Androgen Deprivation Therapy A Question of Timing

Transcription

1 Androgen Deprivation Therapy A Question of Timing James Johnston BSc MBChB FRACS (Urol) Disclosure 1

2 OUTLINE History Watchful waiting Node positive patient Recurrence Intermittent Androgen Suppression Historical 2

3 Historical Historical 3

4 Alan Turing, convicted of homosexual acts in 1952, accepted castration over prison 4

5 John Hunter Circa 1840 The prostate gland, Cowper's glands and the glands along the urethra are in the perfect male large and pulpy, secreting a considerable quantity of slimy mucus which is salty to the taste; while in the castrated animal these are small, flabby, tough and ligamentous and have little secretion. Charles Huggins Born in Halifax, Nova Scotia 21 consecutive men with locally advanced or metastatic disease at the University of Chicago Noticeable improvement in all but 3. Those with small testicles at time of castration had a poor prognosis Nobel Prize

6 Andrew Schally pig to obtain 800ug of LHRH Nobel prize 1977 Androgens 6

7 Androgens Testosterone is the major androgen Estrogen is formed from aromatization in the peripheries and inhibits pituitary production of LH Testosterone plasma half life minutes 7

8 Adrenal Gland DHT Testicles Estrogens Peripheries 8

9 Androgen s Passes in to cell Converted to DHT Interacts with AR Chaperonins released Moves to nucleus Associates with cofactors Androgen response elements in the promoter region of genes Androgen Deprivation Inhibit secretion Inhibit action Cyproterone Flutamide Bicalutamide Enzalutamide Medical Estrogen LHRH agonists LHRH antagonist Ketaconazole Abiraterone Surgical Orchiectomy 9

10 What has changed in prostate cancer PSA Earlier stage at diagnosis The use of medicine compared to surgery People are living longer People with advanced prostate cancer are living longer Side effects Hot Flashes Anemia Muscle Wasting Obesity Osteoporosis / Fracture Sexual dysfunction Gynecomastia Cardiovascular Disease Weakness Cognitive function 10

11 Poll everywhere Go to Pollev.com/jamesjohnst202 Text JAMESJOHNSTO202 to to join then A to E depending on your answer Index patient 1 85 year old man Prostate Cancer 3+4=7 5 out of 12 cores Left and Right Apex and Mid Gland T3 clinically PSA at diagnosis 11 In 3 years time what PSA would prompt you to start ADT A) 22 B) 43 C) 55 D) 63 E) Any PSA, symptomatic mets 11

12 Watchful Waiting Conservative management until progression biochemical progression Local progression Systemic progression Localized prostate cancer with limited life expectancy 12

13 SPCG -4, Scandinavian Study Death from any cause All RR 0.75 (p value 0.007) < (<0.001) > (0.89) Death from prostate cancer All 0.62 (0.01) < (0.008) > (0.41) Distant metastasis All 0.59 (<0.001) < (0.001) > (0.14) Bill-Axelson et al 2011, NEJM 364; Men under 80 Refused or where unsuitable due to cancer or co-morbidities 468 underwent immediate ADT 471 Deferred ADT 8 years follow up Reason for deferred to have ADT New symptomatic disease which threatened serious consequences 13

14 PSA >50 cf to <8-3.5 fold higher chance of dying in both ADT and deferred 7yr cumulative incidence of death - ADT arm 9.2% - Deferred arm 7.9% Although survival may not be significantly better would benefit from imediatte ADT to prevent complications from progressive disease PSA doubling time in those with PSA between 8 and 50 <12months cf to >12 months fold higher risk of dying 7 year cumulative incidence of prostate cancer death 47.6% if PSA DT <12 months cf to 11.4% if PSA DT >12 months 14

15 6 years later, 12 years follow up. % of patients with objective progression Objective progression at 10 years 42% in deferred arm v 30% Appearance of hot spots on bone scan 32 v 16% Time to castrate resistance was similar HR 0.91 deferred to immediate Studer et al 2014 Euro Urol 66; Mortality 80% in deferred arm and 76% in immediate arm had passed away at completion Non PCa mortality 49 v 40% HR 1.15 PCa mortality 25 v 23% HR 1.05 But all cause mortality slightly higher at yr 10 74% v 64% Studer et al 2014 Euro Urol 66;

