title: Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. Interval to testosterone recovery after hormonal therapy for prostate cancer and risk of death. Androgen priming and chemotherapy in advanced prostate cancer: evaluation of determinants of clinical outcome. The efficacy and safety of degarelix: a 12‐month, comparative, randomized, open‐label, parallel‐group phase III study in patients with prostate cancer Morbidity and functional outcomes of salvage radical prostatectomy for locally recurrent prostate cancer after radiation therapy. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. Multinational, double-blind, phase III study of prednisone and either satraplatin or placebo in patients with castrate-refractory prostate cancer progressing after prior chemotherapy: the SPARC trial. Casodex 10-200 mg daily, used as monotherapy for the treatment of patients with advanced prostate cancer. An overview of the efficacy, tolerability and pharmacokinetics from three phase II dose-ranging studies. Casodex Study Group. The efficacy and complications of salvage cryotherapy of the prostate. Prostate cancer-specific survival following salvage radiotherapy vs observation in men with biochemical recurrence after radical prostatectomy. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1–2 study Using PSA to guide timing of androgen deprivation in patients with T0-4 N0-2 M0 prostate cancer not suitable for local curative treatment (EORTC 30891). Immediate or deferred androgen deprivation for patients with prostate cancer not suitable for local treatment with curative intent: European Organisation for Research and Treatment of Cancer (EORTC) Trial 30891. Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Role of androgen deprivation therapy for node-positive prostate cancer. Early versus delayed hormonal therapy for prostate specific antigen only recurrence of prostate cancer after radical prostatectomy. Duration of first off-treatment interval is prognostic for time to castration resistance and death in men with biochemical relapse of prostate cancer treated on a prospective trial of intermittent androgen deprivation. Intermittent versus continuous total androgen blockade in the treatment of patients with advanced hormone-naive prostate cancer: results of a prospective randomized multicenter trial. Reconsideration of orchiectomy in the treatment of advanced prostatic carcinoma. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. Phase II multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxel-treated castration-resistant prostate cancer. Additional analysis of the secondary end point of biochemical recurrence rate in a phase 3 trial (CS21) comparing degarelix 80 mg versus leuprolide in prostate cancer patients segmented by baseline characteristics.
abstract: BACKGROUND Mitoxantrone-based chemotherapy palliates pain without extending survival in men with progressive and rogen-independent prostate cancer . We compared docetaxel plus estramustine with mitoxantrone plus prednisone in men with metastatic , hormone-independent prostate cancer . METHODS We r and omly assigned 770 men to one of two treatments , each given in 21-day cycles : 280 mg of estramustine three times daily on days 1 through 5 , 60 mg of docetaxel per square meter of body-surface area on day 2 , and 60 mg of dexamethasone in three divided doses before docetaxel , or 12 mg of mitoxantrone per square meter on day 1 plus 5 mg of prednisone twice daily . The primary end point was overall survival ; secondary end points were progression-free survival , objective response rates , and post-treatment declines of at least 50 percent in serum prostate-specific antigen ( PSA ) levels . RESULTS Of 674 eligible patients , 338 were assigned to receive docetaxel and estramustine and 336 to receive mitoxantrone and prednisone . In an intention-to-treat analysis , the median overall survival was longer in the group given docetaxel and estramustine than in the group given mitoxantrone and prednisone ( 17.5 months vs. 15.6 months , P=0.02 by the log-rank test ) , and the corresponding hazard ratio for death was 0.80 ( 95 percent confidence interval , 0.67 to 0.97 ) . The median time to progression was 6.3 months in the group given docetaxel and estramustine and 3.2 months in the group given mitoxantrone and prednisone ( P<0.001 by the log-rank test ) . PSA declines of at least 50 percent occurred in 50 percent and 27 percent of patients , respectively ( P<0.001 ) , and objective tumor responses were observed in 17 percent and 11 percent of patients with bidimensionally measurable disease , respectively ( P=0.30 ) . Grade 3 or 4 neutropenic fevers ( P=0.01 ) , nausea and vomiting ( P<0.001 ) , and cardiovascular events ( P=0.001 ) were more common among patients receiving docetaxel and estramustine than among those receiving mitoxantrone and prednisone .  Pain relief was similar in both groups . CONCLUSIONS The improvement in median survival of nearly two months with docetaxel and estramustine , as compared with mitoxantrone and prednisone , provides support for this approach in men with metastatic , and rogen-independent prostate cancer PURPOSE To assess whether the risk of death is associated with the time to testosterone recovery ( TTR ) after radiotherapy ( RT ) and hormonal therapy ( HT ) for prostate cancer ( PCa ) . PATIENTS AND METHODS Between 1995 and 2001 , 206 men with localized , unfavorable-risk PCa were r and omized to receive RT or RT plus 6 months of HT . A multivariate postr and omization Cox regression analysis was used to assess whether the TTR in years was associated with the risk of death after adjusting for the known prognostic factors , age , Adult Comorbidity Evaluation-27 score , and the use of HT for recurrence . RESULTS Of the 102 men r and omized to receive RT and HT  , 57 ( 56 % ) had a TTR of > 2 years , and none of these men had died of PCa after a median follow-up of 7.6 years . As the TTR increased , the risk of death decreased significantly ( adjusted hazard ratio , 0.60 ; 95 % confidence interval , 0.43 - 0.84 ; p = .003 ) . A significant interaction was noted between the TTR and the comorbidity score ( p = .002 ) . The survival estimates were similar ( p = 0.17 ) across the TTR values in men with moderate to severe comorbidity ; however , these estimates increased significantly ( p < .001 ) with decreasing PCa-specific mortality ( p = .006 ) as the TTR increased in men with no or minimal comorbidity . CONCLUSION The results of our study have shown that a longer TTR after RT plus 6 months of HT for unfavorable-risk PCa is associated with a lower risk of death in men with no or minimal comorbidity We conducted a r and omized clinical trial in men with stage D2 prostate cancer to test whether and rogen priming potentiates the efficacy of cytotoxic chemotherapy .  