Current role of androgen deprivation after surgery or radiotherapy of high-risk PCa Morgan Roupret, MD, PhD Pitié Salpétrière Hospital University Paris 6

Established factors that determine PCa Risk Extent ~ Clinical/path stage (TNM) Grade ~ Gleason patterns (1-5) Volume ~ Serum PSA level Each is an independent predictor of risk, but when combined the predictive accuracy increases T-Stage (alone) can be low or high risk

Treatment of PCa Time (years)

Treatment of PCa High-grade PIN Time (years)

Treatment of PCa Localised prostate cancer High-grade PIN TxN0M0 Radical prostatectomy Radiotherapy ‘Active Surveillance’ Ablative therapies Time (years)

Treatment of PCa Localised prostate cancer Locally advanced High-grade PIN TxN0M0 T3-4 Radical prostatectomy Radiotherapy ‘Active Surveillance’ Ablative therapies Time (years) Radiotherapy Hormonal therapy

Treatment of PCa Localised prostate cancer Metastatic disease Hormone insensitive Locally advanced High-grade PIN TxN0M0 T3-4 D1.5 D2 D2.5 D3 Radical prostatectomy Radiotherapy ‘Active Surveillance’ Ablative therapies Hormonal therapy Time (years) Radiotherapy Hormonal therapy Chemotherapy

Treatment of PCa The Challenge = T3 PCa Localised prostate cancer Metastatic disease Hormone insensitive Locally advanced High-grade PIN TxN0M0 T3-4 D1.5 D2 D2.5 D3 Radical prostatectomy Radiotherapy ‘Active Surveillance’ Ablative therapies Hormonal therapy Time (years) Radiotherapy Hormonal therapy Chemotherapy The Challenge = T3 PCa

Gonadotropin releasing hormone Androgen deprivation suppresses tumour prostate cells Hipotalame Gonadotropin releasing hormone GnRH Estrogens Pituitary LH & FSH Gonadotropins Testosterone Prostate atrofia Tumour cells death Prostate Testis

Transition of tumour prostate cells under hormone-deprivation Androgen – independence Androgen - dependence Androgen-resistance

Historical Background Androgen supression has a supressor effect prostate cell growth. It can be obtained both with surgical castration or estrogens. Huggins C and Hodges CV. Cancer Res 1941;1:293. The VAGURG clinical trials proved that 1, 3 y 5mg de DES are equally effective. 3 and 5mg are associated with higher cardiovascular mortality. Byar DP et al. NCI Monogr 1988;7:165

Schally and associates purify un LHRH-agonist in 1971. Schally et al. Biochem Biophys Res Commun 1971;43:393 LHRHa show in a randomized clinical trial its equivalence to 3mg de DES in reducing serum testosterone to castration levels The Leuprolide Study Group. N Engl J Med 1984;311:1281 Only one clinical trial showed 9 mo increased survival for triptoreline (97%) in comparison to leuprolide (90,5%). Heyns DF et al. Br J Urol 2003;92:226

EAU Guidelines, 2007

an unsolvable equation? The T3 Dilemma an unsolvable equation? 2. External beam radiotherapy (EBM) and concomitant hormonal therapy 1. What is a T3? 3. A role for surgery ?

The T3 Dilemma 1. What is a T3?

appropriate definition? Locally Advanced PCa: appropriate definition? Sphincter invasion T4 Neuro-Vascular Bundle Invasion NV bundle Invasion NV bundle Extension Seminal Vesicle Extension Bladder neck T4

Locally advanced PCa (T3) Definition : T3N0M0 (+ biopsies, MRI) cT3a cT3b (Boccon Gibod L, I J Clin Pract 2003) Prevalence : 10% in screening situation / 15-20% in daily practice Heterogeneous prognosis factors (cT, PSA, Gleason, pT…) 15-25% pT2 40-50% pT3 10% pT4 25-30% pN1 « High Risk » of biochemical and clinical progression (Schelhammer PF, Semin Urol Oncol 1997 - Visser O, NTG 1996 - CCAFU 2007)

Definition of cT3 = DRE cT3 has been re-defined Over stadification = 9 - 27 % Carver et al J Urol 2006, Hsu et al Eur Urol 2007, Xylinas et al, BJU 2009 cT3 has been re-defined MRI endopelvic coil = improvement sensibility, specificity

Difficult to dissociate volume, local invasion and agressivity in current series (lack of randomized trials) Apperance of a ‘T3-MRI’

2. External beam radiotherapy (EBM) and concomitant hormonal therapy The T3 Dilemma 2. External beam radiotherapy (EBM) and concomitant hormonal therapy

