Biochemical failure after surgerywhat. Bern, Switzerland

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1 Biochemical failure after surgerywhat to do? Urs E. Studer Bern, Switzerland

2 Biochemical failure after rad Prostatectomy Adjuvant radiation therapy?

3 Progression free survival after Salvage Radiotherapy for P Ca Overall progression-free probability after salvage radiotherapy Progression-free probability after salvage radiotherapy stratified by preradiotherapy prostate-specific antigen PSA 0.5 ng/ml PSA > 1.5 ng/ml A. J. Stephenson, P. T. Scardino et al., J Clin Oncol 25: ,2007.

4 100% 80% 60% 40% Adjuvant Radiotherapy for T3N0M0 Prostate Cancer SWOG 8794 Survival by treatment arm Number at risk RT No RT 20% At Risk Death Median In Years 10-Year Estimate Adjuvant RT % No Adjuvant RT % 0% Years from Registration I.M. Thompson et al., J. Urol., 181: , March 2009

5 Adjuvant Radiotherapy for T3N0M0 Prostate Cancer SWOG 8794 Study participant characteristics Observation Adjuvant Radiation No. Subjects Median age Median yrs followup % Pathological extent of disease: Extracapsular extension or pos margin Seminal vesicle invasion Both No. with Gleason score data % Gleason score: No. with preop PSA data % Preop PSA: Less than 10 ng/ml ng/ml or Greater No. with postop PSA data % Postop PSA: Less than 0.2 ng/ml ng/ml or Greater % I.M. Thompson et al., J. Urol., 181: , March 2009

6 Adjuvant Radiotherapy for T3N0M0 Prostate Cancer SWOG 8794 Material and Methods: In terms of statistical analysis the primary end point of S8794 was metastasis-free survival, defined as the time from randomization to first evidence of metastasis or death due to any cause.. Jama,96:

7 Adjuvant Radiotherapy for T3N0M0 Prostate Cancer, SWOG 8794 Jama,96:

8 100% 80% 60% 40% Adjuvant Radiotherapy for T3N0M0 Prostate Cancer SWOG 8794 Survival by treatment arm Number at risk RT No RT 20% At Risk Death Median In Years 10-Year Estimate Adjuvant RT % No Adjuvant RT % 0% Years from Registration I.M. Thompson et al., J. Urol., 181: , March 2009

9 Long term results of immediate post-operative operative radiotherapy after radical prostatectomy in pt3n0 prostate cancer (EORTC 22911). M. Bolla (Grenoble, France), H. van Poppel, B. Tombal, K. Vekemans, L. Da Pozzo, Th.M. de Reijke, A. Verbaeys, J.-F. Bosset, R. Van Velthoven, M. Colombel, C. Van de Beek, P. Verhagen, F. van den Bergh, C. Sternberg, Th. Gasser, G. Van Tienhoven, P. Scalliet, K. Haustermans, C. Liberatoscioli, L. Collette for the EORTC Radiation Oncology and Genito-Urinary Groups

10 EORTC trial DESIGN Who PS 0-1 Age 75 y T0-3N0M0 PCa S U R G E R Y Randomization Extraprostatic invasion and/or Seminal vesicle invasion and/or Positive surgical margins Wait and see (W&S) until local l failure Post-op op radiotherapy (RTX: 60 Gy/6wks) 1005 patients with pt2-t3n0 T3N0 prostate cancer operated and randomized were entered from 1992 to 2001 First study results with 5 years median follow-up (Bolla et al. Lancet 2005) showed significant difference in clinical and biochemical progression-free survival The median follow-up is now 10.6 years

11 Biochemical PFS (intent-to-treat) % 6% ( ) 41.1% ( ) 45.8 HR= %CI: (0.41,0.59) 0 Logrank P< Postop RT Wait and see 0 (years) O N Number of patients at risk : Treatment Arm Wait-and-See Irradiation

12 Distant control % 70 ( ) % 50 ( ) HR= %CI: (0.67, 1.44) Logrank P= Wait and see Postop RT 0 (years) O N Number of patients at risk : Treatment Arm Wait-and-See Irradiation

