Oncology 12 Locally Advanced Prostate Cancer Matthew Liew Michal Smolski Mr Jeremy Oates

Summary of talk Lecture - M Smolski Microteaching – M Liew Definition of LAPC Problems with staging Treatment options Prognosis Microteaching – M Liew neoadjuvant and adjuvant treatment combined with radiotherapy Viva questions – M Liew Is there a role for RRP in men with LAPC? Define PSA failure following treatment How do you deal with rising PSA post radical treatment?

Locally Advanced Prostate Cancer (LAPC) Proportion of patients presenting with LAPC (T3 or T4) has decreased in the past 20 years largely as a result of widespread PSA screening Cooperberg MR et al, JCO. 2005 Accounts for over 27% of new CaP presentations in UK 25-40% of cT1/T2 CaP fail after radical treatment Boustead et al, BJUI. 2007 It remains a common clinical challenge and management is controversial Eastham JA et al. Urol Oncol 2010

LAPC: Definition There is no universally agreed definition of ‘locally advanced’ disease amongst clinicians Payne, BJC. 2011 .... Many believe that definition should include localised tumours (T1/2) with ‘high risk’ features. No universal definition. Yossepowitch et al. [10] compared eight different definitions of high-risk PCa to classify 4708 men treated with RP. Depending on the definition used, the 5-yr BCR-free survival ranged from 49% to 80%. Clearly, because of the lack of a uniform definition of high-risk PCa, studies evaluating high-risk PCa include heterogeneous populations and report a large variance in outcomes.  Therefore there is an urgent need to produce a subclassification of high-risk PCa into different prognostic categories. 4

LAPC: Definition Clinical diagnosis whereby the tumour has extended beyond the capsule with no evidence of nodal or distant metastatic spread Oh WK et al. JCO 1999. 5

Tumor fixed or invades adjacent structures T3b Seminal vesicle invasion T3a Extracapsular extension (UL/BL) AJCC 2009 Clinical disease American joint committee on cancer

LAPC: Definition cT3b-4 National Comprehensive Cancer Network (NCCN) clinical practice guidelines in Oncology.

LAPC: Definition All the following definitions apply and have been used in clinical trial settings: T3 or T4; or N1 with any T stage, without evidence of distant metastasis. Clinical T1/ T2 with high risk features* with likelihood of EPE or clinically undetectable mets. PT2/T3 with high risk features owing to upstaging following radical prostatectomy. EUA guidelines: T3-T4, Nx-N0, M0 * ‘High risk’ features (D’Amico, 1997): PSA >20 ng/ml or Gleason score >7 8

LAPC: Natural history Prostate cancer is inherently biologically heterogeneous Development of metastatic disease from T3/T4 CaP significantly reduces disease specific survival (56.5% to 5.7% 15 years) Stage N 15 year PFS 15 year DSS % 95% CI T1-T2 300 48 37.3-58.7 80.9 73.6-88.2 T3-T4 183 46.6 32.7-60.5 56.5 44.6-68.4 M+ 159 6.2 0.8-10.6 5.7 -0.1-11.5 Johansson et al, JAMA,1997;227:467-471

Prognostic model for high risk CaP Stratification of High-risk Prostate Cancer into Prognostic Categories: A European Multi-institutional Study Prognostic model for high risk CaP Joniau et al. Eur Urol 2015  a good prognosis subgroup (one single high-risk factor); an intermediate prognosis subgroup (PSA >20 ng/ml and stage cT3–4); and a poor prognosis subgroup (GS 8–10 in combination with at least one other high-risk factor). The predictive accuracy of the models was summarized and compared. Survival estimates and clinical and pathologic outcomes were compared between the three subgroups. Joniau et al. Eur Urol 2015

Case Pt 83 ASA 3 WHO 2 CaP G4+3 cT2b PSA10 What’s next?