Eighty-five men with progressive prostate cancer refractory to orchiectomy were treated continuously with aminoglutethimide and hydrocortisone to lower adrenal and rogen secretion and were administered cyclic intravenous ( IV ) chemotherapy . The patients were r and omized to receive either and rogen priming or no additional treatment for three days before and on the day of chemotherapy . Median duration of follow-up was 43 months . Response rate ( remission plus disease stabilization ) was not significantly different between the stimulation and control arm when the analysis was restricted to evaluable patients ( 79 % v 73 % , respectively ) or when it was extended to all patients ( 46 % v 61 % ) . Median duration of response was similar for the stimulation and control arm ( 9 and 10 months , respectively ) . Median survival was 10 months in the stimulation and 15 months in the control group ( P = .0047 ) . The and rogen sensitivity of the tumors was supported by the greater toxicity in the stimulation arm associated with and rogen administration . Factors found to be independently associated with improved clinical outcome included a high Karnofsky score and hematocrit , long duration of response to the initial castration , and normalization of an elevated serum acid phosphatase on treatment . We conclude that in this group of patients with advanced disease , and rogen priming does not potentiate the efficacy of chemotherapy and is actually associated with a worse outcome . Furthermore , our data emphasize the heterogeneity of biologic behavior of prostate cancer To evaluate the efficacy and safety of degarelix , a new gonadotrophin‐releasing hormone ( GnRH ) antagonist ( blocker ) , vs leuprolide for achieving and maintaining testosterone suppression in a 1‐year phase III trial involving patients with prostate cancer PURPOSE Few patients with locally recurrent prostate cancer after external beam ( EB ) or interstitial ( I ) radiotherapy ( RT )  are considered c and i date s for salvage radical prostatectomy ( RP ) due to high reported rates of major complications and urinary incontinence . We report the morbidity associated with salvage RP in 100 consecutive patients . MATERIAL S AND METHODS From 1984 to 2003 salvage RP was performed for recurrent prostate cancer following EBRT in 58 cases , and IRT in 42 ( 28 retropubic ) and ( 14 transperineal ) . Clinical information was obtained from a prospect i ve data base . RESULTS Since 1993 , the major complication rate has decreased significantly ( 13 % vs 33 % , p = 0.02 ) , including the rectal injury rate ( 2 % vs 15 % , p = 0.01 ) . Compared with retropubic IRT and /or pre-radiotherapy pelvic lymph node dissection the risk of major complications following EBRT or transperineal IRT was significantly less ( OR 0.2 , p = 0.006 ) . At 5 years an estimated 39 % of patients were dry and 68 % required 1 pad daily or less . A total of 23 patients with moderate-severe incontinence underwent artificial sphincter placement . The anastomotic stricture rate was 30 % . The 5-year potency rate was 28 % following unilateral or bilateral nerve sparing RP and 45 % in previously potent patients . CONCLUSIONS Due to patient selection the major complication rate after salvage RP has improved significantly with time and it is similar to that of st and ard RP . Rates of anastomotic stricture and moderate to severe incontinence are higher than those observed after st and ard RP . However , most patients recover reasonable urinary continence and a substantial number of select patients recover potency . The acceptable morbidity profile of salvage RP following EBRT and transperineal IRT should persuade more physicians to consider patients for this potentially curative procedure PURPOSE To up date eligibility and outcome measures in trials that evaluate systemic treatment for patients with progressive prostate cancer and castrate levels of testosterone . METHODS A committee of investigators experienced in conducting trials for prostate cancer defined new consensus criteria by review ing previous criteria , Response Evaluation Criteria in Solid Tumors ( RECIST ) , and emerging trial data . RESULTS The Prostate Cancer Clinical Trials Working Group ( PCWG2 ) recommends a two- objective paradigm : ( 1 ) controlling , relieving , or eliminating disease manifestations that are present when treatment is initiated and ( 2 ) preventing or delaying disease manifestations expected to occur . Prostate cancers progressing despite castrate levels of testosterone are considered castration resistant and not hormone refractory . Eligibility is defined using st and ard disease assessment s to authenticate disease progression , prior treatment , distinct clinical subtypes , and predictive models . Outcomes are reported independently for prostate-specific antigen ( PSA ) , imaging , and clinical measures , avoiding grouped categorizations such as complete or partial response . In most trials , early changes in PSA and /or pain are not acted on without other evidence of disease progression , and treatment should be continued for at least 12 weeks to ensure adequate drug exposure . Bone scans are reported as " new lesions " or " no new lesions , " changes in soft-tissue disease assessed by RECIST , and pain using vali date d scales . Defining eligibility for prevent/delay end points requires attention to estimated event frequency and /or r and om assignment to a control group . CONCLUSION PCWG2 recommends increasing emphasis on time-to-event end points ( ie , failure to progress ) as decision aids in proceeding from phase II to phase III trials . Recommendations will evolve as data are