SUMMARY. 3. Emerging understanding of mechanisms of resistance to current treatments

Size: px

Start display at page:

Download "SUMMARY. 3. Emerging understanding of mechanisms of resistance to current treatments"

Thomasina Marsh
5 years ago
Views:

2 SUMMARY 1. Discuss the active agents in prostate cancer currently available in Australia 2. Celebrate the growing role for Prostate Medical Oncologists in Multi Disc Teams active treaments overall survival benefits in advanced cases clinical trials moving active agents into earlier stages of prostate cancer physician care re metabolic, bone health 3. Emerging understanding of mechanisms of resistance to current treatments

1 ST TARGETED THERAPY IN ONCOLOGY - ADT STUDIES ON PROSTATIC CANCER II. THE EFFECTS OF CASTRATION ON ADVANCED CARCINOMA OF THE PROSTATE GLAND CHARLES HUGGINS, M.D.; R. E. STEVENS Jr.

3 1 ST TARGETED THERAPY IN ONCOLOGY - ADT STUDIES ON PROSTATIC CANCER II. THE EFFECTS OF CASTRATION ON ADVANCED CARCINOMA OF THE PROSTATE GLAND CHARLES HUGGINS, M.D.; R. E. STEVENS Jr., M.D.; CLARENCE V. HODGES, M.D. Arch Surg. 1941;43(2): doi: /archsurg Endocrine-induced regression of cancers Nobel Lecture, December 13, 1966

4 EXCITING JOURNEY OVER THE LAST 10 YEARS Little progress from Huggins discovery in 1941 and nobel lecture in 1966 Apart from ADT, no agents that provided a survival advantage until 2004 Pallative treatments Prednisolone - Mitoxantrone - Radioisotopes (strontium)

5 SYSTEMIC THERAPY FOR CRPCA PRE Prednisone for palliation n = 38; 19% improvement in pain Antiandrogen withdrawal response n = 9; 29% had a 50% in PSA Mitoxantrone and Prednisone for palliative Phase III RCT,, n = 161 Primary endpoint = palliative response Tannock et al. J Clin Oncol 1989;7: Scher and W.K. Kelly. J Clin Oncol 1993;11: Tannock et al. J Clin Oncol 1996;14: H.I.

6 DRUGS THAT PROLONG OS FOR CRPC Presented By Mark Stein at 2014 ASCO Annual Meeting

7 ADENOCARCINOMA OF THE PROSTATE Biologically Diverse Cancer Gleeson Pattern, PSA secretion Response to Castration and other Systemic Therapies Metastatic Pattern Individualize Patient Care 7

8 LOCALIZED VERSUS CASTRATE-RESISTANT PROSTATE CANCER Presented By Levi Garraway at 2014 ASCO Annual Meeting

9 PHASES OF PROSTATE CANCER

10 DOCETAXEL TAX 327 study met castrate resistant Tannock et al. N Eng J Med 2004;351: SWOG study met castrate resistant Petrylak et al. N Eng J Med 2004;351: CHAARTed study castrate naïve disease volume Sweeney et al. ASCO plenary 2014 GETUP-AFU15 castrate naïve disease volume Gravis et al. Lancet Onc 2013, 14:149-58

11 TAX-327 Study: Design Stratification: Pain level PPI 2 or AS 10 vs. PPI <2 or AS <10 KPS 70 vs. 80 R A N D O M I Z A T I O N Docetaxel 75 mg/m 2 q3 wkly + Prednisone 5 mg bid Docetaxel 30 mg/m 2 wkly 5 of 6 wks + Prednisone 5 mg bid Mitoxantrone 12 mg/m 2 q3 wkly + Prednisone 5 mg bid Treatment duration in all 3 arms = 30 wks n=1,006 patients Tannock IF. N Engl J Med 2004;351:

12 TAX-327 STUDY: RESULTS MITOX (n=337) TAX qw (n=334) TAX q3w (n=335) p Value PSA 32% 48% 45% Decreased Pain 22% 31% 35% 0.01 QOL 13% 23% 22% 0.009

13 Probability of Surviving TAX-327 STUDY: OVERALL SURVIVAL Median survival Hazard (mos) ratio p-value Combined: D 3 wkly: Mitoxantrone 16.4 Docetaxel 3 wkly Mitoxantrone Months Eisenberger MA. Proc Am Soc Clin Oncol 2004;23:2, Abstract 4.

