title: Increased survival with enzalutamide in prostate cancer after chemotherapy. 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. Early salvage radiation therapy does not compromise cancer control in patients with pT3N0 prostate cancer after radical prostatectomy: results of a match-controlled multi-institutional analysis. The efficacy and safety of degarelix: a 12‐month, comparative, randomized, open‐label, parallel‐group phase III study in patients with prostate cancer 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. Intermittent versus continuous androgen deprivation in prostate cancer. 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. Lower baseline prostate-specific antigen is associated with a greater overall survival benefit from sipuleucel-T in the Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) trial. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. Prostate cancer-specific survival following salvage radiotherapy vs observation in men with biochemical recurrence after radical prostatectomy. 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 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. Development of a Second-Generation Antiandrogen for Treatment of Advanced 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. A phase III extension trial with a 1-arm crossover from leuprolide to degarelix: comparison of gonadotropin-releasing hormone agonist and antagonist effect on 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 Enzalutamide ( formerly called MDV3100 ) targets multiple steps in the and rogen-receptor-signaling pathway , the major driver of prostate-cancer growth . We aim ed to evaluate whether enzalutamide prolongs survival in men with castration-resistant prostate cancer after chemotherapy . METHODS In our phase 3 , double-blind , placebo-controlled trial , we stratified 1199 men with castration-resistant prostate cancer after chemotherapy according to the Eastern Cooperative Oncology Group performance-status score and pain intensity . We r and omly assigned them , in a 2:1 ratio , to receive oral enzalutamide at a dose of 160 mg per day ( 800 patients ) or placebo ( 399 patients ) . The primary end point was overall survival . RESULTS The study was stopped after a planned interim analysis at the time of 520 deaths . The median overall survival was 18.4 months ( 95 % confidence interval [ CI ] , 17.3 to not yet reached ) in the enzalutamide group versus 13.6 months ( 95 % CI , 11.3 to 15.8 ) in the placebo group ( hazard ratio for death in the enzalutamide group , 0.63 ; 95 % CI , 0.53 to 0.75 ; P<0.001 ) . The superiority of enzalutamide over placebo was shown with respect to all secondary end points : the proportion of patients with a reduction in the prostate-specific antigen ( PSA ) level by 50 % or more ( 54 % vs. 2 % , P<0.001 ) , the soft-tissue response rate ( 29 % vs. 4 % , P<0.001 ) , the quality -of-life response rate ( 43 % vs. 18 % , P<0.001 ) , the time to PSA progression ( 8.3 vs. 3.0 months ; hazard ratio , 0.25 ; P<0.001 ) , radiographic progression-free survival ( 8.3 vs. 2.9 months ; hazard ratio , 0.40 ; P<0.001 ) , and the time to the first skeletal-related event ( 16.7 vs. 13.3 months ; hazard ratio , 0.69 ; P<0.001 ) . Rates of fatigue , diarrhea , and hot flashes were higher in the enzalutamide group . Seizures were reported in five patients ( 0.6 % ) receiving enzalutamide . CONCLUSIONS Enzalutamide significantly prolonged the survival of men with metastatic castration-resistant prostate cancer after chemotherapy . ( Funded by Medivation and Astellas Pharma Global Development ; AFFIRM Clinical Trials.gov number , NCT00974311 . ) 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 BACKGROUND Previous r and omised trials demonstrated that adjuvant radiation therapy ( aRT ) improves cancer control in patients with pT3 prostate cancer ( PCa ) . However , there is currently no evidence supporting early salvage radiation therapy ( eSRT ) as equivalent to aRT in improving freedom from biochemical recurrence ( BCR ) after radical prostatectomy ( RP ) . OBJECTIVE To evaluate BCR-free survival for aRT versus observation followed by eSRT in cases of relapse in patients undergoing RP for pT3pN0 , R0-R1 PCa . DESIGN , SETTING , AND PARTICIPANTS Using a European multi-institutional cohort , 890 men with pT3pN0 , R0-R1 PCa were identified . INTERVENTION All patients underwent RP . Subsequently , patients were stratified into two groups : aRT versus initial observation followed by eSRT in cases of relapse . OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES : Propensity-matched analysis was employed , and patients were stratified into two groups : aRT versus observation and eventual eSRT , defined as RT given at a postoperative serum prostate-specific antigen ( PSA ) ≤ 0.5 ng/ml at least 6 mo after RP . BCR , defined as PSA > 0.20 ng/ml and rising after administration of RT , was compared between aRT and initial observation followed by eSRT in cases of relapse using Kaplan-Meier and Cox regression methods . RESULTS AND LIMITATIONS Overall , 390 ( 43.8 % ) and 500 ( 56.2 % ) patients were treated with aRT and initial observation , respectively . Within the latter group , 225 ( 45.0 % ) patients experienced BCR and underwent eSRT . In the postpropensity-matched cohort , the 2- and 5-yr BCR-free survival rates were 91.4 % and 78.4 % in aRT versus 92.8 % and 81.8 % in patients who underwent initial observation and eSRT in cases of relapse , respectively ( p=0.9 ) . No differences in the 2- and 5-yr BCR-free survival rates were found , even when patients were stratified according to pT3 substage and surgical margin status ( all p ≥ 0.4 ) . These findings were also confirmed in multivariable analyses ( p=0.6 ) . Similar results were achieved when the cut-off to define eSRT was set at 0.3 ng/ml ( all p ≥ 0.5 ) . CONCLUSIONS The current study suggests that timely administration of eSRT is comparable to aRT in improving BCR-free survival in the majority of pT3pN0 PCa patients .  Therefore , eSRT may not compromise cancer control but significantly reduces overtreatment associated with aRT 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 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 . BACKGROUND Castration resistance occurs in most patients with metastatic hormone-sensitive prostate cancer who are receiving and rogen-deprivation therapy .  Replacing and rogens before progression of the disease is hypothesized to prolong and rogen dependence . METHODS Men with newly diagnosed , metastatic , hormone-sensitive prostate cancer , a performance status of 0 to 2 , and a prostate-specific antigen ( PSA ) level of 5 ng per milliliter or higher received a luteinizing hormone-releasing hormone analogue and an anti and rogen agent for 7 months . We then r and omly assigned patients in whom the PSA level fell to 4 ng per milliliter or lower to continuous or intermittent and rogen deprivation  , with patients stratified according to prior or no prior hormonal therapy , performance status , and extent of disease ( minimal or extensive ) . The co primary objectives were to assess whether intermittent  therapy  was noninferior to continuous therapy with respect to survival , with a one-sided test with an upper boundary of the hazard ratio of 1.20 , and whether quality of life differed between the groups 3 months after r and omization . RESULTS A total of 3040 patients were enrolled , of whom 1535 were included in the analysis : 765 r and omly assigned to continuous and rogen deprivation and 770 assigned to intermittent and rogen deprivation . The median follow-up period was 9.8 years . Median survival was 5.8 years in the continuous-therapy group and 5.1 years in the intermittent-therapy group ( hazard ratio for death with intermittent therapy , 1.10 ; 90 % confidence interval , 0.99 to 1.23 ) . Intermittent therapy was associated with better erectile function and mental health ( P<0.001 and P=0.003 , respectively ) at month 3 but not thereafter . There were no significant differences between the groups in the number of treatment-related high- grade adverse events . CONCLUSIONS Our findings were statistically inconclusive . In patients with metastatic hormone-sensitive prostate cancer , the confidence interval for survival exceeded the upper boundary for noninferiority , suggesting that we can not rule out a 20 % greater risk of death with intermittent therapy than with continuous therapy , but too few events occurred to rule out significant inferiority of intermittent therapy . Intermittent therapy result ed in small improvements in quality of life . ( Funded by the National Cancer Institute and others ; Clinical Trials.gov number , NCT00002651 . ) 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 OBJECTIVE To explore the prognostic and predictive value of baseline variables in 512 patients with metastatic castration-resistant prostate cancer from the phase III Immunotherapy for Prostate Adenocarcinoma Treatment ( IMPACT ) trial who were r and omized to receive sipuleucel-T or control .  