generated on the utility of intermediate end points to predict clinical benefit PURPOSE Prostate-specific antigen ( PSA ) is a glycoprotein that is found almost exclusively in normal and neoplastic prostate cells . For patients with metastatic disease , changes in PSA will often ante date changes in bone scan . Furthermore , many but not all investigators have observed an association between a decline in PSA levels of 50 % or greater and survival . Since the majority of phase II clinical trials for patients with and rogen-independent prostate cancer ( AIPC ) have used PSA as a marker , we believed it was important for investigators to agree on definitions and values for a minimum set of parameters for eligibility and PSA declines and to develop a common approach to outcome analysis and reporting . We held a consensus conference with 26 leading investigators in the field of AIPC to define these parameters . RESULT We defined four patient groups : ( 1 ) progressive measurable disease , ( 2 ) progressive bone metastasis , ( 3 ) stable metastases and a rising PSA , and ( 4 ) rising PSA and no other evidence of metastatic disease .  The purpose of determining the number of patients whose PSA level drops in a phase II trial of AIPC is to guide the selection of agents for further testing and phase III trials . We propose that investigators report at a minimum a PSA decline of at least 50 % and this must be confirmed by a second PSA value 4 or more weeks later . Patients may not demonstrate clinical or radiographic evidence of disease progression during this time period . Some investigators may want to report additional measures of PSA changes ( ie , 75 % decline , 90 % decline ) . Response duration and the time to PSA progression may also be important clinical end point . CONCLUSION Through this consensus conference , we believe we have developed practical guidelines for using PSA as a measurement of outcome . Furthermore , the use of common st and ards is important as we determine which agents should progress to r and omized trials which will use survival as an end point BACKGROUND Sipuleucel-T , an autologous active cellular immunotherapy , has shown evidence of efficacy in reducing the risk of death among men with metastatic castration-resistant prostate cancer . METHODS In this double-blind , placebo-controlled , multicenter phase 3 trial , we r and omly assigned 512 patients in a 2:1 ratio to receive either sipuleucel-T ( 341 patients ) or placebo ( 171 patients ) administered intravenously every 2 weeks , for a total of three infusions . The primary end point was overall survival , analyzed by means of a stratified Cox regression model adjusted for baseline levels of serum prostate-specific antigen ( PSA ) and lactate dehydrogenase . RESULTS In the sipuleucel-T group , there was a relative reduction of 22 % in the risk of death as compared with the placebo group ( hazard ratio , 0.78 ; 95 % confidence interval [ CI ] , 0.61 to 0.98 ; P=0.03 ) . This reduction represented a 4.1-month improvement in median survival ( 25.8 months in the sipuleucel-T group vs. 21.7 months in the placebo group ) . The 36-month survival probability was 31.7 % in the sipuleucel-T group versus 23.0 % in the placebo group . The treatment effect was also observed with the use of an unadjusted Cox model and a log-rank test ( hazard ratio , 0.77 ; 95 % CI , 0.61 to 0.97 ; P=0.02 ) and after adjustment for use of docetaxel after the study therapy ( hazard ratio , 0.78 ; 95 % CI , 0.62 to 0.98 ; P=0.03 ) . The time to objective disease progression was similar in the two study groups . Immune responses to the immunizing antigen were observed in patients who received sipuleucel-T.  Adverse events that were more frequently reported in the sipuleucel-T group than in the placebo group included chills , fever , and headache . CONCLUSIONS The use of sipuleucel-T prolonged overall survival among men with metastatic castration-resistant prostate cancer . No effect on the time to disease progression was observed . ( Funded by Dendreon ; Clinical Trials.gov number , NCT00065442 . PURPOSE This multinational , double-blind , r and omized , placebo-controlled , phase III trial assessed the efficacy and tolerability of the oral platinum analog satraplatin in patients with metastatic castrate-refractory prostate cancer ( CRPC ) experiencing progression after one prior chemotherapy regimen . PATIENTS AND METHODS Nine hundred fifty patients were r and omly assigned ( 2:1 ) to receive oral satraplatin ( n = 635 ) 80 mg/m(2 ) on days 1 to 5 of a 35-day cycle and prednisone 5 mg twice daily or placebo ( n = 315 ) and prednisone 5 mg twice daily . Primary end points were progression-free survival and overall survival ( OS ) . The secondary end point was time to pain progression ( TPP ) . RESULTS A 33 % reduction ( hazard ratio [ HR ] = 0.67 ; 95 % CI , 0.57 to 0.77 ; P < .001 ) was observed in the risk of progression or death with satraplatin versus placebo . This effect was maintained irrespective of prior docetaxel treatment . No difference in OS was seen between the satraplatin and placebo arms ( HR = 0.98 ; 95 % CI , 0.84 to 1.15 ; P = .80 ) . Compared with placebo , satraplatin significantly reduced TPP ( HR = 0.64 ; 95 % CI , 0.51 to 0.79 ; P < .001 ) . Satraplatin was generally well tolerated , although myelosuppression and GI disorders occurred more frequently with satraplatin . CONCLUSION Oral satraplatin delayed progression of disease and pain in patients with metastatic CRPC experiencing progression after initial chemotherapy but did not provide a significant OS benefit . Satraplatin was generally well tolerated . These results suggest activity for satraplatin in patients with CRPC who experience progression after initial chemotherapy OBJECTIVES To evaluate the efficacy , tolerability , endocrinological effects and the pharmacokinetics of Casodex , when given as monotherapy during daily dosing of 10 - 200 mg to patients with advanced prostate cancer . METHODS A total of 390 patients with advanced prostate cancer were treated for a minimum of 12 weeks with a daily monotherapy dose of Casodex . The doses ranged from 10 to 200 mg . Objective assessment s of efficacy included : review of measurable metastases , prostate dimension , prostatic acid phosphatase and prostate-specific antigen ( PSA ) levels . Subjective assessment s of efficacy included review of urological symptoms , performance status , bone scan and analgesic requirement . Pharmacokinetic sample s were taken at various time points up to 3 months , and assayed using an achiral HPLC method . RESULTS Clear objective responses were observed , particularly at doses of 50 mg and above . Specifically , the median percentage decrease in PSA at 50 mg was 90.0 % , and at 100 and 200 mg it was 93.4 and 94.8 % , respectively . Up to 53 % of symptomatic patients demonstrated a subjective response at 3 months . Casodex was well tolerated at all doses with no effect on haematological or cardiovascular parameters and no effect on renal function . The expected pharmacological effects of potent anti and rogen therapy , such as breast tenderness ( 58 % ) , gynaecomastia ( 48 % ) , and hot flushes ( 17 % ) , were reported , but these incidences reflected the direct eliciting of these events . The intrinsic efficacy of Casodex was demonstrated despite increases of 60 % in testosterone levels . However , this increase reached a plateau after 4 - 12 weeks of therapy , but the majority of values remained within the normal range . Casodex has a half-life of approximately 1 week , enabling once-daily dosing with no effect of age or renal impairment on its pharmacokinetics . CONCLUSION Casodex has a favourable side effect profile compared with the known safety profiles of other anti and rogens and has demonstrated intrinsic efficacy . Casodex warrants further investigation as a monotherapy for the management of advanced prostate cancer PURPOSE A phase I/II study was done to evaluate the efficacy and complications of salvage cryotherapy as a treatment for locally recurrent prostate cancer following full dose radiation therapy and /or systemic therapy . The efficacy of single and double freeze-thaw cycles was compared using posttreatment prostate specific antigen ( PSA ) levels and prostate biopsies as end points . MATERIAL S AND METHODS A total of 150 patients with locally recurrent prostate cancer following radiation , hormonal therapy and /or systemic chemotherapy underwent salvage cryotherapy using  a single  ( 71 men , mean followup 17.3 months ) or  double  ( 79 men , mean followup 10.0 months )  freeze-thaw cycle .  PSA was measured approximately every 3 months postoperatively and sextant biopsies were repeated 6 months postoperatively . Complications were assessed by retrospective chart review and a mailed quality of life survey . RESULTS Overall , 45 patients ( 31 % ) had persistently undetectable PSA .  Patients with a history of radiation therapy only who underwent a double freeze-thaw cycle had a higher negative biopsy rate ( 93 versus 71 % , p < 0.02 ) and lower biochemical failure rate ( defined as an increase in serum PSA of 0.2 ng./ml . above the nadir value , 44 versus 65 % , p < 0.03 ) than those who underwent a single freeze-thaw cycle . The main complications of salvage cryotherapy were urinary incontinence ( 73 % of the patients ) , obstructive symptoms ( 67 % ) , impotence ( 72 % ) and severe perineal pain ( 8 % ) . CONCLUSIONS Salvage cryotherapy impacts local tumor control as evident by the high frequency of negative posttreatment biopsies . A double freeze-thaw cycle appears more effective than a single cycle . Like salvage prostatectomy , salvage cryotherapy causes significant morbidity CONTEXT Biochemical disease recurrence after radical prostatectomy often prompts salvage radiotherapy , but no studies to date have had sufficient numbers of patients or follow-up to determine whether radiotherapy improves survival , and if so , the subgroup of men most likely to benefit . OBJECTIVES To quantify the relative improvement in prostate cancer-specific survival of salvage radiotherapy vs no therapy after biochemical recurrence following prostatectomy , and to identify subgroups for whom salvage treatment is most beneficial . DESIGN , SETTING , AND PATIENTS Retrospective analysis of a cohort of 635 US men undergoing prostatectomy from 1982 - 2004 , followed up through December 28 , 2007 , who experienced biochemical and /or local recurrence and received no salvage treatment ( n = 397 ) , salvage radiotherapy alone ( n = 160 ) , or salvage radiotherapy combined with hormonal therapy ( n = 78 ) . MAIN OUTCOME MEASURE Prostate cancer-specific survival defined from time of recurrence until death from disease . RESULTS With a median follow-up of 6 years after recurrence and 9 years after prostatectomy , 116 men ( 18 % ) died from prostate cancer , including 89 ( 22 % ) who received no salvage treatment , 18 ( 11 % ) who received salvage radiotherapy alone , and 9 ( 12 % ) who received salvage radiotherapy and hormonal therapy . Salvage radiotherapy alone was associated with a significant 3-fold increase in prostate cancer-specific survival relative to those who received no salvage treatment ( hazard ratio [ HR ] , 0.32 [ 95 % confidence interval { CI } , 0.19 - 0.54 ] ; P<.001 ) . Addition of hormonal therapy to salvage radiotherapy was not associated with any additional increase in prostate cancer-specific survival ( HR , 0.34 [ 95 % CI , 0.17 - 0.69 ] ; P = .003 ) . The increase in prostate cancer-specific survival associated with salvage radiotherapy was limited to men with a prostate-specific antigen doubling time of less than 6 months and remained after adjustment for pathological stage and other established prognostic factors . Salvage radiotherapy initiated more than 2 years after recurrence provided no significant increase in prostate cancer-specific survival .  Men whose prostate-specific antigen level never became undetectable after salvage radiotherapy did not experience a significant increase in prostate cancer-specific survival .  