14 CONCLUSIONS REGARDING TAX-327 AND SWOG 9916 For the first time, a survival benefit was clearly demonstrated in this patient population Docetaxel chemotherapy given every three weeks increased overall survival decreased risk of death by 24% absolute increase in median survival of 2.5 months Docetaxel chemotherapy demonstrated a higher rate of pain response, quality of life improvement and PSA Tannock IF. N Engl J Med 2004;351: Petrylak DP. N Engl J Med 2004;351:

16 E3805 CHAARTED: CHEMOHORMONAL THERAPY VERSUS ANDROGEN ABLATION RANDOMIZED TRIAL FOR EXTENSIVE DISEASE IN PROSTATE CANCER Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

17 EARLY CHEMO+ADT: A DEBATE IN ONE SLIDE A NEED FOR RANDOMIZED PHASE 3 TRIAL Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

18 THE CHAARTED HYPOTHESIS Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

19 E3805 CHAARTED TREATMENT Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

20 E3805 CHAARTED: CHEMOHORMONAL THERAPY VS. ANDROGEN ABLATION FOR METASTATIC PROSTATE CANCER Presented By Evan Yu at 2015 Genitourinary Cancers Symposium

21 OS BY EXTENT OF METASTATIC DISEASE AT START OF ADT Presented By Mary-Ellen Taplin at 2015 Genitourinary Cancers Symposium

22 CHARTERED DATA HAS CHANGED THE STANDARD OF CARE FOR MEN WITH HORMONE SENSITIVE HIGH VOLUME METASTATIC DISEASE Presented By Mary-Ellen Taplin at 2015 Genitourinary Cancers Symposium

23 SLIDE 7 Presented By Evan Yu at 2015 Genitourinary Cancers Symposium

24 KEY DIFFERENCES BETWEEN GETUG-AFU 15 AND CHAARTED Presented By Evan Yu at 2015 Genitourinary Cancers Symposium

25 SHOULD WE JUST TREAT LOW VOLUME/RISK DISEASE USING THE CHAARTED DEFINITION? Presented By Evan Yu at 2015 Genitourinary Cancers Symposium

26 GRADE 3-5 HEMATOLOGIC TOXICITY FROM TAX327 IN MCRPC VS. GETUG-AFU 15 VS. CHAARTED Presented By Evan Yu at 2015 Genitourinary Cancers Symposium

27 DOCETAXEL PK VARIES WITH CASTRATION STATE Presented By Evan Yu at 2015 Genitourinary Cancers Symposium

28 WHAT ARE THE IMPLICATIONS OF THESE PK DIFFERENCES? Presented By Evan Yu at 2015 Genitourinary Cancers Symposium

29 SUMMARY RECOMMENDATIONS Presented By Evan Yu at 2015 Genitourinary Cancers Symposium

31 31

32 2014:NEGATIVE PHASE 3 TRIALS IN PROSTATE CA Presented By Mary-Ellen Taplin at 2015 Genitourinary Cancers Symposium

33 CABAZITAXEL Tubulin binding Taxane Activity against Docetaxel resistant tumours D E B O N O E T A L T R O P I C I N V E S T I G A T O R S L A N C E T , O C T 2, ( )

34 Phase III TROPIC Study Design mcrpc patients who progressed during and after treatment with a docetaxel-based regimen (N=755) Stratification factors ECOG PS (0, 1 vs. 2) Measurable vs. non-measurable disease cabazitaxel 25 mg/m² q 3 wk + prednisone* for 10 cycles (n=378) mitoxantrone 12 mg/m² q 3 wk + prednisone* for 10 cycles (n=377) Primary endpoint: OS Secondary endpoints: Progression-free survival (PFS), response rate, and safety de Bono et al. Lancet 2010 October;376:

35 TROPIC RESULTS Mitoxantrone Cabazitaxel HR p Value OS 12.7m 15.1m RECIST RR 4.4% 14.4% PSA RR 17.8% 39.2% Pain Response 7.7% 9.2% 0.63

36 Overall Survival Results Proportion of OS (%) Median OS (months) Hazard Ratio 95% CI MP CBZP P-value < months 6 months 12 months 18 months 24 months 30 months Number at risk MP CBZP