Combination Hormone therapy and irradiation: rational Spatial cooperation (local + distant) Additive effect Supra-additive apoptotic effect More important in case of neo-adjuvant hormonal treatment Prolonged decrease of cells growth

major trials have defined IRRADIATION + long HT as a standard in T3 PCa  RTOG 85–31  EORTC 22863  EPC RTOG 92–02 EORTC 22961

In favor of Hormone therapy Median follow-up 7.6 years Trial RTOG 85-31 (MV Pilepich IJROBP 2005;61:1285-90) Goserelin Tt adjuvant undefined (start = last week. EBR) EBR 65 – 70 Gy 977 patients T3 N ou T1-2 N1 After RP : pT3a R1 ou pT3b EBR 65 – 70 Gy Surveillance HT if clinical recurrence In favor of Hormone therapy Median follow-up 7.6 years Results at 10 years  local recurrence (23% vs 38%)  M+ (24% vs 39%)  specific death (16% vs 22%)  overall survival (49% vs 39%) Advantage ++ Tumors SG > 7 No  overall survival if GS < 6 No  specific survival if GS ≥ 7

In favor of hormontherapy Median follow-up 66 months EORTC Trial 22863 (M Bolla Lancet 2002;360:103-108) EBR 50 Gy pelvis 20 Gy boost Goserelin adjuvant Tt 3 years (start = J1 RT) + anti-androgen 1st month 415 patients T3-4, N0-x T1-2, N0-x, G3 EBR 50 Gy pelvis 20 Gy boost Surveillance HT if recurrence In favor of hormontherapy Median follow-up 66 months All patients  local control  M+  survie bNED  specific survival  overall survival (78% vs 62% at 5 years)  death from cardiovascular causes at 10 years (6% vs 4,2%)

Time from randomisation (years) Trial EORTC 22863 100 90 80 70 60 50 40 30 20 10 Combined treatment Overall survival % Log-rank p < 0,0001 HR : 0,51 IC 95 % ; 0,36 - 0,73 Irradiation alone 1 2 3 4 5 6 7 8 Time from randomisation (years) 0 N Patients at risk 81 50 208 207 199 197 177 183 146 166 106 142 70 93 46 71 30 43 16 24 0 : number of death; n : number of patients Bolla, Lancet 2002

Locally advanced PCa EORTC 22863: at 10 years RTOG 85-31: at 10 years EBR EBR + HT Overall survival 39.8% 58.1% P< 0,0004 RT RT + HT Overall survival 38% 47% P< 0,004

What about EBR+ HT versus HT alone? TAP 032 trial RADIOTHERAPY COMBINED WITH ANDROGEN DEPRIVATION (leuprorelin) vs ADT IN CLINICALLY LOCALLY ADVANCED PROSTATE CANCER Mottet et al. ASCO 2010 Am Soc Clin Oncol; 4-8th June 2010 Abstr

TAP 032: STUDY DESIGN R1 – M0b < 90 days Treatment period : 3 years (ADT) (1 visit / 6 months) Without treatment period : 2 years (1 visit / 6 months) Post protocol follow-up (1 visit / year) R1 R2 2 months M6 M12 M18 M24 M30 M36 V V V V 3,5 4 4,5 5 M0b randomization M0a Selection M6 M12 M18 M24 M30 M36 V V V V 3,5 4 4,5 5 Centralized PSA (Hybritech) / 6 months Acute toxicity RTOG: M6

RESULTS 1 5 years overall PFS (ASTRO definition) % patients Years ADT group Combined group ADT group Combined group Median PFS: 7.7 vs 1.7 years p < 0.0001

RESULTS 2 5 years overall PFS (Phoenix definition) ADT group Combined group % patients Years ADT group Combined group Median PFS: 6.96 vs 3.46 years p = 0.0005

The T3 Dilemma 3. A role for surgery ?

“I cannot cure this patient” Why NO SURGERY for cT3 ? “I cannot cure this patient” Can have occult metastatic spread Can be pT3b = metastatic (?) Can be lymphnode positive – incurable (?) Can be T4 : damage to sphincter,rectum… I cannot obtain negative margins (= RT…)

Why NO SURGERY for cT3 ? “I cannot cure this patient” Can have occult metastatic spread Can be pT3b = metastatic (?) Can be lymphnode positive – incurable (?) Can be T4 : damage to sphincter,rectum… I cannot obtain negative margins (= RT…) “Let’s just give hormones and radiotherapy”