Salvage radiotherapy also was associated with a significant increase in overall survival . CONCLUSIONS Salvage radiotherapy administered within 2 years of biochemical recurrence was associated with a significant increase in prostate cancer-specific survival among men with a prostate-specific antigen doubling time of less than 6 months , independent of other prognostic features such as pathological stage or Gleason score . These preliminary findings should be vali date d in other setting s , and ultimately , in a r and omized controlled trial BACKGROUND MDV3100 is an and rogen-receptor antagonist that blocks and rogens from binding to the and rogen receptor and prevents nuclear translocation and co-activator recruitment of the lig and -receptor complex . It also induces tumour cell apoptosis , and has no agonist activity . Because growth of castration-resistant prostate cancer is dependent on continued and rogen-receptor signalling , we assessed the antitumour activity and safety of MDV3100 in men with this disease . METHODS This phase 1 - 2 study was undertaken in five US centres in 140 patients . Patients with progressive , metastatic , castration-resistant prostate cancer were enrolled in dose-escalation cohorts of three to six patients and given an oral daily starting dose of MDV3100 30 mg . The final daily doses studied were 30 mg ( n=3 ) , 60 mg ( 27 ) , 150 mg ( 28 ) , 240 mg ( 29 ) , 360 mg ( 28 ) , 480 mg ( 22 ) , and 600 mg ( 3 ) . The primary objective was to identify the safety and tolerability profile of MDV3100 and to establish the maximum tolerated dose . The trial is registered with Clinical Trials.gov , number NCT00510718 . FINDINGS We noted antitumour effects at all doses , including decreases in serum prostate-specific antigen of 50 % or more in 78 ( 56 % ) patients , responses in soft tissue in 13 ( 22 % ) of 59 patients , stabilised bone disease in 61 ( 56 % ) of 109 patients , and conversion from unfavourable to favourable circulating tumour cell counts in 25 ( 49 % ) of the 51 patients . PET imaging of 22 patients to assess and rogen-receptor blockade showed decreased (18)F-fluoro-5alpha-dihydrotestosterone binding at doses from 60 mg to 480 mg per day ( range 20 - 100 % ) . The median time to progression was 47 weeks ( 95 % CI 34-not reached ) for radiological progression . The maximum tolerated dose for sustained treatment ( > 28 days ) was 240 mg . The most common grade 3 - 4 adverse event was dose-dependent fatigue ( 16 [ 11 % ] patients ) , which generally resolved after dose reduction . INTERPRETATION We recorded encouraging antitumour activity with MDV3100 in patients with castration-resistant prostate cancer . The results of this phase 1 - 2 trial vali date in man pre clinical studies implicating sustained and rogen-receptor signalling as a driver in this disease . FUNDING Medivation , the Prostate Cancer Foundation , National Cancer Institute , the Howard Hughes Medical Institute , Doris Duke Charitable Foundation , and Department of Defense Prostate Cancer Clinical Trials Consortium OBJECTIVE EORTC trial 30891 compared immediate versus deferred and rogen-deprivation therapy ( ADT ) in T0 - 4 N0 - 2 M0 prostate cancer ( PCa ) . Many patients r and omly assigned to deferred ADT did not require ADT because they died before becoming symptomatic . The question arises whether serum prostate-specific antigen ( PSA ) levels may be used to decide when to initiate ADT in PCa not suitable for local curative treatment . METHODS PSA data at baseline , PSA doubling time ( PSADT ) in  patients receiving no ADT  , and time to PSA relapse ( > 2 ng/ml ) in patients whose PSA declined to < 2 ng/ml within the first year after immediate ADT  were analyzed in 939 eligible patients r and omly assigned to immediate ( n=468 ) or deferred ADT ( n=471 ) . RESULTS In both arms , patients with a baseline PSA>50 ng/ml were at a>3.5-fold higher risk to die of PCa than patients with a baseline PSA < or=8 ng/ml . If baseline PSA was between 8 and 50 ng/ml , the risk of PCa death was approximately 7.5-fold higher in patients with PSADT<12 mo than in patients with PSADT>12 mo . Time to PSA relapse after response to immediate ADT correlated significantly with baseline PSA , suggesting that baseline PSA may also reflect disease aggressiveness . CONCLUSIONS Patients with a baseline PSA>50 ng/ml and /or a PSADT<12 mo were at increased risk to die from PCa and might have benefited from immediate ADT , whereas patients with a baseline PSA<50 ng/ml and a slow PSADT ( > 12 mo ) were likely to die of causes unrelated to PCa , and thus could be spared the burden of immediate ADT PURPOSE This study ( EORTC 30891 ) attempted to demonstrate equivalent overall survival in patients with localized prostate cancer not suitable for local curative treatment treated with immediate or deferred and rogen ablation .  PATIENTS AND METHODS We r and omly assigned 985 patients with newly diagnosed prostate cancer T0 - 4 N0 - 2 M0 to receive and rogen deprivation either immediately ( n = 493 ) or on symptomatic disease progression or occurrence of serious complications ( n = 492 ) . RESULTS Baseline characteristics were well balanced in the two groups . Median age was 73 years ( range , 52 to 81 ) . At a median follow-up of 7.8 years , 541 of 985 patients had died , mostly of prostate cancer ( n = 193 ) or cardiovascular disease ( n = 185 ) . The overall survival hazard ratio was 1.25 ( 95 % CI , 1.05 to 1.48 ; noninferiority P > .1 ) favoring immediate treatment , seemingly due to fewer deaths of nonprostatic cancer causes ( P = .06 ) . The time from r and omization to progression of hormone refractory disease did not differ significantly , nor did prostate-cancer specific survival . The median time to the start of deferred treatment after study entry was 7 years . In this group 126 patients ( 25.6 % ) died without ever needing treatment ( 44 % of the deaths in this arm ) . CONCLUSION Immediate and rogen deprivation result ed in a modest but statistically significant increase in overall survival but no significant difference in prostate cancer mortality or symptom-free survival . This must be weighed on an individual basis against the adverse effects of life-long and rogen deprivation , which may be avoided in a substantial number of patients with a deferred treatment policy BACKGROUND Appropriate timing of and rogen deprivation treatment ( ADT ) for prostate cancer is controversial . Our aim was to determine whether immediate ADT extends survival in men with node-positive prostate cancer who have undergone radical prostatectomy and pelvic lymphadenectomy compared with