primary, do you recommend treatment of the primary tumour in addition to systemic therapy? 1 - Yes, in the majority of patients 10 % 2 - In a minority of selected patients Option No Option Abstain 52 % 38 % Option 3 Option Unqualified to answer 0 Published open access in European Urology.

33 10 Areas of controversy for APCCC Management of castration-sensitive/naive prostate cancer 2. Management of castration-resistant prostate cancer (CRPC): sequencing/combination treatment for mcrpc 3. Use ofnovelimagingmodalities 4. Molecular characterization: Tissue and blood based biomarkers in daily clinical practice 5. Germline/somatic mutations 6. Management of high risk and locally advanced prostate cancer 7. Oligometastatic and oligo-progressive prostate cancer 8. Side effects of systemic treatment: Prevention and management 9. Palliative and supportive/preventive care 10. Global access to prostate cancer drugs and treatment in countries with limited resources

De novo oligometastatic disease (no prior prostate treatment) www.apccc.

without ADT or Docetaxel 3 - Radical local treatment of all lesions including the primary (surgery or RT) + ADT

+/- Docetaxel 8 % 6 % Option 1 5 - Radical local treatment of all lesions including the primary (surgery or RT) +

34 De novo oligometastatic disease (no prior prostate treatment) Which treatment do you recommend in men with newly-diagnosed oligometastatic prostate cancer with an untreated primary? Lifelong ADT +/- Docetaxel 2 - Radical local treatment of all lesions including the primary (surgery or RT) without ADT or Docetaxel 3 - Radical local treatment of all lesions including the primary (surgery or RT) + ADT 6-12m +/- Docetaxel 4 - Radical local treatment of all lesions including the primary (surgery or RT) + ADT 24-36m +/- Docetaxel 8 % 6 % Option Radical local treatment of all lesions including the primary (surgery or RT) + lifelong ADT +/- Docetaxel Option 2 25 % 6 - Abstain Option Unqualified to answer 31 % Option 4 69% for an option including radical localtreatment 22 % 8 % Option 5 Option 6 Published open access in European Urology.

35 Some «philosophical» thoughts about defining best practice

36 Some areas of Non-Consensus in APCCC are good areas for research! «Oligometastatic» disease In CNPC: Addition of docetaxel to ADT in low-volume disease Adjuvant versus early salvage RT Best use of next generation imaging Clinical trials!

37 Thank you! All the panellists, helpers and sponsors Special thanks to Aurelius Omlin

38 EORTC GUCG trials, opportunities for collaboration Silke Gillessen, MD Chair of the EORTC GUCG

European Organization for Research and Treatment of Cancer

1962 Main mission: promote and conduct research to improve

International Multidisciplinary Develop new treatments Define

39 European Organization for Research and Treatment of Cancer (EORTC) Private and not for profit organization created in 1962 Main mission: promote and conduct research to improve cancer care Core activity: conduct clinical trials International Multidisciplinary Develop new treatments Define new standards of care Large academic trials Henri Tagnon, Co-founder of EORTC

40 Clinical research is not a luxury but essential to Define state-of-the-art treatment Promote innovative research and rapid access to new agents Translate laboratory discoveries into practice Identify ineffective and/or redundant treatments Guarantee best medical practice Less than 5% of cancer patients benefit from clinical trials

41 EORTC by the numbers (2016) A world-class network An expert HQ Unique output ± 5,000 collaborators 870 institutions 35 countries 21 groups & task-forces 198 employees > 195,000 patients in database 24,000 patients in follow-up 12 new studies open to patient entry in ongoing studies 19 studies in protocol outline development 111 collaborative groups 15 studies in protocol development 15 studies in regulatory activation Working on 193 studies

42 EORTC 1545-ENZARAD Randomised phase 3 trial of enzalutamide in androgen deprivation therapy with radiation therapy for high risk, clinically localised, prostate cancer EORTC Study Coordinator: Valérie Fonteyne (Universitair Ziekenhuis Gent, BE)

43 EORTC 1407-TIGER A Randomized Phase III Trial of TIP vs. TI-CE as Initial Salvage Chemotherapy for Patients with GCT PI: Darren Feldman, MD Statistician: Susan Halabi, PhD Alliance GU Chair: Michael Morris, MD ECOG PI: David Vaughn, MD SWOG PI: David Quinn, MD COG PI: Lindsay Frasier, MD EORTC PI: Thomas Powles, MD Endorsed by SWOG, ECOG, COG, EORTC, ANZUP

44 Current Status In total 44 sites are open EORTC: 7 sites open Belgium (1) the Netherlands (1) Italy (2) Ireland (1) Spain (1) France (1) 55/420 patients have been recruited in total, 5/192 in Europe

45 EORTC 1201 A PROSPECTIVE RANDOMISED PHASE III STUDY OF ANDROGEN DEPRIVATION THERAPY (+/- DOCETAXEL) WITH OR WITHOUT LOCAL RADIOTHERAPY WITH OR WITHOUT ABIRATERONE ACETATE AND PREDNISONE IN PATIENTS WITH METASTATIC HORMONE-NAÏVE PROSTATE CANCER (PEACE 1) Study Sponsor: Unicancer EORTC Groups: GUCG and ROG Full protocol approved: 17/07/2014 Study coordinator: Karim Fizazi (Villejuif, FR) EORTC GUCG Study coordinator: Dominik Berthold (Lausanne, CH) EORTC ROG Study Coordinatory: Alberto Bossi (Villejuif, FR)

46 EORTC 1414-ROG-GUCG Phase IIIb randomized trial comparing irradiation plus long term adjuvant androgen deprivation with GnRH antagonist versus GnRH agonist plus flare protection in patients with very high risk localized or locally advanced prostate cancer. A joint study of the EORTC ROG and GUCG - Pegasus Study Coordinators: Pr. Pedro Lara (Las Palmas) for EORTC ROG Pr. Dirk Boehmer (Berlin) for EORTC ROG Pr. Bertrand Tombal (Brussels) for EORTC GUCG Study Supported by Ferring Pharmaceuticals

47 EORTC GUCG Study 1333 (PEACE III): A Randomized multicenter phase III trial comparing enzalutamide vs. a combination of Ra223 and enzalutamide in asymptomatic or mildly symptomatic castration resistant prostate cancer patients metastatic to bone. SC: Pr. Tombal Bertrand, Cliniques Universitaires Saint-Luc, Belgium SC: Pr. Gillessen Silke, Kantonsspital St Gallen, Switzerland

48 Accrual 82/560 patients registered (as of 16/08/2017)

49 Site activation (as of 16/08/2017) Country Total sites # open sites # sites recruiting Belgium (BE) Denmark (DK) France (FR) 14 0 NA Ireland (IE) 4 0 NA Italy (IT) Poland (PO) Spain (ES) Switzerland (CH) The United Kingdom (GB) Additional sites are currently being added in BE (2), ES (5), CH (1), PO (2) Collaboration with the US and Canada is being set up with intergroup partners (ACCRU and CUOG).

50 EORTC GUCG Study 1532 (ODM-201): A phase 2 Randomized Open-Label Study of Oral ODM-201 vs. androgen deprivation therapy (ADT) with LHRH agonists or antagonist in Men with Hormone Naive Prostate Cancer SC: Pr. Tombal Bertrand, Cliniques Universitaires Saint-Luc, Belgium

51 The End

Initial hormone therapy (and more) for metastatic prostate cancer

Initial hormone therapy (and more) for metastatic prostate cancer Silke Gillessen, MD Medical Oncology Kantonsspital St.Gallen Switzerland silke.gillessen@kssg.ch Conflicts of interest Speakers Bureau