16 44% never received ADT at end point 31% died without it Studer et al 2014 Euro Urol 66; Metastatic Disease VACURG II 1508 men Stage III/IV Placebo v diethylstilbestrol Patients on placebo never treated with active therapy Therefore immediate vs no therapy Byar et al Cancer 1973; 32: mg dose stopped prematurely due to cardiovascular deaths 16

17 VACURG I Assigned to placebo or orchiectomy No difference in cancer specific survival between groups Patients were allowed to switch to active therapy at symptomatic progression Overall recommendation is that patients with prostate cancer should not be treated until their symptoms require relief Blackard et al Urology 1973; 16: Medical Research Council Prostate Cancer Working Group men with locally advanced or metastatic setting Reduced morbidity Improved survival for M0 patients 54 v 70% favoring early vs deferred No difference in M1 patients 65 v 69% early v delayed Br J Urol 1997; 79:

18 Summary Localized disease with life expectancy less than 10 years In symptomatic metastatic disease give ADT In asymptomatic metastatic disease probably give ADT In non metastatic disease consider initiating ADT when PSA >50 Doubling time <12 months Symptomatic progression Index patient 2 75 year old man Post Radical Prostatectomy T3b, 4+4=8, PSA 18 pre op, margins clear, nodes negative Post op PSA 0.01 In 2 years time what PSA would prompt you to start ADT A) I would have already started it B) 0.03 C) 0.08 D) 0.20 E)

19 Biochemical recurrence post radical prostatectomy 0.2ng/ml or greater with a second confirmatory lab value AUA guidelines 2007 and adopted by EAU Radical Prostate N= & 1997 PSA recurrence N = 315 (15%) Clinical met s 8 years median 5 years median Death Pound et al JAMA ,

20 Natural History Antonarakis et al BJUI 2012; 109: men with progression post radical prostatectomy Johns Hopkins Hospital No salvage or adjuvant therapy prior to metastatic disease Results 8 yr median follow up - 30% developed mets Median metastatic free survival - 10 years Hazard Ratio multivariable analysis Gleason Gleason PSA Dt >15month 1 PSA Dt PSA Dt PSA Dt <3 months 33.3 No difference for stage, margin or time to recurrence (differs from an earlier review by Freedland et al 2005) Antonarakis et al BJUI 2012; 109: 32-9 Freedland et al JAMA 2005; 294(4):

21 Early v late Moul et al 2004 Department of Defense center for for Prostate Disease Research (PSA era) 5382 men underwent radical prostatectomy 1352 men with PSA 0.2ng/ml and post op follow up >6 months Early = after recurrence but before clinical mets Late = no ADT before clinical mets or end of follow up Moul et al J Urol 2004; 171 (14): 1141 Decreased rates of metastasis for Gleason 7 or more & PSADT < 12months, HR 2.12 Moul et al J Urol 2004; 171 (14):

22 Adjuvant vs PSA cut off s: Siddiqui et al 2008 Mayo Clinic Prostatectomy Registry Node negative radical prostatectomy patients who received ADT Adjuvant within 90 days vs ADT at 0.4, or systemic progression Siddiqui et al J Urol 2008; 179: 1830 Improved 10yr BCR free and progression free but not overall survival, If given at PSA less than 0.4 Benefit is lost for those who progress with PSA >0.4 Siddiqui et al J Urol 2008; 179:

23 T3b disease: Siddiqui et al 2011 Mayo Clinic Prostatectomy Registry patients with T3b who underwent adjuvant ADT (within 90 days) Matched 1:1 with T3b who had no adjuvant treatment Margin status, pathological Gleason score, pre op PSA, Age, year of surgery Median follow up 10 years Siddiqui et al BJUI 2011; 107: At 10 years for T3b disease adjuvant ADT show improved BCR free - 60% vs 16% Local recurrence free - 87 v 76% Systemic free % Cancer specific survival - 94 v 87% Not overall survival - 75 v 69% non sig 23