those who received ADT only once disease progressed . METHODS Eligible patients from 36 institutes in the USA were r and omly assigned in 1988 - 93 to receive immediate ADT ( n=47 ) or to be observed ( n=51 ) , with ADT to be given on detection of distant metastases or symptomatic recurrences . Patients were followed up every 3 months for the first year and every 6 months thereafter . The primary endpoint was progression-free survival ; secondary endpoints were overall and disease-specific survival . Analysis was by intention to treat . To ensure that the treatment groups were comparable , we did a retrospective central pathology review of slides and re grade d the Gleason scores for available sample s. This trial pre date s the requirement for clinical trial registration . FINDINGS At median follow-up of 11.9 years ( range 9.7 - 14.5 for surviving patients ) , men assigned immediate ADT had a significant improvement in overall survival ( hazard ratio 1.84 [ 95 % CI 1.01 - 3.35 ] , p=0.04 ) , prostate-cancer-specific survival ( 4.09 [ 1.76 - 9.49 ] , p=0.0004 ) , and progression-free survival ( 3.42 [ 1.96 - 5.98 ] , p<0.0001 ) . Of 49 histopathology slides received ( 19 immediate ADT , 30 observation ) , 16 were down grade d from the original Gleason score ( between groups < or = 6 , 7 , and > or = 8) and five were up grade d. We recorded similar proportions of score changes in each group ( p=0.68 ) , and no difference in score distribution by treatment ( p=0.38 ) . After adjustment for score , associations were still significant between treatment and survival ( overall , p=0.02 ; disease-specific , p=0.002 ; progression-free survival , p<0.0001 ) . INTERPRETATION Early ADT benefits patients with nodal metastases who have undergone prostatectomy and lymphadenectomy , compared with those who receive deferred treatment . The beneficial effects of early ADT , rather than an imbalance in risk factors , are likely to explain the differences in outcomes between treatments PURPOSE To determine the impact of adjuvant and rogen deprivation therapy ( ADT ) for patients who have node-positive prostate cancer in the prostate-specific antigen ( PSA ) era . PATIENTS AND METHODS We used linked Surveillance , Epidemiology and End Results -Medicare data to construct a cohort of men who underwent radical prostatectomy ( RP ) between 1991 and 1999 and who had positive regional lymph nodes . We classified men as receiving adjuvant ADT if they received ADT within 120 days of RP , and we compared them to the men who had not received adjuvant ADT . We used propensity scores to balance potential confounders of receiving adjuvant ADT ( ie , tumor characteristics , extent of nodal disease , demographics , receipt of radiation therapy ) and Cox proportional hazard methods to measure the impact of adjuvant ADT on overall survival ( OS ) , stratified by propensity score quintile . We conducted a sensitivity analysis that used 90 , 150 , 180 , and 365 days as the definition for adjuvant ADT . RESULTS A total of 731 men were identified , 209 of whom received ADT within 120 days of RP . There was no statistically significant difference in OS between the adjuvant ADT and non-ADT group ( HR , 0.97 ; 95 % CI , 0.71 to 1.27 ) . There was no statistically significant survival difference with 90 , 150 , 180 , and 365 days as the adjuvant ADT definition . CONCLUSION Deferring immediate ADT in men with positive lymph nodes after RP may not significantly compromise survival . Because observational studies should be considered hypothesis-generating studies , these results should be vali date d in a prospect i ve fashion in a similar patient population PURPOSE Hormonal therapy ( HT ) is the current mainstay of systemic treatment for prostate specific antigen ( PSA ) only recurrence ( PSAR ) , however , there is virtually no published literature comparing HT to observation in the clinical setting . The goal of this study was to examine the Department of Defense Center for Prostate Disease Research observational data base to compare clinical outcomes in men who experienced PSAR after radical prostatectomy by early versus delayed use of HT and by a risk stratified approach . MATERIAL S AND METHODS Of 5,382 men in the data base who underwent primary radical prostatectomy ( RP ) , 4,967 patients were treated in the PSA-era between 1988 and December 2002 . Of those patients 1,352 men who had PSAR ( PSA after surgery greater than 0.2 ng/ml ) and had postoperative followup greater than 6 months were used as the study cohort . These patients were further divided into an early HT group in which patients ( 355 ) received HT after PSA only recurrence but before clinical metastasis and a late HT  group for patients ( 997 ) who received no HT before clinical metastasis or by current followup . The primary end point was the development of clinical metastases . Of the 1,352 patients with PSAR  clinical metastases developed in 103 ( 7.6 % ) . Patients were also stratified by surgical Gleason sum , PSA doubling time and timing of recurrence . Univariate and multivariate Cox proportional hazard models were used to evaluate the effect of early and late HT on clinical outcome . RESULTS Early HT was associated with delayed clinical metastasis in patients with a pathological Gleason sum greater than 7 or PSA doubling time of 12 months or less ( Hazards ratio = 2.12 , p = 0.01 ) . However , in the overall cohort early HT did not impact clinical metastases . Race , age at RP and PSA at diagnosis had no effect on metastasis-free survival ( p > 0.05 ) . CONCLUSIONS The retrospective observational multicenter data base analysis demonstrated that early HT administered for PSAR after prior RP was an independent predictor of delayed clinical metastases only for high-risk cases at the current followup . Further study with longer followup and r and omized trials are needed to address this important issue PURPOSE This was an exploratory analysis of a trial of intermittent and rogen deprivation ( IAD ) in men with biochemical relapse ( BR ) to establish first cycle characteristics prognostic for progression to castration-resistant prostate cancer ( CRPC ) and death . PATIENTS AND METHODS Men with BR of prostate cancer after radical prostatectomy ( RP ) or radiation ( RT ) were treated with and rogen deprivation therapy ( ADT ) comprised of leuprolide and flutamide . After 9 months on treatment , ADT was stopped , and monthly prostate-specific antigen ( PSA ) levels were observed during the off-treatment interval . When the PSA reached a threshold value ( 1 ng/mL for RP , 4 ng/mL for RT ) , ADT was resumed in a new cycle . Patients were treated intermittently in this manner until CRPC , which was defined as > or = two consecutive increasing PSA values while on ADT with castrate testosterone levels . RESULTS Seventy-two of 100 patients enrolled onto the study met criteria for this analysis . The duration of the first off-treatment interval ( < or = v > 40 weeks ) was associated with shorter time to CRPC ( hazard ratio = 2.9 ; 95 % CI , 1.1 to 7.7 ; P = .03 ) and death ( hazard ratio = 3.8 ; 95 % CI , 1.1 to 13.6 ; P = .04 ) after adjusting for age , stage , grade , and PSA at diagnosis . CONCLUSION In patients who completed the first cycle of IAD , a duration of the first off-treatment interval of < or = 40 weeks defines a subset of patients at higher risk of CRPC and death . Conversely , patients with an off-treatment interval of more than 40 weeks have a significantly better long-term prognosis The aim of this study was to compare the efficacy of total intermittent and rogen deprivation ( IAD ) versus total continuous and rogen deprivation ( CAD ) for treating patients with advanced prostate cancer in a phase III r and omized trial . A total of 68 evaluable patients with hormone-naive advanced or relapsing prostate cancer were r and omized to receive combined and rogen blockade according to a continuous ( n = 33 ) or intermittent ( n = 35 ) regimen . Therapeutic monitoring was assessed by use of serum prostate-specific antigen ( PSA ) measurements . Patients in the CAD and IAD groups were equally stratified for age , biopsy Gleason score , and baseline serum PSA levels . The outcome variable was time to and rogen-independence of the tumor , which was defined as increasing serum PSA levels despite and rogen blockade . Mean follow-up was 30.8 months . The 35 IAD-treated patients completed 91 cycles , and 19 of them ( 54.3 % ) completed > or = 3 cycles . Median cycle length and percentage of time off therapy were 9.0 months and 59.5 , respectively . The estimated 3-year progression rate was significantly lower in the IAD group ( 7.0 % + /- 4.8 % ) than in the CAD group ( 38.9 % + /- 11.2 % , P = 0.0052 ) . Our data suggest that IAD treatment may maintain the and rogen-dependent state of advanced human prostate cancer , as assessed by PSA measurements , at least as long as CAD treatment . Further studies with longer follow-up times and larger patient cohorts are needed to determine the comparative impacts of CAD and IAD on survival The results of a large r and omized prospect i ve clinical trial conducted by the Veterans Administration Co-operative Urological Research Group ( VACURG ) in 1968 are up date d and reevaluated . In this study , placebo , diethylstilbestrol ( DES , 5 mg/day ) , orchiectomy plus placebo , and orchiectomy plus DES were compared in patients whose conditions were initially diagnosed as stage III and IV carcinoma of the prostate . Results showed that orchiectomy alone or in combination with estrogen did not improve overall survival rates in stage III and IV carcinoma of the prostate . In the two treatment groups receiving estrogen , however , there were fewer deaths due to cancer of the prostate , but this effect tended to be offset by an increased number of deaths due to cardiovascular causes . Deaths from other causes showed no particular pattern with respect to treatment . These studies showed that estrogen is more effective than orchiectomy in preventing deaths from cancer and that the addition of orchiectomy to estrogen does not offer any clear-cut advantage over estrogen therapy alone . If cancer symptoms necessitate treatment , initial therapy with estrogen is preferred . Orchiectomy should be reserved for those circumstances in which a patient is not reliable , can not tolerate estrogens , or has severe cardiovascular disease To test the hypothesis that maximal and rogen blockade improves the effectiveness of the treatment of prostatic cancer , we conducted a r and omized , double-blind trial in patients with disseminated , previously untreated prostate cancer ( stage D2 ) . All 603 men received leuprolide  , an analogue of gonadotropin-releasing hormone that inhibits the release of gonadotropins , in combination with either placebo or flutamide , a nonsteroidal anti and rogen that inhibits the binding of and rogens to the cell nucleus . As compared with the 300 patients receiving leuprolide and placebo , the 303 patients r and omly assigned to receive leuprolide and flutamide had a longer progression-free survival ( 16.5 vs. 13.9 months ; P = 0.039 ) and an increase in the median length of survival ( 35.6 vs. 28.3 months ; P = 0.035 ) . The differences between the treatments were particularly evident for men with minimal disease and good performance status ; however , further studies should be conducted in this subgroup . Symptomatic improvement was greatest during the first 12 weeks of the combined and rogen blockade , when leuprolide alone often produces a painful flare in the disease . We conclude that in patients with advanced prostate cancer , treatment with leuprolide and flutamide is superior to treatment with leuprolide alone PURPOSE Persistence of lig and -mediated and rogen receptor signaling has been documented in castration-resistant prostate cancers ( CRPCs ) . Abiraterone acetate ( AA ) is a potent and selective inhibitor of CYP17 , which is required for and rogen bio synthesis in the testes , adrenal gl and s , and prostate tissue . This trial evaluated the efficacy and safety of AA in combination with prednisone to reduce the symptoms of secondary hyperaldosteronism that can occur with AA monotherapy . PATIENTS AND METHODS Fifty-eight men with progressive metastatic CRPC who experienced treatment failure with docetaxel-based chemotherapy received AA ( 1,000 mg daily ) with prednisone ( 5 mg twice daily ) . Twenty-seven ( 47 % ) patients had received prior