37 SLIDE 29 Presented By Levi Garraway at 2014 ASCO Annual Meeting

39 SLIDE 7 Presented By Supriya Mohile at 2014 ASCO Annual Meeting

40 BALANCING THE RISK BENEFIT OF ADT Presented By Kim Chi at 2013 ASCO Annual Meeting

41 RANDOMIZED TRIALS OF IAD VS. CAD Presented By Kim Chi at 2013 ASCO Annual Meeting

42 CUMULATIVE DRUG EXPOSURE Presented By Kim Chi at 2013 ASCO Annual Meeting

43 SUMMARY OF THE DATA Presented By Kim Chi at 2013 ASCO Annual Meeting

44 SUMMARY OF THE DATA Presented By Kim Chi at 2013 ASCO Annual Meeting

45 OPTIONS - CASTRATE SENSITIVE DISEASE Castrate Sensitive, no metastatic delay initiation of ADT initiation with aim for IAD/CAD Castrate Sensitive, metastatic Low volume Mets IAD/CAD Clinical trial ENZAMET CAD plus Enzalutamide/bicalutamide (ANZUP) High Volume Mets CAD and Docetaxel Castrate Resistant no metastatic offer the PROSPER trial - randomised double blind trial of enzalutamide vs placebo primary end point is time to first Metastasis and PSA is blinded to pt and investigator during the trial

46 COU-AA-302: STUDY DESIGN Presented By Mary-Ellen Taplin at 2015 Genitourinary Cancers Symposium

47 COU AA 302 Pre Docetaxel AA/pred vs placebo/pred Primary end point OS and rpfs Both primary end points met OS 35.3 vs 30.1 months P HR 0.79 AA decreased risk of progression 47% Delayed time to opiate/chemo use Improves QoL Remained safe/well tolerated over long exposure PBS Approval Dec 2014 in pts determined to be chemotherapy intolerant 47

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

48 PREVAIL: A PHASE 3 TRIAL OF ENZALUTAMIDE AFTER PROGRESSION ON ANDROGEN DEPRIVATION THERAPY IN MEN WITH METASTATIC PROSTATE CANCER: 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 Presented By Mary-Ellen Taplin at 2015 Genitourinary Cancers Symposium

49 PREVAIL (ENZALUTAMIDE) Presented By Mary-Ellen Taplin at 2015 Genitourinary Cancers Symposium

50 MOST COMMON ADVERSE EVENTS* AND ADVERSE EVENTS OF INTEREST Presented By Mary-Ellen Taplin at 2015 Genitourinary Cancers Symposium

51 COMMENTS Presented By Mary-Ellen Taplin at 2015 Genitourinary Cancers Symposium

52 PHASE III COU-AA-301 STUDY DESIGN Patients 1195 patients with progressive, mcrpc Failed 1 or 2 chemotherapies, one of which contained docetaxel R A N D O M I Z E D 2:1 Abiraterone 1000 mg daily Prednisone 5 mg BID N=797 Placebo daily Prednisone 5 mg BID n=398 Efficacy endpoints (ITT) Primary end point: OS (25% improvement; HR 0.8; 12 mo vs 15 mo) Secondary end points (ITT): TTPP rpfs PSA response QoL (FACT-P, EORTC-QLQ-C30) Stratification according to ECOG performance status (0-1 vs. 2) Worst pain over previous 24 hours (BPI short form; 0-3 [absent] vs [present]) Prior chemotherapy (1 vs. 2) Type of progression (PSA only vs. radiographic progression with/without PSA progression) de Bono et al. NEJM 2011 May;364:

53 OVERALL SURVIVAL RESULTS (ESMO 2010) Survival (%) 100 HR = ( ) P < Abiraterone acetate: 14.8 months (95%CI: 14.1, 15.4) Placebo: 10.9 months (95%CI: 10.2, 12.0) 2 Prior Chemo OS: 1 Prior Chemo OS 14.0 mos AA vs 10.3 mos placebo 15.4 mos AA vs 11.5 mos placebo Days from Randomization

54 PHASE III AFFIRM STUDY DESIGN mcrpca Patients Failed 1 or 2 prior chemo-therapies, one of which was docetaxel n=1680 R A N D O M I Z E D 2:1 MDV mg p.o. qd + Prednisone Placebo + Prednisone u Efficacy Endpoints Overall survival