24 EAU Guidelines HIGH RISK Doubling time <3 months T3b Gleason 8-10 Time to recurrence <3 years LOW RISK Doubling time >12 months >3 years Gleason <7 Organ confined, T3a or less Ultrasensitive PSA era Hong et al Urology 2010;76(3): patients 3 year follow up post radical Biochemical recurrence free survival based on PSA nadir Less than % to % 0.02 to % 0.05 or greater % How is it used in calculating doubling time? - not clear 24

25 Index patient 3 72 year old man T2c, 3+4=7, PSA 18 pre op, 2/11 nodes positive 6 months post radical prostatectomy (first PSA), what PSA would prompt you to start ADT A) Undetectable B) 0.05 C) 0.10 D) 0.40 E)

26 Messing Trial 1988 to 1993 Aimed to recruit 240 Messing et al. The lancet oncology 2006; 7: Wong et al men, observational study, SEER data No difference in overall survival for those who received ADT within 120 v those who did not. HR 0.97 Wong et al J Clin Oncol 2008, 27,

27 Touijer et al men observational study MSK 1988 to 2010 Overall survival 60%, Cancer specific survival 72% Freedom from metastasis 65% If not recurred in 5 years then 81% chance of recurrence free Gleason >7 (HR 2.23) 3 or more LN (HR 2.61) Touijer et al Eur Urol 65 (2014) So, in practical terms Post radical prostatectomy node positive patients If they have 3 or more nodes involved and Gleason 8 give ADT Otherwise check the PSA 27

28 Index patient 4 80 year old man treated with external beam radiation therapy 5 years ago Pre radiation PSA 17, G 3+4=7 6 out of 12 cores, T2b PSA nadir 1.2 Last year the PSA rose to 3.2 Otherwise asymptomatic What PSA would prompt you to start ADT A) 4.0 B) 6.0 C) 7.5 D) 10 28

29 Pinover et al Cancer (4) treated with EBRT in Philadelphia 74Gy (61-80 range) 3D conformal technique Policy was to treat men with ADT if PSA DT < 12 months But some men refuse Observe men with PSA DT >12 months 248 men who demonstrated PSA failure Looked at freedom from distant metastasis PSA DT <12 months PSA nadir 1.5 PSA DT >12 months Gleason score 29

30 Kestin et al 2004 Retrospective comparative study from the USA men with t1-3n0m0 treated with EBRT 66.6 Gy Early ADT = after biochemical failure before clinical failure Late ADT = after clinical failure 5 year outcome Early Late Local failure rate 4% 33% Distant metastasis rate 13% 44% Cancer specific death 9% 24% Death due to any cause 32% 48% Kestin et al Int J Rad Onc, Biol Phys (2) INTERMITTENT THERAPY 30

31 Index patient 5 80 year old man Radical Prostatectomy 3 years earlier Diagnosis PSA 11, pt3b, G 4+4=8, margins clear, node negative PSA post op 0.8 nadir 1 cycle of 9 months cycle PSA nadir to 0.1 with ADT At 2 years post first cycle of intermittent androgen deprivation, what PSA would prompt you start ADT? A) 3.2 B) 5.2 C) 7.0 D)

32 Intermittent Androgen Suppression Intermittent androgen suppression is an approach that balances the benefits of early ADT while reducing treatment-related side effects and expense Dr Martin Gleave European Urology 66 (2014) Re exposure of prostate cancer stem cells to androgen can reintroduce apoptotic potential Therefore prolonging time to castrate resistance 32

33 Shionogi model Bruchovsky, Rennie, Coldman Goldenberg et al. Cancer Res 1990; 50 (8): LNCaP prostate tumor model Sato N, Gleave M, Bruchovsky N Rennie S, Goldenberg. Lange P, Sullivan L. J steroid Biochem Mol Biol 1996; 58(2) IAS prolonged time to androgen-independent PSA gene regulation from 26 days to 77 days Klotz, Herr Morse, Whitmore Cancer 1986; 58:

34 A feasibility study 47 locally advanced or metastatic disease 8 of whom had progression following radiation therapy Goldenberg et al Urology (5) An improvement in sense of well being and the recovery of libido and potency in men who reported normal or near normal sexual function before the start of therapy 34

