Should ADT be started before metastasis in Prostate Cancer?

Transcription

1 Should ADT be started before metastasis in Prostate Cancer? Mario A. Eisenberger, MD R. Dale Hughes Professor Oncology/Urology The Johns Hopkins University

2 ADT in M0 Prostate Cancer Primary ADT vs local Rx ADT + RT Surgical Adjuvant ADT Biochemical Relapsed disease

3 Primary Androgen-deprivation therapy versus radical prostatectomy as monotherapy among clinically localized prostate cancer patients Jinan Liu et al Onco Targets Ther. 2013; 6:

4 ADT in M0 Prostate Cancer Primary ADT vs local Rx ADT + RT Surgical Adjuvant ADT Biochemical Relapsed disease

5 RT+/- ADT and ADT alone in advanced Prostate Cancer Study Extent N Treatment Overall Survival % TROG Localized 818 RT vs. RT+ ADT 3 vs. RT + ADT 6 10yr : 57,63,70 DFCI Localized 206 RT vs. RT ADT6 8yr : 61,74 RTOG Localized 1979 RT vs. RT+ ADT 4 10 yr: 57,62 RTOG EORTC PR.3/PRO7 Locally Advanced Locally Advanced Locally Advanced 471 RT vs. RT+ ADT 4 10yr: 34, RT vs RT+ADT yr: 39.8, ADT vs ADT+RT 7yr: 66,74 Prostate cancer specific Mortality% 10yr : 22,19,11 8yr: 12, 3 10yr: 8,4 10yr: 36,23 10yr: 30.4,10.3 7yr: 19,9 Modified from D Amico et al Campbell Urology Chapter 116, Table ,page 2707,2016

6 ADT in M0 Prostate Cancer Primary ADT vs local Rx ADT + RT Surgical Adjuvant ADT Biochemical Relapsed disease

7 Proportion Alive Fig. 2 Prostate Cancer-Specific Survival by Treatment Logrank p= Messing et al NEJMs Time (Years) Treatment Arm TOTAL D of DIS ALIVE/DOC MEDIAN Immediate ADT Not reached Observation yrs

8 Proportion Alive and Progression-Free Fig. 3 Progression-Free Survival (Any) by Treatment (ECOG 3866) Logrank p=< Time (Years) Messing et al,nejm 1997 TOTAL PROG/DIED CENS MEDIAN Immediate ADT yrs Observation yrs

9 TAX Design D(HT), n/n = 62/17 I(HT), n/n = 55/51 D(CHT), n/n = 56/20 I(CHT), n/n = 55/50 n/n = number of actual randomized/treated patients per treatment arm 9

10 Schweizer et al, Cancer 119,3610,2013 TAX-3501

11 ADT in M0 Prostate Cancer Primary ADT vs local Rx ADT + RT Surgical Adjuvant ADT Biochemical Relapsed disease

12 Death in Patients With Recurrent Prostate Cancer After Radical Prostatectomy: PSADT Subgroups and Their Associated Contributions to All-Cause Mortality Stephen J. Freedland, Elizabeth B. Humphreys, Leslie A. Mangold, Mario Eisenberger, Frederick J. Dorey, Patrick C. Walsh, Alan W. Partin Journal of Clinical Oncology, Vol 25, No 13 (May 1), 2007: pp

13 PSADT<3 mos PSADT PSADT mos PSADT >15 mos

14 10-year Estimate of Prostate- Cancer Specific Survival Recurrence >3 years after surgery Gleason Gleason sum <8 sum >8 PSADT (months) > (96-100) (93-98) (75-99) (58-98) (62-94) (37-89) < (29-83) (10-63) Recurrence <3 years after surgery Gleason Gleason sum <8 sum >8 93 (80-98) 85 (49-97) 55 (25-82) 15 (3-53) 86 (61-96) 69 (30-92) 26 (7-62) 1 (<1-55)

15 Biochemical Relapses D Amico et al JNCI 2003 N = 1451

16 NRG/RTOG 9601 Post RRP elevated/persistent PSA (pt3n0/pt2n0), PSA ng/ml) RT (64.8x36) +bicalutamide (150mg daily) Median follow up =12.6 years AT 10 years Actuarial survival 82 % RT+ B vs. 78% RT (HR 0.75 (95% CI ,p.018 one sided p sided test Freedom from PSA progression, 2.3% vs 30% (p<0001) PCS deaths 14% vs 23% (p<001) Similar RT toxicity other toxicity??

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18 Biochemical Relapses Bone Metastasis Deferred ADT Variable Median (range), years Median f/u after RP (years) 10 (2-18) Actuarial median failure RP to PSA failure (years) 2 (1-12) PSA failure to metastasis (years) 3 (0-11) RP to metastasis (years) 5 (0-15) Metastasis to death (years) 7 (1-15) RP to death (years) 14 (2-18) Makarov et al J Urol 179,2008

19 Proportion Alive Fig. 1 Overall Survival by Treatment (ECOG 3866) Logrank p=0.04 Messing et al,nejm Time (Years) Treatment Arm TOTAL DEAD ALIVE MEDIAN Immediate ADT yrs Observation yrs

20 Immediate versus deferred initiation of androgen deprivation therapy in prostate cancer patients with PSA-only relapse. An observational follow-up study Fig. 2. Overall (A) and prostate cancer-specific (B) survival, standardised for baseline and time-varying variables, for immediate versus deferred androgen deprivation therapy (ADT), Cancer of the Prostate Strategic Urologic Research Endeavour (CaPSURE) X. Garcia-Albeniz, J.M. Chan, A. Paciorek, R.W. Logan, S.A. Kenfield, M.R. Cooperberg, P.R. Carroll, M.A Hernán European Journal of Cancer, Volume 51, Issue 7, 2015,

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22 ASCO Value Framework Update Statement by ASCO President Julie M. Vose, MD, MBA, FASCO May 31, 2016 ASCO has chosen to define value in cancer care by emphasizing three critical elements : clinical benefit (efficacy), toxicity (safety), and cost (efficiency).. Head-to-head trials remain the only scientifically valid way to compare two treatments, given differences in trial designs, patient populations, cancer stages, and other factors.