13 Deaths due to prostate cancer % 50 (3.2 75) 7.5) % 30 ( ) 10 HR= %CI: (0.46, 1.33) Logrank P= Wait and see Postop RT 0 (years) O N Number of patients at risk : Treatment Arm Wait-and-See Irradiation

14 Overall survival (intent-to-treat) % ( ) HR= %CI: (0.91, 1.53) Logrank P= % 60 ( ) Wait and see 50 Postop RT (years) O N Number of patients at risk : Treatment Arm Wait-and-See Irradiation

15 Systemic therapy-free survival Postop RT Wait and see Overall Logrank test: p= (years) O N Number of patients at risk : Treatment Arm Wait-and-See Irradiation

16 JCO;321,14-16, 2013

17 JCO;321,14-16, 2013

18 JCO: 32, Supplement 4, 2014

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20 Late salvage radiotherapy.the increased risk of CSM among men receiving late salvage radiotherapy is unlikely to be causative, but likely is attributable to the fact that most men with postprostatectomy PSA levels >0.5 ng/ml have coexisting systemic disease and thus are unlikely to benefit from salvage radiotherapy; this cohort also had worse features in terms of Gleason score, preoperative PSA levels, and year of diagnosis. A.J.Stephenson, P.T. Scardino et al., Eur Urol 2013

21 232 patients with bilateral nerve-sparing radical prostatectomy Tim me to conti inence rec covery Urinary continence recovery after radical prostatectomy n=361 Time to continence recovery Suardi N., et al., University Vita-Salute San Raffaele, Milan, Eur Urol 65: 546, 2014

22 Metastasis- free survival (%) Years following biochemical recurrence St. A. Boorjian, et al., J Urol: 188; 1761, 2012

23 Cancer-specific survival (%) Years following biochemical recurrence St. A. Boorjian, et al., J Urol: 188; 1761, 2012

24 PSA doubling time before salvage Rx ttt for biochemical failure after rad. P ectomy predicts probabilty of progressive disease Freedom from Biochemical Failure for PSADT before s RT Freedom from Metastasis for PSADT before s RT William C.Jackson, Felix Y. Feng et al., Radiation Oncology 2013, 8:170

25 Biochemical failure after rad Prostatectomy Immediate hormonal manipulation? 5 alpha reductase inhibitors, eg. Finasteride, Dutasteride

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27 Cancer Res. Aacrjournal.org, 21, American Association for Cancer

28 Relative and Absolute Risk of Prostate Cancer According to Modified Gleason Score (mgs), PCPT and REDUCE Trial. Marc R. Theoret,M.D.,et al.,n Engl J Med: 365,2,2011

29 Biochemical failure after rad Prostatectomy Immediate hormonal manipulation? 5 alpha reductase inhibitors, eg. Finasteride, Dutasteride 1t 1st generation of Antiandrogens, eg. Bicalutamide id

30 PSA secretion under bicalutamide OD (570 nm m) Cell proliferation (mean ± SD) 05mmol mmol 5.0 mmol Control Treatment time (hours) x-fold x- -fold PSA mrna in C4-2 cells Control 10 mmol/l 100 mmol/l 1000 mmol/l Bicalutamide PSA protein in C4-2 cells Control 10 mmol/l 100 mmol/l 1000 mmol/l Bicalutamide Peternac D, Thalmann G.N et al. J Urol 2006;176:

31 Cancer Research 59,: 5030,Oktober 1,1999

32 /03/ /0 Vol. 170, , October 2003 The Journal of Urology Printed in U.S.A. Copyright 2003 by American Urological Association DOI: /01.ju f Review Article ANDROGEN RECEPTORS IN PROSTATE CANCER ZORAN CULIG, HELMUT KLOCKER, GEORG BARTSCH, HANNES STEINER, AND ALFRED HOBISCH From the Departments of Urology, University of Innsbruck (ZK; HK; GB; HS; AH), Innsbruck and General Hospoital Feldkirch (AH), Feldkirch Austria C l i A ti d i d f tl i iti ti i th f Conclusions: Antiandrogenic drugs frequently acquire agonisticproperties in thepresenceof mutated ARs.