LAPC: Investigations Prostate multiparametric MRI should be used in local staging only if its results change patient management. Bone scan is recommended in asymptomatic patients only if the PSA level > 10 ng/mL or Gleason score ≥ 8 or clinical stage ≥ T3 (i.e. intermediate-/high-risk situations). Lymph node imaging (using CT or MRI) is recommended in asymptomatic patients only if the PSA level > 10 ng/mL or Gleason score ≥ 8 or clinical stage ≥ T3 (i.e. intermediate-/high-risk situations). 12

Problems with local staging in LAPC Discussed fully in oncology 10… DRE underestimates tumour extension1 (Positive correlation in <50%) TRUS reveals only 60% of pT3 lesions2 : ‘no better than DRE’3 MRI effective, but not sufficiently reliable to make mandatory Moderate ability to localise extra-capsular extension (problems with T3A) Can show seminal vesicle involvement Spigelman SS et al. J Urol 1986; 136(6):1228-1230 Enlund A et al. Acta Radiol 1990;31(6):597-600 Liebross RH etal. Cancer 1999;85(7):1577-1585

Problems with nodal staging in LAPC Only useful when findings affect outcome i.e. planned curative treatment High PSA, poor differentiation, peri-neural invasion associated with nodal disease Gleason 4 If predominant pattern 4 or >3 cores, N1 risk 20-45% Remaining pts, risk <2.5% (i.e. Staging not indicated) MRI or CT for determining presence of pelvic LN metastasis Radiological threshold traditionally at 1cm Eur Urol Feb 2012: LN dissection in RRP: 25% of <1cm LN removed were positive. May be reactive (FNA/ LN biopsy is associated with false negative rate of 40%) Haese A et al. Cancer 2002;95(5):1016-1021

Case CaP G4+3 PSA10 T3 N0 M0 Treatment options?

Treatment of LAPC Management depends on: Extent of disease Life expectancy 5-10 years for treatment with curative intent Co-morbidity Patient’s expectations/ wishes Grade of tumour PSA

LAPC: Treatment Options Observation/ deferred treatment Radiotherapy +/- hormone therapy Radical surgery +/- hormone therapy Radical surgery +/- radiotherapy Hormone therapy +/- radiotherapy ….typically requires a multimodal approach 17

LAPC: Deferred Treatment Generally used for patients unfit for radical treatment -> ADT when disease progresses. No RCT showing that ADT may be safely delayed until metastatic progression. No survival advantage with imm. orchidectomy compared with delayed Rx Rana et al, BJC. 1994 EORTC 30981 (Studer et al, JCO, 2006): RCT of 985 asymptomatic M0 pts unfit for local definitive Rx- compared imm. ADT or ADT on symptomatic progression. Imm. ADT assoc with a small increase in OS, BUT no sig difference in CaP mortality. MRC study (BJU, 1997): 943 patients not suitable for curative treatment. Early vs delayed hormones also showed a survival benefit for immediate ADT treatment (26% vs 46% distant mets, respectively) Adolfsson (J Urol, 1999): 50 unsymptomatic pts with well differentiated T3M0 CaP long term FU. 5- and 10- year CSS: 90% and 74%; with freedom from treatment 40% and 30%... WW might be a treatment option for selected Pts with non-poorly diff T3 tumours and a LE <10 years. EORTC The EORTC 30891 trial recruited 1005 patients with T0-4N0-2M0 prostate cancer not suitable for/unwilling to undergo local treatment with curative intent. The trial showed a small, but significant difference in overall survival in favor of immediate androgen deprivation (ADT) compared to deferred ADT. Thus, some subgroups of patients obviously did benefit from immediate ADT, however, other patients didn’t require ADT at all: after a median time of 7 years, only 50% of the patients on the deferred ADT arm had started treatment and 25% died without ever requiring ADT Patients with a serum PSA > 50ng/ml at entry and/or with a PSA doubling time ≤ 12 months are at increased mortality risk. We recommend immediate ADT for these high risk patients. Patients with low PSA and slow doubling time may likely be spared the burden of ADT. These results are exploratory and require validation by other randomized trials. MRC study 1997. n=938 (501 locally advanced disease). The majority of deaths (67%) were attributed to prostate cancer. Cancer-specific mortality was 55% in the early AD group and 43% in the deferred group (P = .001). Overall survival was also improved in the immediate AD arm (P = .02). The reduction in prostate cancer death was primarily due to patients with M0 disease.