23 Immediate versus deferred hormonal therapy by stage ( modified from Walsh et al 2002) Stage Primary Treatment Delays PFS Survival Advantage Treatment Recommendations M+ N/A Yes Likely Treat T2,3, N x Radiation Yes Yes in high risk Intermediate? T1-2, N1 Surgery Yes Possible Evidence level unestablished Treat Clinical studies or no RX BCR Surgery or Radiation Probably No evidence Unmet Need Deferred treatment Walsh PC, DeWeese TL, Eisenberger MA. A Structured Debate. Immediate Versus Deferred Androgen Suppression In Prostate Cancer: Evidence For Deferred Treatment. J. Urol Vol 166, 2001:

24 Hypothesis Clinical /biological models that predict for response to ADT could help clinicians better select appropriate candidates for ADT (personalized treatment)

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27 Prospective clinical trial designs incorporating genomic sequencing Richard Simon, Sameek Roychowdhury Nature Reviews-Drug Discovery 12,358,2013

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29 ありがとう Спасибо teşekkür ederim धन यव द Gràcies grazie 謝謝 Obrigado شكرا Thank you תודה Merci Beaucoup Muchas Gracias σας ευχαριστώ Vielen Dank Bedankt

30 And we ask the same question every year! "מ ה נ ש ת נ ה MAH NISHTANAH WHAT IS THE BEST TIMING?

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33 Improved Overall Survival Trends of Men with Newly Diagnosed M1 Prostate Cancer: A SWOG Phase III Trial Experience (S8494, S8894 and S9346) Catherine M. Tangen, Maha H.A. Hussain, Celestia S. Higano, Mario A. Eisenberger, Eric J. Small, George Wilding, Bryan J. Donnelly, Paul F. Schelhammer, E. David Crawford, Nicholas J. Vogelzang, Isaac J. Powell, Ian M. Thompson Jr. Figure 1. Kaplan-Meier survival curves stratified by clinical trial The Journal of Urology, Volume 188, Issue 4, 2012,

34 Time from random assignment to first pain, ureteric obstruction, and/or new metastasis was significantly longer in patients with immediate orchiectomy (i; P <.01); 44 patients in the immediate arm and 27 in the deferred arm (d) died before symptoms occurred. Urs E. Studer et al. JCO 2004;22: by American Society of Clinical Oncology

35 Cancer-specific survival. Urs E. Studer et al. JCO 2004;22: by American Society of Clinical Oncology

36 Overall survival. Urs E. Studer et al. JCO 2004;22: by American Society of Clinical Oncology

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39 Proportion Alive and Progression-Free PSA Progression-Free Survival by Treatment Logrank p=< Time (Years) TOTAL PROG/DIED CENS MEDIAN Hormones yrs Observation yrs

40 Proportion Alive Fig. 2 Prostate Cancer-Specific Survival by Treatment Logrank p= Messing et al NEJMs Time (Years) Treatment Arm TOTAL D of DIS ALIVE/DOC MEDIAN Immediate ADT Not reached Observation yrs

41 The Journal of Urology

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43 Survival with Newly Diagnosed Metastatic Prostate Cancer in the Docetaxel Era : Data from 917 Patients in the Control Arm of the STAMPEDE Trial (MRC PR08, CRUK/06/019) Fig. 2. Failure-free and overall survival for newly diagnosed M1 patients in the STAMPEDE trial control arm.ffs = failure-free survival; IQR = interquartile range. Nicholas David James, Melissa R. Spears, Noel W. Clarke, David P. Dearnaley, Johann S. De Bono, Joanna Gale, John Hetherington, Peter J. Hoskin, Robert J. Jones, Robert Laing, Jason F. Lester, Duncan McLaren, Christopher C. Parker, Mahesh K.B. Parmar, Alastair W.S. Ritchie, J. Martin Russell, Räto T. Strebel, George N. Thalmann, Malcolm D. Mason, Matthew R. Sydes European Urology, Volume 67, Issue 6, 2015,

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45 The prostate cancer clinical paradigms in the 21 st Century Localized disease Local Treatment Metastatic Disease Hormone -Naive Androgen Deprivation Androgen deprivation Non Metastatic Relapsed Metastatic Relapsed Hormone -Naive Non Metastatic Castration Resistant Metastatic Castration Resistant Death M0 M+

46 Biochemically Relapsed (M0) PCa Therapeutic Considerations Natural History Level of Evidence

47 Andrew J. Stephenson et al. JAMA (11):

48 ADT in M0 Prostate Cancer Primary ADT vs local Rx ADT + RT Surgical Adjuvant ADT Biochemical Relapsed disease

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50 Natural History with deferred ADT Johns Hopkins Fig. 1. Median (range) failure times in hormone naïve men with metastasis after radical prostatectomy Deferred ADT Median Survival from BCR = 11 years Makarov et al J Urol 179,2008

51 Andrew J. Stephenson et al. JAMA (11):

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53 CPDR-JHU metastasis natural history study (Combing data sets) AUA Unpublished