33 Bicalutamide (150 mg) versus placebo as immediate therapy alone or as adjuvant to therapy with curative intent for early nonmetastatic prostate cancer 1.0 rviving 0.8 Proportio on not su Placebo Bicalutamide 150 mg HR 1.47; 95% Cl 1.06, 2.03 Time to death (years) Fig.2. Kaplan-Meier curve shows overall survival in patients with localized disease receiving 150 mg bicalutamide in addition to standard care vs standard care alone. Scandinavian Prostatic Cancer Group, J. Urol., 172: ,

34 Biochemical failure after rad Prostatectomy Immediate hormonal manipulation? 5 alpha reductase inhibitors, eg. Finasteride, Dutasteride 1t 1st generation of Antiandrogens, eg. Bicalutamide id LHRH Agonists/Orchiectomy

35 Diabetes and Cardiovascular Disease During Androgen Deprivation Therapy for Prostate Cancer Nancy L Keating, A. James O'Malley, and Matthew R. Smith ABSTRACT Patients and Methods Observational study of a population-based cohort of 73,196 fee-for-service Medicare enrollees age 66 years or older who were diagnosed d with locoregional l prostate t cancer during 1992 to 1999 and observed through Results More than one third of men received a GnRH agonist during follow-up. GnRH agonist use was associated with increased risk of incident diabetes (adjusted hazard ratio [HR], 1.44; P <.001), coronary heart disease (adjusted HR, 1.16; 16; P <.001), myocardial infarction (adjusted HR, 1.11; P =.03), and sudden cardiac death (adjusted HR, 1.16; P =.004). Men treated with orchiectomy were more likely to develop diabetes (adjusted HR, 1.34; P <.001) but not coronary heart disease, myocardial infarction, or sudden cardiac death (all P >.20). J Clin Oncol 24: , 2006

36 Trial design and objectives Patients with newly diagnosed untreated asymptomatic T0-4 N0-2 M0 (UICC 1982) PCa not suitable for local treatment with curative intent 82.3% were T2-T4 Median age 73 y; PSA 16.2 ng/ml R Immediate orchiectomy or depot LH-RH N=492 Deferred* orchiectomy or depot LH-RH N=493 *Treatment starts upon events of symptoms from metastases, ureteric obstruction or decrease > of WHO performance status. Not for only rise in PSA, new hot spots or asymptomatic mets updated results with 12.9 years of median follow-up

37 Time to first objective progression Deferred/immediate HR=1.62(95%CI: ) P< % 27.2% Deferred ADT first objective progression Immediate ADT first objective progression 0 (years) O N Number of patients at risk : Immediate ADT Deferred ADT

38 Time to first objective progression Deferred/immediate HR=1.62(95%CI: ) P< % Deferred ADT first objective progression years 27.2% Immediate ADT first objective progression 10 0 (years) O N Number of patients at risk : Immediate ADT Deferred ADT

39 Time to first objective progression Deferred/immediate HR=1.62(95%CI: ) P< % 27.2% Deferred ADT first objective progression Immediate ADT first objective progression 0 (years) O N Number of patients at risk : Immediate ADT Deferred ADT

40 Time to first objective progression Deferred/immediate HR=1.62(95%CI: ) P< % Deferred ADT first objective progression ? 27.2% Immediate ADT first objective progression 10 0 (years) O N Number of patients at risk : Immediate ADT Deferred ADT

41 Time to objective progression on immediate OR deferred e ed ADT Patients with objective PD on the deferred ADT arm = ADT SENSITIVE DISEASE HR versus immediate= 1.62 (CI: ) P< Patients with first objective PD on the immediate ADT arm = CASTRATE RESISTANT Time on ADT Patients with objective PD after deferred ADT = CASTRATE RESISTANT HR to immediate= 0.91 (CI: ) P= (years) O N Number of patients at risk : Immediate Def. 1 st PD Def. ADT refract.