35 Meta analysis, Magnan et al JAMA Onc 2015 Magnan et al JAMA Oncology 2015; 1 (9): PR7 trial, National Cancer Institute of Canada Non metastatic hormone sensitive Prior radiation therapy Non inferiority trial Median follow up 6.9 years 1386 patients Median survival IAD 8.8 years, CAD 9.1 years Slightly better but not significant quality of scores for intermittent Crook et al N Engl J med 2012;367(10)

36 SWOG, S9346 trial Newly diagnosed Metastatic hormone sensitive Non inferiority trial If PSA dropped to below 4 Randomized to continuous or intermittent therapy 765 continuous androgen deprivation therapy 770 intermittent therapy Median follow up 9.8 years HR 1.10 (0.99 to 1.23) Because non inferiority limit of 1.20 pre set was within 90% confidence interval can not conclude it is non inferior Because lower limit of 90% confidence interval was below 1, then also can not conclude it was significantly inferior either 36

37 Quality of life At 3 and 9 months IAS had improved Erectile function Libido Mental health Physical functioning At 15 months Only improved physical functioning remained Bipolar Androgen Therapy With each cycle testosterone recovery takes longer Keizman et al Prostate (15) Instituting ADT cycle is based on PSA not testosterone Therefore is ADT initiated before testosterone recovered and apoptotic potential regained? Schweizer et al Science Translational Medicine 2015; 7 (269): 269ra2 Pilot study of 16 men with asymptomatic CRPC patients 7 of 14 showed PSA reponse and 5 of 10 showed radiological repsonse 4 men remained on BAT for >1 year 37

38 Take Home Messages This is not a new topic But one that wont go away as prostate cancer management continues to evolve Prostate cancer can kill and is usually due to castrate resistance, therefore considering when to start castration is important Prostate cancer is heterogeneous There is no one size fits all PSA Triggers No prior treatment non metastatic 6-10 No prior treatment metastatic PSA relapse post radical 3-5 PSA relapse after radiation

39 What Next? BATMAN? Newer modalities Haere Ra Farewell 39

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41 Meta analysis Magnan JAMA Oncol (9) IAD not inferior to CAD for survival Some QOL criteria improved Metastatic setting Hussain et al J clin Oncol (24) PSA response is powerful predictor of survival PSA falling to <0.2 by 7-8 months are ideal PSA failing to fall below 4 unlikely to benefit Haere Ra 41

42 Goldenberg et al cancer (5) 1685 Majority of patients require 32 weeks of treatment to reduce PSA Lu Yao et al 2008 JAMA men, SEER 10Yr prostate cancer specific survival 80.1 v 82.6% ADT vs conservative (favoring non ADT use) -?more aggressive disease requiring ADT 10yr overall survival 30.2 v 30.3% Subset of poorly differentiated cancers (g8-10) 10yr p cancer spec survival 59.8% survival vs 54.3%, no difference in overall survival 17.3 v 15.3% Primary ADT = within first 180 days No PSA analysis High use v low use (IVA instrumental variable analysis) 42

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44 Duchesne et al Journal of Clinical Oncology 2015, 33 Suppl TOAD (timing of androgen deprivation therapy) Abstract in Journal of Clinical Oncology 6 yr overall survival 86 v 79% Local disease progression HR 0.51 Distant disease progression HR 0.54 No difference to time to CRPC Two groups of patients proportions are not clear Following BCR after definitive therapy EBRT & RT Localised or metastatic disease not suitable for curative therapy Neoadjuvant No short or long term survival or biochemical recurrence rates 3 RCT, Witjes 1997, Soloway 2002, Klotz 2003 Perhaps reduced positive margin rates by 50% Lee et al

45 Post RP recurrence rad therapy Treating those with PSA <0.5 gives an 80 % chance of being disease free at 5 years Wait and see approach is appropriatte for those with PSA Dt >12 months 6 months of goserelin with SRT improved biochemical progression free survival at 5 years but not survival (GETUG-AFU 16 study ) Salvage Lymph node dissection - complete biochemical response can be achieved Most patients progress after 2 years Ideal patient not worked out yet use selectively 45