Case 2 66 CaP G4+3 15%, PSA 10, T3, N0, M0 ASA 1 WHO 0

LAPC: Surgical Treatment ‘Reserved for patients with low risk of extra-prostatic spread/ LN involvement therefore NOT widely accepted treatment for LAPC’ Surgical treatment of cT3 disease has traditionally been discouraged due to increased PSM, LN mets and distant relapse. Local recurrence in pT3 disease has been reported in up to 30% (Hanks et al, 1988)

LAPC: Surgical Treatment ‘Reserved for patients with low risk of extra-prostatic spread/ LN involvement therefore NOT widely accepted treatment for LAPC’ Surgical treatment of cT3 disease has traditionally been discouraged due to increased PSM, LN mets and distant relapse. Local recurrence in pT3 disease has been reported in up to 30% (Hanks et al, 1988) However data from Mayo clinic challenged this view (Amling et al, 1997) Large group of clinical T3 disease treated with primary radical prostatectomy. 25% organ confined disease on pathology-> potentially cured by surgery alone CSS rates at 5, 10 and 15 years were 93%, 84% and 74% respectively. Other studies provide increasing evidence supporting the role of surgery in LAPC (Gerber 1997, Ward JF 2005 and Hsu 2007)

LAPC: Surgical Treatment Monotherapy cT3 Disease, Gleason Score <8 PSA < 10ng/ml Lymph Nodes and Seminal Vesicles Negative 10 yr Cancer Specific Survival 57 – 72% (OS – 60%) Van Poppel H et al. Eur Urol 2008;53:253 22

Radical Prostatectomy in LAPC: 10 yr Single Institution Studies No of Pts Overall Survival % Cancer Spec Survival % Biochemical PFS % Ward et al 2005 841 76 90 43 (PSA >0.4) Hsu et al 2007 200 77 91 51 (PSA >0.2) Ward 5652 pts fu 10years ccs 90% 10 year no diff t2 t3 morbidity and survial Ward et al. BJU Int 2005;95:751 Hsu C-Y et al. Eur Urol 2007;51:121 23

Surgery Versus Radiotherapy for Locally Advanced Prostate Cancer (SPCG-15) This prospective, open randomized phase III surgical trial seeks to study whether radical prostatectomy (with or without the combination of external radiation) improves prostate-cancer specific survival in comparison with primary radiation treatment and hormonal treatment among patients diagnosed with locally advanced (T3) prostate cancer.

Open vs minimally invasive surgery No randomised trials. Retrospective analyses only.1,2 1.Pierorazio et al. BJU Int 2013;112:751 2.Punnen et al. BJU Int 2013;112:E314 Both equivalent??

RP is a reasonable treatment option in selected patients with cT3a PCa, GS 8-10 or PSA > 20.

Case 2 66 CaP G4+3 15%, PSA 9, T3, N0, M0 ASA 1 WHO 0 RP What is his further management?

Radical Prostatectomy in LAPC Most patients benefit from Multimodality Treatment Therapy Multimodal Adjuvant Radiotherapy Salvage Radiotherapy Hormone Treatment 29

Immediate Post Op Radiotherapy After Radical Prostatectomy 1005 Pts PT2/T3N0 Randomised to Adj: RT or WW Path: Risk Factors Surgical Margins +ve Invasion of Seminal Vesicles Follow –up 5y Biochemical Progression Free Clinical Progression Free Survival Radiotherapy Biochemical PFS Wait & See Radiotherapy Wait & See Clinical PFS Bolla M et al. Lancet 2005;366:572– EORTC Study 22911 30

Immediate Post Op Radiotherapy After Radical Prostatectomy 60Gy DXT 5 years FU immediate (adjuvant) vs deferred: Biochem PFS: 72% vs 51% (p<0.0001) Clinical PFS: 83% vs 75% (p=0.004) OS: approx. 92% (no difference at 5 years) Grade 3 toxicity: 4.2% vs 2.6% (p=0.07)  Bolla By year 5, immediate postoperative irradiation could prevent 291 events/1,000 patients with positive margins versus 88 events/1,000 patients with negative margins.  Provided careful pathology of the prostatectomy is performed, our results suggest that immediate postoperative radiotherapy might not be recommended for prostate cancer patients with negative surgical margins. These findings require validation on an independent data set Bolla M et al. Lancet 2005;366:572– EORTC Study 22911 31

SWOG 8794 Immediate Post Op Radiotherapy After Radical Prostatectomy (JAMA, 2006) 425 pts with pT3 disease to receive DXT to prostate bed immediately post prostatectomy, or observation and salvage Rx FU at 10 years: Significant improvement in biochemical control in immediate DXT group Trend towards improved metastasis- free survival HR 0.75 (0.55-1.02) and OS HR 0.8 (0.58-1.09) SEs (immediate DXT vs observation): Proctitis (3.3% vs 0%) Urethral stricture (17.8% vs 9.5%) Urinary incontinence (6.5% vs 2.8%). … There are now new standards of DXT treatment i.e. dose increase to 64-66 Gy and more precise delivery methods (3DCRT ‘gold standard’ or IMRT). Among the 425 men, median follow-up was 10.6 years In men who had undergone radical prostatectomy for pathologically advanced prostate cancer, adjuvant radiotherapy resulted in significantly reduced risk of PSA relapse and disease recurrence, although the improvements in metastasis-free survival and overall survival were not statistically significant. 

