Updates in Prostate Cancer Therapy Sequencing Strategies. Debates and Didactics in Hematology and Oncology. July 26, 2015.

Transcription

1 Updates in Prostate Cancer Therapy Sequencing Strategies Debates and Didactics in Hematology and Oncology July 26, Sea Island, GA Bradley C. Carthon, MD. Ph.D. Assistant Professor, Winship Cancer Institute Emory University, Atlanta, GA

2 None Disclosures

3 Prostate Cancer Disease States CRPC Localized Clinically Localized Disease Rising PSA CRPC Metastases Pre-Chemo CRPC Metastases: Post Chemo Prostatectomy Radiation Salvage Tx HIFU/Cryo HSPC Metastases

4 Lorente et al Jun;16(6):e279-e292 Sequencing Overview of Approved Agents in CRPC

5 Prostate Cancer Disease States CRPC Localized Clinically Localized Disease Rising PSA CRPC Metastases Pre-Chemo CRPC Metastases: Post Chemo Prostatectomy Radiation Salvage Tx HIFU/Cryo HSPC Metastases

6 Androgen Receptor Modulation Phase II, Randomized Study of MK Bicalutamide Combination in Patients With Rising PSA at High-Risk of Progression After Primary Therapy PATIENTS: PSA Recurrence after Primary Therapy N=104 R A N D O M I Z E 1:1 Bicalutamide Bicalutamide + MK2206 End Point: Primary Undetectable PSA Secondary PSA Decline PSA Response Safety Time to Nadir PSA RR ClinicalTrials.gov Identifier: NCT , ECOG-Acrin

7 Enzalutamide vs. Lupron/Enzalutamide vs. Lupron/Placebo (EMBARK) PATIENTS: High-Risk Nonmetastatic Prostate Cancer Progressing After Definitive Therapy N=1860 R A N D O M I Z E 1:1:1 Enzalutamide Lupron/Enzalutamide Lupron/Placebo End Point: Primary Metastasis Free Survival Secondary OS PCSS Time CRPC Time SRE PSA undetect ClinicalTrials.gov Identifier: NCT

8 Prostate Cancer Disease States CRPC Localized Clinically Localized Disease Rising PSA CRPC Metastases Pre-Chemo CRPC Metastases: Post Chemo HSPC Metastases

9 E3805 CHAARTED Treatment Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

10 Primary endpoint: Overall survival Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

11 OS by extent of metastatic disease at start of ADT Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

12 Slide 63 Presented By Nicholas James at 2015 ASCO Annual Meeting

13 Docetaxel: Survival M1 Patients Presented By Nicholas James at 2015 ASCO Annual Meeting

14 GETUG-AFU 15 TRIAL DESIGN Presented By Gwenaelle Gravis at 2015 Genitourinary Cancers Symposium

15 Slide 13 Presented By Gwenaelle Gravis at 2015 Genitourinary Cancers Symposium

16 Slide 14 Presented By Gwenaelle Gravis at 2015 Genitourinary Cancers Symposium

17 Chemotherapy in Hormone Sensitive Disease Benefit shown now in 2 randomized studies 3 rd study shows a PFS trend in smaller sample size Likely greater benefit in M1 or higher volume disease Practice changing with ADT+ upfront taxane Therapy thereafter varies, will require analyses

18 Mechanisms of Castration Resistance

19 Prostate Cancer Disease States CRPC Localized Clinically Localized Disease Rising PSA CRPC Metastases Pre-Chemo CRPC Metastases: Post Chemo HSPC Metastases

20 Carthon B., Rossi P. Probl Cancer Jan-Feb;39(1):52-62

21 177Lu Radiolabeled Monoclonal Antibody HuJ591 (177Lu-J591) and Ketoconazole in Patients With Prostate Cancer PATIENTS: High-Risk Localized CRPC with Increasing PSA No Mets. N=140 R A N D O M I Z E 2:1 Ketoconazole + Hydrocortisone + Placebo ( 111 In-J591 ) Ketoconazole + Hydrocortisone Lu-J591 End Point: Primary Progression to Metastases Secondary PSA RR Toxcity PFS MFS OS Imaging ClinicalTrials.gov Identifier: NCT

22 Carthon B., Rossi P. Probl Cancer Jan-Feb;39(1):52-62

23 Carthon B., Rossi P. Probl Cancer Jan-Feb;39(1):52-62

24 Ryan et al, ASCO 2012 [TITLE]

25 (COU-AA-302): Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapynaive men with metastatic CRPC Ryan et al. Lancet Onc 2015 Feb; 16 (2):

26 PREVAIL: A Phase 3 Trial of Enzalutamide After Progression on Androgen Deprivation Therapy in Men with Metastatic Prostate Cancer: <br />TM Beer, AJ Armstrong, CN Sternberg, C Higano, P Iversen, Y Loriot, DE Rathkopf, S Bhattacharya, J Carles, J de Bono, CP Evans, AM Joshua, C Kim, G Kimura, P Mainwaring, H Mansbach, K Miller, SB Noonberg, P Venner, B Tombal. NEJM 2014;371(5):424-33<br /> Presented By Mary-Ellen Taplin at 2015 Genitourinary Cancers Symposium