ketoconazole . The primary outcome was > or = 50 % prostate-specific antigen ( PSA ) decline , with objective response by Response Evaluation Criteria in Solid Tumors ( RECIST ) criteria , and changes in Eastern Cooperative Oncology Group ( ECOG ) performance status ( PS ) and circulating tumor cell ( CTC ) numbers . Safety was also evaluated . RESULTS A > or = 50 % decline in PSA was confirmed in 22 ( 36 % ) patients , including 14 ( 45 % ) of 31 ketoconazole-naïve and seven ( 26 % ) of 27 ketoconazole-pretreated patients . Partial responses were seen in four ( 18 % ) of 22 patients with RECIST-evaluable target lesions . Improved ECOG PS was seen in 28 % of patients . Median time to PSA progression was 169 days ( 95 % CI , 82 to 200 days ) . CTC conversions with treatment from > or = 5 to < 5 were noted in 10 ( 34 % ) of 29 patients . The majority of  AA-related adverse events were grade 1 to 2 , and no AA-related grade 4 events were seen . CONCLUSION AA plus prednisone was well tolerated , with encouraging antitumor activity in heavily pretreated CRPC patients . The incidence of mineralocorticoid-related toxicities ( hypertension or hypokalemia ) was reduced by adding low-dose prednisone . The combination of AA plus prednisone is recommended for phase III investigations BACKGROUND Recent data suggest prostate-specific antigen ( PSA ) progression may predict overall survival in prostate cancer patients . OBJECTIVE To compare the activity of degarelix and leuprolide regarding PSA recurrence-free survival . DESIGN , SETTING , AND PARTICIPANTS Phase 3 , 1-yr , multicentre , r and omised , open-label trial comparing the efficacy and safety of degarelix at 240 mg for 1 mo , and then 80 mg monthly ( 240/80 mg ) ; degarelix at 240 mg for 1 mo , and then 160 mg monthly ; and leuprolide at 7.5 mg/mo . Overall , 610 patients with histologically confirmed prostate cancer ( all stages ) , for whom and rogen deprivation therapy was indicated , were included . The primary end point of this trial has been reported previously ; the protocol led and exploratory subgroup analyses reported in this paper focus on degarelix at 240/80 mg ( dose approved by the US Food and Drug Administration and the European Medicine Evaluation Association for the treatment of patients with hormone-naive advanced prostate cancer ) . MEASUREMENTS PSA progression-free survival ( two consecutive increases in PSA of 50 % compared with nadir and ≥ 5 ng/ml on two consecutive measurements at least 2 wk apart or death ) and change in PSA were review ed . Effects of baseline disease stage ( localised , locally advanced , and metastatic ) and PSA level ( < 10 , 10 - 20 , > 20 - 50 , and > 50 ng/ml ) were analysed . RESULTS AND LIMITATIONS Patients receiving degarelix showed a significantly lower risk of PSA progression or death  compared with leuprolide ( p=0.05 ) . PSA recurrences occurred mainly in patients with advanced disease and exclusively in those with baseline PSA > 20 ng/ml . Patients with PSA > 20 ng/ml had a significantly longer time to PSA recurrence  with degarelix ( p=0.04 ) . The relatively low number of patients in each subgroup is a limitation of this study . CONCLUSIONS These results generate the hypothesis that degarelix at 240/80 mg offers improved PSA control compared with leuprolide  . PSA recurrences occurred almost exclusively in patients with metastatic prostate cancer or high baseline PSA during this 1-yr study . Further studies are warranted to confirm these findings
target: LHRH antagonists decrease testosterone without any testosterone surge , and they may be associated with an oncologic benefit compared with LHRH analogues .
  Complete and rogen blockade has a small survival benefit of about 5 % .
  Intermittent and rogen deprivation results in noninferior oncologic efficacy when compared with continuous and rogen-deprivation therapy ( ADT ) in well-selected population s. In locally advanced and metastatic PCa , early ADT does not result in a significant survival advantage when compared with delayed ADT .
  LHRH antagonists decrease testosterone without any testosterone surge , and they might be associated with an oncologic benefit compared with LHRH analogues .
  Complete and rogen blockade has a small survival benefit of about 5 % .
  Intermittent and rogen deprivation results in noninferior oncologic efficacy when compared with continuous and rogen-deprivation therapy ( ADT ) in well-selected population s. In locally advanced and metastatic PCa , early ADT does not result in a significant survival advantage when compared with delayed ADT .
background: OBJECTIVE To present a summary of the 2013 version of the European Association of Urology ( EAU ) guidelines on the treatment of advanced , relapsing , and castration-resistant prostate cancer ( CRPC ) .
  The guidelines were up date d , and levels of evidence and /or grade s of recommendation were added to the text based on a systematic review of the literature that included a search of online data bases and bibliographic review s. EVIDENCE SYNTHESIS Luteinising hormone-releasing hormone ( LHRH ) agonists are the st and ard of care in metastatic prostate cancer ( PCa ) .
  Treatment of CRPC includes sipuleucel-T , abiraterone acetate plus prednisone ( AA/P ) , or chemotherapy with docetaxel at 75mg/m(2 ) every 3 wk .
  Cabazitaxel , AA/P , enzalutamide , and radium-223 are available for second-line treatment of CRPC following docetaxel .
  CONCLUSIONS The knowledge in the field of advanced , metastatic , and castration-resistant PCa is rapidly changing .
  PATIENT SUMMARY We present a summary of the 2013 version of the European Association of Urology guidelines on treatment of advanced , relapsing , and castration-resistant prostate cancer ( CRPC ) .
  Luteinising hormone-releasing hormone ( LHRH ) agonists are the st and ard of care in metastatic prostate cancer ( PCa ) .
  Relapse after local therapy is defined by prostate-specific antigen ( PSA ) values > 0.2 ng/ml following radical prostatectomy ( RP ) and > 2 ng/ml above the nadir and after radiation therapy .
  Therapy for PSA relapse after RP includes salvage radiation therapy at PSA levels < 0.5 ng/ml and salvage RP or cryosurgical ablation of the prostate in radiation failures .