Ongoing multicentre trial: RADICALS Radiotherapy and Androgen Deprivation In Combination After Local Surgery use current standards of care (i.e. dose delivery) International phase 3 study. 4000 pts [start 12/11/2007; End mid 2015] Examine timing of post op DXT: adjuvant vs delayed Addition and duration of concomitant ADT Randomise to no ADT vs 6 months vs 24 months (There is little data available on ADT post prostatectomy) Inclusion • Post-operative serum PSA ≤0.2ng/ml • More than 4 weeks and less than 22 weeks after radical prostatectomy • At least one of: pT3/4 - Gleason 7-10 (biopsy or surgical sample) Pre-operative PSA ≥10ng/ml - positive margins www.radicals-trial.org Hormon duration arm – no 6 24 Radiotherapy timing early vs delayed

Lymph Node Staging in CaP The most accurate staging method for the assessment of lymph node involvement is eLND Low-risk (cT1c-2a and Gleason score ≤6 and PSA <10) lymph node dissection can be safely omitted Intermediate-risk (cT2b-c or Gleason score 7 or PSA 10-20) High-risk (≥cT3 or Gleason score ≥8 or PSA >20) eLND * should be performed if the risk of positive lymph nodes exceeds 5% and limited LND should no longer be performed. Heidenreich A, Bolla M, Joniau S. et al. EAU prostate cancer guidelines. www.uroweb.org * eLND: extended to aortic bifurcation 34

Radical Prostatectomy Node Involvement Schumacher MC et al.Eur Urol 2008;54:344 35

Post Radical Prostatectomy Any T Stage with Node Involvement Messing E M et al.Lancet Oncol 2006;7:472 36

ECOG 7887 98 patients with nodal metastasis (T1-2, N+) treated with prostatectomy and LN dissection Randomised to adjuvant ADT or observation Median FU 11.9 years Results: Addition of adjuvant ADT increased OS by 2.6 years median OS 13.9 vs 11.3 years Increased CSS: 4.09 (p=0.0004)

Case 3 75 CaP G4+4 60%, PSA 15, T3, N0, M0 ASA 1 WHO 0 What are the management options?

LAPC: Radical Radiotherapy Increased radiation dose is associated with increased cancer cell death.... BUT also increased toxicity to normal surrounding tissue 3DCRT improves precision of EBRT as allows beams to be shaped to target volume. (Dearnaley Lancet 1999): Same efficacy but significantly reduced rectal toxicity compared to unshaped EBRT (at 64Gy). > subsequently increased doses subsequently used (Pollack et al, IJROBP. 2002): randomised 305 patients with T1-3 disease and PSA >10 to receive 70Gy or 78Gy Significant ‘freedom from failure’ rate 42% vs 62% respectively. Freedom from metastasis: 88% vs 98% at 6 years. IMRT is an advanced form of 3DCRT using computer assisted technology to modify and shape the intensity of radiotherapy beams to increase precision further. 64 -74 in 2gy -78 pollack 39

LAPC: Radical Radiotherapy EBRT (external beam radiotherapy) is an established treatment for all stages of CaP In locally advanced disease, some patients may have early disease progression if used alone (Shipley et al, JAMA. 1999) Major independent prognostic factors for CaP related death in patients treated with EBRT are: Gleason score (GS), T stage and LN status: Risk Group 1: GS 2-6, T1-2, N0 Risk Group 2: GS 2-6, T3N0; or GS 2-6, N+, or GS 7, T1-2N0. Risk Group 3: GS 7, T3N0; or GS 7, N+, or GS 8-10, T1-2N0. Risk Group 4: GS 8-10, T3N0; or GS 8, N+, GS 8-10N+ Risk Group 5 year DSS (%) 10 year DSS (%) 15 year DSS (%) 1 96 86 72 2 94 75 61 3 83 62 39 4 64 34 27 Four prognostic groups predict long-term survival from prostate cancer following radiotherapy alone on Radiation Therapy Oncology Group clinical trials. Int J Radiat Oncol Biol Phys. 2000 Jun 1;47(3):609-15. Roach et al, 2000 40