27 PREVAIL: A Phase 3 Trial Of Enzalutmide Pre-Chemo PFS OS Beer et al. N Engl J Med 2014; 371:

28 Parker, C. et al. ASCO 2012 [TITLE]

29 [TITLE] Parker, C. et al. ASCO 2012

30 Parker, C. et al. N Engl J Med 2013; 369: [TITLE]

31 Carthon B., Rossi P. Probl Cancer Jan-Feb;39(1):52-62

32 Carthon B., Rossi P. Probl Cancer Jan-Feb;39(1):52-62

33 Systemic Therapy Trials in mcrpc Agent Trial Target Population Arms HR Survival (months) Reference Docetaxel TAX 327 N= 1006 mcrpc with or without symptoms Docetaxel/prednisone vs mitoxantrone/prednisone vs 16.5 Tannock, I. et al. N Engl J Med 351: , 2004 Docetaxel SWOG Sipuleucel-T N=674 IMPACT N = 512 mcrpcwith or without symptoms Few symptoms mcrpc Docetaxel /Estramustine vs. Mitoxantrone 17.5 vs Petrylak et al. N Engl J Med 351: , 2004: Sipuleucel T vs Control vs 21.7 Kantoff, P. et al. N Engl J Med 363:411-22, 2010 Cabazitaxel TROPIC N = 755 Post-Docetaxel Cabazitaxel/prednisone vs Mitoxantrone/prednisone vs 12.7 de Bono, J. et al. Lancet 376: , 2010 Abiraterone COU AA-301 N = 1195 Post-Docetaxel Abiraterone/prednisone vs Placebo/prednisone vs 10.9 de Bono, J. et al. N Engl J Med 364: , 2011 Radium 223 ALSYMPCA N = 921 Post-Docetaxel (or unsuitable) Radium-223/BSC* vs placebo/bsc vs 11.3 Parker, C. et al. ASCO J Clin Oncol 30, (suppl; abstr LBA4512), MDV3100 AFFIRM N = 1199 Post-Docetaxel MDV3100 vs Placebo vs 13.6 Scher, H. et al. ASCO J Clin Oncol 30, (suppl 5; abstr LBA1), Abiraterone COU-AA-302 Few Symptoms mcrpc Abiraterone/prednisone vs Placebo/prednisone vs 30.3 Ryan et al. Lancet Onc 2015 Feb; 16 (2):

34 Data on Sequencing of Oral Hormonal Agents Abi --> Enzalutmide Enzalutmide --> Abi Lorente et al Jun;16(6):e279-e292

35 Selected Studies of Combinations and Sequencing A Phase 2 Study Determining Safety and Tolerability of Enzalutamide (Formerly MDV3100) in Combination With Abiraterone Acetate in Bone Metastatic Castration- Resistant Prostate Cancer Patients, NCT , Astellas Pharma Global Development, Inc Phase 3 Study of Enzalutamide With or Without Abiraterone and Prednisone in Treating Patients With Castration-Resistant Metastatic Prostate Cancer, NCT , Alliance for Clinical Trials in Oncology A Randomized Phase IIa Efficacy and Safety Study of Radium-223 Dichloride With Abiraterone Acetate or Enzalutamide in Metastatic Castration-resistant Prostate Cancer (CRPC), NCT , Bayer. A Multi-center, Single Arm Study of Enzalutamide in Patients With Progressive Metastatic Castration-Resistant Prostate Cancer Previously Treated With Abiraterone Acetate (Phase IV), NCT , Astellas Pharma Europe B.V.

36 Ongoing Trials on Sequencing and Combination Lorente et al Jun;16(6):e279-e292

37 A Randomized Phase II Study of Sequencing Abiraterone Acetate and Enzalutamide in Metastatic Castration-Resistant Prostate Cancer PATIENTS: Metastatic CRPC N=118 R A N D O M I Z E 1:1 Enzalutamide CROSSOVER Abiraterone + Prednisone End Point: Primary Combo PSA RR Secondary Individual PSA RR Biomarkers of resistance ClinicalTrials.gov Identifier: NCT , British Columbia Cancer Agency

38 AR Splice Variants Presented By Emmanuel Antonarakis at 2015 Genitourinary Cancers Symposium

39 OS to Enza/Abi (n=62) Presented By Mary-Ellen Taplin at 2015 Genitourinary Cancers Symposium

40 2014:Negative Phase 3 Trials in Prostate Ca Presented By Mary-Ellen Taplin at 2015 Genitourinary Cancers Symposium

41 Summary on Sequencing 2015 Multiple trials support early chemotherapy in hormone sensitive state Trend for earlier use of oral secondary hormonal agents in hormone sensitive and CRPC disease Data supports efficacy of multiple agents pre-chemotherapy in CRPC Sipuleucel - T, Abiraterone/Enzalutamide, Alpharadin Cytotoxic chemotherapy plays a role in symptomatic and visceral disease Multiple agents initially shown to have OS benefit post-chemotherapy Multitude of studies pending on order of these agents Clinical trials offer options and should be utilized when possible

42 Acknowledgements Debates and Didactics Course Organizers Sagar Lonial, MD Fadlo Khuri, MD GU Medical Oncology Working Group Omer Kucuk, MD Wayne Harris, MD Participating Patients and Clinician Researchers