42 Prostate Cancer Mortality Deferred/immediate HR=1.05 (95%CI: ) P= % (CI: %) 21.0% (CI: %) (years) O N Number of patients at risk : Treatment Immediate (P Ca) Deferred (P Ca)

43 90 80 Prostate cancer mortality 100 Gray test P< PSA-DT 12 m 50 ~ 7-fold increased risk of death due to prostate 40 cancer PSA-DT 12-24m PSA-DT>48 m 10 PSA-DT 24-48m 0 (years) O N Number of patients at risk : PSA DT <=12 m >12-24 m > m >48m Studer U. E., Colette L. and EORTC GU group, AUA meeting 2007

44 Cause of death by year of death Significant difference in Pca specific survival in favour of immediate ADT P=

45 A significant lower incidence of biochemical progress or metastatic disease at a specific time after biochemical relapse observed in patients who got immediate adj radiation therapy and/or ADT (multimodality treatment) compared to patients with deferred treatment is not a surrogate endpoint for survival

46 Early vs delayed hormonal Therapy for PSA recurrence after radical Prostatectomy Bone me etastase es-free su urvival (% %) 100 Late HT 80 Early HT p= Time (Years) J. Moul et al., J. Urol., 171: , 2004

47 Prostate cancer specific survival of 2426 men with BCR after radical prostatectomy. No adjuvant ADT after RRP Alive from pros state can ncer (%) Years from BCR to death or last follow-up 15 St.A. Boorjian, M.L. Blute et al., Eur Urol., 2011 in press

48 PSA Relapse after radical Prostatectomy PSA doubling time >15 months Stephen J. Freedland, Patrick C. Walsh, et al,j Clin Oncol,2007,25:

49 PSA Relapse after radical Prostatectomy PSA doubling time 3 9 months Stephen J. Freedland, Patrick C. Walsh, et al,j Clin Oncol,2007,25:

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69 Conclusions A PSA relapse after radical prosttectomy is not a death sentence PSA doubling time may be a helpful tool «blind «adjuvant treatment hardly controls a systemic disease, treat proven local recurrences Prolonged biochemicalrecurrence freesurvivalis is not a surrogate endpoint for suvival as long as the patients on the control arm do nt get the same treatment when showing clinical progressive disease

70 Phase III results of adjuvant radiotherapy (RT) versus waitand-see (WS) in patients with pt3 prostate cancer following radical prostatectomy (RP) (ARO 96-02/AUO AP 09/95): Ten years follow-up. Results: 78 pts. (20%) did not achieve an undetectable PSA and were stated as progressive disease (arm A: 45 pts., arm B: 33 pts.). Additionally, 34 pts. (23%) from the RT-arm did not receive RT. Therefore, 114 pts. had RT (arm A) and 159 pts. WS (arm B). Median follow up was months for arm A and months for arm B. bned at 10 years increased to 56% for arm A (RT) compared with 35% for arm B (WS) (hazard ratio= 0.51; P = Out of 307 ITT pts., 15 died from prostate cancer, 23 for other and 5 for unknown reasons. There was no significant profit from ART regarding the endpoints metastasis-free survival (p=0.56) or overall survival (p=0.59). Wiegel T. et al., J Clin Oncol 31, 2013 (suppl 6; abstr 4)

71 Local recurrence after retropubic radical prostatectomy for prostate cancer does not exclusively occur at the anastomotic site Daniel P. Nguyen, et al. BJU Int. : 112, E243,2012

72 Multimodal treatment for high risk prostate cancer with high dose intensity modulated radiation therapy preceded or not by radical prostatectomy, concurrent intensified dose docetaxel and long term androgen deprivation therapy: results of a prospective phase II trial Andrea Guttilla, et all. Surviva al Probablit ty Surviva al Probablit ty Time (months) Time (months) +Censored 95% Confidence Limits Radiat Oncol: 14; 9,24, Jan 2014

73 P Ca Death (% %) PSA doubling time in patients with recurrences after radical prostatectomy PSA - DT < 3 months PSA - DT months PSA - DT months PSA - DT > 15 months Time After Biochemical Recurrence (years) St.J. Freedland, P.C. Walsh, A.W. Patin et al., J Clin Oncol 25: , 2007