LAPC: Radical Radiotherapy EBRT (external beam radiotherapy) is an established treatment for all stages of CaP In locally advanced disease, some patients may have early disease progression if used alone (Shipley et al, JAMA. 1999) Major independent prognostic factors for CaP related death in patients treated with EBRT are: Gleason score (GS), T stage and LN status: Risk Group 1: GS 2-6, T1-2, N0 Risk Group 2: GS 2-6, T3N0; or GS 2-6, N+, or GS 7, T1-2N0. Risk Group 3: GS 7, T3N0; or GS 7, N+, or GS 8-10, T1-2N0. Risk Group 4: GS 8-10, T3N0; or GS 8, N+, GS 8-10N+ Risk Group 5 year DSS (%) 10 year DSS (%) 15 year DSS (%) 1 96 86 72 2 94 75 61 3 83 62 39 4 64 34 27 Roach et al, 2000 … conventional EBRT alone is inadequate for high risk CaP treatment 41

Microteaching

Radical Radiotherapy EUA Guidelines 2014 LE For high-risk patients, long-term ADT before and during radiotherapy is recommended, as it results in increased overall survival. 2a In patients with locally advanced PCa (T3-4 N0 M0), who are fit enough to receive EBRT, the recommended treatment is EBRT plus long-term ADT and the use of ADT alone is inappropriate. 1b In patients with pathological tumour stage T3 N0 M0, immediate post-operative external irradiation after RP may improve the biochemical and clinical disease-free survival, with the highest impact in cases of positive margins. In patients with locally advanced PCa T3-4 N0 M0, concomitant and adjuvant hormonal therapy for a total duration of 3 years, with external-beam irradiation for patients with WHO 0-2 performance status, is recommended, as it improves the overall survival. In a subset of patients with T2c-T3 N0-x and a Gleason score of 2-6, short-term ADT before and during radiotherapy may favourably influence overall survival In patients with very high-risk prostate cancer, c-pN1 M0 with no severe co-morbidity, pelvic external irradiation and immediate long-term adjuvant hormonal treatment improve overall survival, disease-specific failure, metastatic failure and biochemical control 2b EUA Guidelines 2014

LAPC: Androgen Deprivation Therapy (ADT) Indications for use in LAPC: Need for local control Need to treat micro-metastasis undetectable with current imaging techniques Treat symptomatic disease Treatment benefits need to outweigh risks… There is still controversy in whether immediate ADT has positive effect on OS and QoL in asymptomatic LAPC (and met CaP) due to lack of quality RCTs. Role of immediate ADT in selected patients (i.e. young, N+ and high PSA) - EORTC 30891 study ASCO guidelines: NO recommendations for initial ADT in asymptomatic progressive or advanced disease Good evidence for use in LAPC is in combination with radiotherapy (LE 1b)

ADT treatment includes: Orchidectomy (‘gold standard’) Simple & cost effective Quick palliation Compliance not a problem Nonreversible Carries significant psychological burden Risk-Surgical complications Side effects-Vasoactive symptoms, weight gain, mood lability, gynaecomastia, fatigue, loss of libido, cognitive changes, osteopaenia, hypercholesterolemia LHRH analogues Costly Risk of tumour flare Potentially reversible Convenient No psychological burden Anti-androgens are inferior compared to LHRHa (Thorpe et al, Eur Uro,1996)

LAPC: Androgen Deprivation Therapy (ADT) SPCG-7 3 months hormones followed by flutamide vs. hormones and addition of RRT (Gy) At 10yrs, 12% absolute risk reduction in prostate cancer deaths in combined group (11.9% vs. 23.9%) corresponding to 56% relative risk reduction. Widmark et al. 2009 Lancet