Which disease for surgery Which disease for surgery? (Gerber GS, Eur Urol 1997 - Van den Ouden D, Eur Urol 1998 Van Poppel H, Eur Urol 2000 - Lerner SE, LWW 2000 ) Best cases for surgery are: Stage cT3a (or MRI or biopsy) rather unilateral N0, M0 PSA ≤ 10-15 ng/ml (< 20 for Guidelines EAU) biopsy GS< 8 What do we need? : Confirm stage T3a Check for lymph node status (risk N+ 25 to 30%) Extensive lymph node dissection (frozen section?) Incorporate RP in a multimodal treatment

T2c, T3a or PSA > 20 ng/ml or GS biopsy ≥ 8 pN+ probability High Risk (D’Amico, JAMA 1998) T2c, T3a or PSA > 20 ng/ml or GS biopsy ≥ 8 Exhaustive lymphadenectomy pN+ expected 34% pN+ observed 55% Partin A, JAMA 1997 - Heidenreich A, Eur Urol 2007

Immediate vs Differed treatment

MRC Trial. Early hormone treatment improves cancer specific and overall survival in patients with advanced prostate cancer.

E.M. Messing et al., Lancet Oncol 7:472-479, 2006 Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy 1.0 0.8 0.6 12 14 10 0.2 0.4 47 51 Proportion alive Number at risk Immediate ADT Observation Observation n = 51 Immediate ADT n = 47 9 35 30 1 Time (years) Log-rank p = 0.04 Hazard ratio (95%Cl)=1.84 (1.01-3.35) 0.9 11 25 17 0.1 2 49 33 0.7 0.3 3 46 48 4 43 45 8 36 31 7 41 32 5 42 38 0.5 6 Overall survival E.M. Messing et al., Lancet Oncol 7:472-479, 2006

EORTC 30891: Intent-to-treat analysis of overall survival 100 90 80 70 60 50 At 10 years At 5 years 40 67.9% 95% CI :(63.7-72.1%) 30 60.1% 95% CI :(56.6-65.4%) 20 36.1% 95% CI :(30.3-41.9%) 10 25.0% 95% CI :(18.9-31.1%) (years) 2 4 6 8 10 12 14 O N Number of patients at risk : Treatment 257 492 428 349 221 112 48 2 Immediate 284 493 432 327 186 82 20 4 Deferred

EORTC 30891: Time until evidence of progression or death due to any cause in patients on the W and W arm and a Serum PSA between 8 and 50 ng/ml (years) 2 4 6 8 10 12 20 30 40 50 60 70 80 90 100 O N Number of patients at risk : PSA-DT 19 21 13 5 1 25 37 33 24 15 39 36 27 3 41 18 <=12 m >12-24 m >24-48 m >48m Logrank p<0.0001 PSA-DT 24-48m PSA-DT 12 m ~4-fold increased risk of progression or death PSA-DT>48 m PSA-DT 12-24m

EORTC Trial 30891: Overall Survival PSA<=8 20/31 11/27 PSA 8.1-20 21/39 20/42 PSA 20.1-50 19/31 16/38 PSA>50 21/30 16/25 Subtotal 81/131 63/132 (61.8 %) (47.7 %) 47/93 41/88 57/112 51/106 45/77 44/78 42/58 40/64 191/340 176/336 (56.2 %) (52.4 %) Total 272/471 239/468 (57.7 %) (51.1 %) Events / Patients Deferred Immediate HR & CI (Deferred Immediate) Age<=70 y Age>70 y Heterogeneity P=0.8 P=0.3 P=0.6 0.25 0.5 1.0 2.0 4.0 better

Intermittent versus continuous ADT Intermittent versus continuous androgen supression in advanced prostate cancer A randomised prospective study. Miller K et al. LBA 1723.J Urol Suppl. 177, 2007. Intermittent androgen deprivation in patients with PSA-relapse after radical prostatectomy. Final results of a european randomized prospective phase-III clinical trial AUO study AP 06/95, EC 507. Tunn Uf et al. A 600. J Urol Suppl.177, 2007. Intermittent androgen deprivation is at present widely offered to patients with CaP in various clinical settings, and its status should no longer be regarded as investigational. EAU.

Transition of tumour prostate cells under hormone-deprivation Androgen – independence Androgen - dependence Androgen-resistance

Conclusions IN case of cT3, explore thoroughly for the risk of micro-metastases N+ VS+ GS  8 High PSA (> 15 ng/ml ?) If the risk exists, gold standard treatment is irradiation + hormonal therapy If no apparent risk , IRM is useful ++ if T2 MRI => RP (young patients) if pN0  post operative EBM if T3a MRI => irradiation + HT short or RP Mg - Role for lymphadenectomy +++ ANDROGEN DEPRIVATION REMAINS AN ESSENTIAL THERAPEUTIC OPTION IN HIGH RISK PCa