55 RESULTS Primary endpoint 4.8 month improvement in overall survival (18.4 months vs 13.6 months)p < % reduction in risk of death HR 0.63 Toxicity very well-tolerated *Crossed BBB - 6 pts had seizures on drug *effect of concurrent prednisone FDA approval for post Docetaxel PREVAIL Pre docetaxel Fully enrolled in June 2012 await results

AR-V7 AND RESISTANCE TO ENZALUTAMIDE AND ABIRATERONE IN PROSTATE CANCER: <BR />ANTONARAKIS ES, LU C, WANG H, LUBER B, NAKAZAWA M, ROESER JC, CHEN Y, MOHAMMAD TA, CHEN Y, FEDOR HL, LOTAN TL, ZHENG Q,

56 AR-V7 AND RESISTANCE TO ENZALUTAMIDE AND ABIRATERONE IN PROSTATE CANCER: ANTONARAKIS ES, LU C, WANG H, LUBER B, NAKAZAWA M, ROESER JC, CHEN Y, MOHAMMAD TA, CHEN Y, FEDOR HL, LOTAN TL, ZHENG Q, DEMARZO AM, ISAACS JT, NADAL R, PALLER CJ, DENMEADE SR, CARDUCCI MA, EISENBERGER MA, LUO J N ENGL J MED SEP 11;371(11): Presented By Mary-Ellen Taplin at 2015 Genitourinary Cancers Symposium

57 HYPOTHESIS: Presented By Joseph Kim at 2015 Genitourinary Cancers Symposium

58 PROSPECTIVE BIOMARKER STUDY Presented By Joseph Kim at 2015 Genitourinary Cancers Symposium

59 PREVALENCE OF AR-V7 IN MCRPC Presented By Mary-Ellen Taplin at 2015 Genitourinary Cancers Symposium

60 RPFS TO ENZA/ABI (N=62) Presented By Mary-Ellen Taplin at 2015 Genitourinary Cancers Symposium

61 OS TO ENZA/ABI (N=62) Presented By Mary-Ellen Taplin at 2015 Genitourinary Cancers Symposium

62 DISCUSSION Presented By Joseph Kim at 2015 Genitourinary Cancers Symposium

63 63

64 HOW DO CANCERS MAINTAIN AR SIGNALLING Androgen receptor Upregulation by gene amplification Mutations ARv567 Intratumoral synthesis of testosterone Overexpression of key enzymes P-450c17 (CYP17) involved in extragonadal androgen biosynthesis Alternative Glucocorticoid receptors

65 AR-V7 AND TAXANES Presented By Emmanuel Antonarakis at 2015 Genitourinary Cancers Symposium

66 RESULTS Presented By Emmanuel Antonarakis at 2015 Genitourinary Cancers Symposium

67 BEST PSA RESPONSE Presented By Emmanuel Antonarakis at 2015 Genitourinary Cancers Symposium

68 PSA PROGRESSION-FREE SURVIVAL Presented By Emmanuel Antonarakis at 2015 Genitourinary Cancers Symposium

69 PROGRESSION-FREE SURVIVAL Presented By Emmanuel Antonarakis at 2015 Genitourinary Cancers Symposium

70 INTERACTION BETWEEN AR-V7 STATUS AND TREATMENT TYPE Presented By Emmanuel Antonarakis at 2015 Genitourinary Cancers Symposium

71 PFS: TAXANE-TREATED VS ABI/ENZA-TREATED PTS Presented By Emmanuel Antonarakis at 2015 Genitourinary Cancers Symposium

72 CONCLUSIONS Presented By Emmanuel Antonarakis at 2015 Genitourinary Cancers Symposium

73 CONCLUSIONS Metastatic Castrate Resistant Prostate Cancer is heterogenous Currently have 4 agents that improve overall survival in advanced stages in Australia Challenge now is sequencing then, and maximising the benefit of each agent AR v7 and other predictive markers of response are needed. Trials combining these active agents in combination with curative RT and surgery are ongoing

SESSIONE PLATINUM SERIES (Best Papers Poster o Abstract on Prostate Cancer) In Oncologia

SESSIONE PLATINUM SERIES (Best Papers Poster o Abstract on Prostate Cancer) In Oncologia Divisione di Oncologia Medica Unità Tumori Genitourinari SESSIONE PLATINUM SERIES (Best Papers Poster o Abstract