EAU 2014 Guidelines: hormonal therapy Castration Benefits LE M1 symptomatic To palliate symptoms and to reduce the risk for potentially catastrophic sequelae of advanced disease (spinal cord compression, pathological fractures, ureteral obstruction, extraskeletal metastasis) 1b M1 asymptomatic Immediate castration to defer progression to a symptomatic stage and prevent serious disease progression-related complications (114) An active clinical surveillance protocol might be an acceptable option in clearly informed patients if survival is the main objective 3 Locally advanced (as single treatment for patients unwilling or unable to receive any form of associated local treatment) Immediate castration should be considered in the most aggressive situations (PSA > 50 ng/mL, PSADT< 12 months). Otherwise a wait-and-see policy with deferred treatment at clinical progression is a reasonable option. 2a Intermittent treatment Threshold to start and stop ADT The threshold is empirically chosen. However, it should reproduce what has been used in clinical trials.m In trials, treatment is usually stopped when the PSA mlevel is < 4 ng/mL (M1) and < 0.5-4 ng/mL (relapsing). Treatment is usually re-started when the PSA is > 4-10 (relapsing) and > 10-20 ng/mL (M1). 4

Any T, N+ disease EBRT + hormones (RTOG 85 - 31) Prostatectomy and LND (no RCT, some studies show CSS 90% - 5years1 Hormones 1. Joniau et al. 2012 Scand J Urol Neph

Conclusions Definition of LAPC is not universally agreed Clinical and Radiological staging is frequently suboptimal Treatment options often include multimodal treatments: Observation/ deferred treatment Hormone therapy Radiotherapy +/- hormone therapy Radical surgery +/- radiotherapy Radical surgery + hormone therapy Optimum treatment options are yet to be defined All cases should be discussed in SMDT setting and require risk stratification to avoid the morbidity of overtreatment and risks of disease progression with under-treatment The results of ongoing clinical trials (e.g. RADICALS) are awaited

LAPC: ADT + Radiotherapy SPCG-7 875 patients with LAPC received MAB therapy alone or combined with 3D conformal RT after 3 months Addition of RT to ADT halved 10-year DSS: 23.9% vs 11.9% (p<0.001) Addition of RT also significantly improved overall mortality (p=0.004) and PSA recurrence (p<0.0001) Widmark et al, Lancet 2009 Disease specific survival (DSS): The percentage of people in a study or treatment group who have not died from a specific disease in a defined period of time. 50

Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial. (Warde et al, Lancet Nov 2011) ‘Up to 45% patients of LAPC are treated by ADT alone (CaPSURE)’ Data regarding addition of RT to ADT in LAPC is unclear Methods: 1057 men with T3/T4 CaP randomised to lifelong ADT +/- RT (65-9 Gy to prostate/SV, 45 Gy to pelvic nodes). Median age: 69.7 Endpoint: OS. Results: Study showed adding radiation to ADT significantly improves survival At 7 yrs, 74% receiving ADT + EBRT were alive compared to 66% receiving ADT alone (p=0.033) HR QoL: small increased GI toxicity (rectal bleeding: 0.5% vs 0.3%). Urinary toxicity 2-3% for both groups. ‘The benefits of combined modality treatment ADT and RT should be discussed with all patients with locally advanced prostate cancer’ 51

LAPC: Radical Radiotherapy + adjuvant ADT 415 patients T1-2, High Grade (WHO Grade 3) Or Stage T3-T4 N0-N1 M0, any grade Randomized to 3 years of hormone ablation with DXT vs DXT alone 70 Gy Endpoint: disease free survival Bolla et al Lancet 2002 360 103 52

LAPC: Radical Radiotherapy + adjuvant ADT EORTC 22863 401 pts. median f/u 4.5 years 5 year estimates n Disease free Overall survival survival DXT 190 48% 62% DXT + Goserelin 195 76% 78% Bolla et al Lancet 2002 360 103 53

Short-term neo-adjuvant androgen deprivation and radiotherapy for locally advanced prostate cancer: 10-year data from the TROG 96.01 randomised trial. (Denham et al, Lancet Oncol. 2011) The magnitude of benefit for 6-month NADT (neoadjuvant androgen deprivation therapy) compared with radiotherapy alone is remarkable at 10 years, risk of death from prostate cancer was halved (from 22·0% to 11·4%), and all-cause mortality was reduced by a third (from 42·5% to 29·2%) TROG 96.01 is an important trial and has two clear messages for current clinical practice: First, it confirms that NADT significantly reduces mortality after radiotherapy for high-risk prostate cancer, and is a standard of care. Second, it helps to resolve the uncertainty regarding NADT duration, and strongly suggests that men receiving NADT should have at least 6 months of treatment