METHODS The most powerful of these prognostic factors , baseline prostate-specific antigen ( PSA ) , was subdivided into quartiles to evaluate treatment effect patterns . Cox regression analyses were used to assess predictors of overall survival ( OS )  and sipuleucel-T treatment effect within PSA quartiles . Median OS was estimated by the Kaplan-Meier method . RESULTS PSA was the strongest baseline prognostic factor ( P < .0001 ) . Furthermore , the sipuleucel-T  treatment effect appeared greater with decreasing baseline PSA . The OS hazard ratio for patients in the lowest baseline PSA quartile ( ≤22.1 ng/mL ) was 0.51 ( 95 % confidence interval , 0.31 - 0.85 ) compared with 0.84 ( 95 % confidence interval , 0.55 - 1.29 ) for patients in the highest PSA quartile ( > 134 ng/mL ) . Estimated improvement in median survival varied from 13.0 months in the lowest baseline PSA quartile to 2.8 months in the highest quartile . Estimated 3-year survival in the lowest PSA quartile was 62.6 % for sipuleucel-T patients and 41.6 % for control patients , representing a 50 % relative increase . CONCLUSION The greatest magnitude of benefit with sipuleucel-T treatment in this exploratory analysis was observed among patients with better baseline prognostic factors , particularly those with lower baseline PSA values . These findings suggest that patients with less advanced disease may benefit the most from sipuleucel-T treatment and provide a rationale for immunotherapy as an early treatment strategy in sequencing algorithms for metastatic castration-resistant prostate cancer BACKGROUND Mitoxantrone plus prednisone reduces pain and improves the quality of life in men with advanced , hormone-refractory prostate cancer , but it does not improve survival . We compared such treatment with docetaxel plus prednisone in men with this disease . METHODS From March 2000 through June 2002 , 1006 men with metastatic hormone-refractory prostate cancer received 5 mg of prednisone twice daily  and were r and omly assigned to receive 12 mg of mitoxantrone per square meter of body-surface area every three weeks , 75 mg of docetaxel per square meter every three weeks , or 30 mg of docetaxel per square meter weekly for five of every six weeks . The primary end point was overall survival . Secondary end points were pain , prostate-specific antigen ( PSA ) levels , and the quality of life . All statistical comparisons were against mitoxantrone . RESULTS As compared with the men in the mitoxantrone group , men in the group given docetaxel every three weeks had a hazard ratio for death of 0.76 ( 95 percent confidence interval , 0.62 to 0.94 ; P=0.009 by the stratified log-rank test ) and those given weekly docetaxel had a hazard ratio for death of 0.91 ( 95 percent confidence interval , 0.75 to 1.11 ; P=0.36 ) . The median survival was 16.5 months in the mitoxantrone group , 18.9 months in the group given docetaxel every 3 weeks , and 17.4 months in the group given weekly docetaxel . Among these three groups , 32 percent , 45 percent , and 48 percent of men , respectively , had at least a 50 percent decrease in the serum PSA level ( P<0.001 for both comparisons with mitoxantrone ) ; 22 percent , 35 percent ( P=0.01 ) , and 31 percent ( P=0.08 ) had predefined reductions in pain ; and 13 percent , 22 percent ( P=0.009 ) , and 23 percent ( P=0.005 ) had improvements in the quality of life . Adverse events were also more common in the groups that received docetaxel . CONCLUSIONS When given with prednisone , treatment with docetaxel every three weeks led to superior survival and improved rates of response in terms of pain , serum PSA level , and quality of life , as compared with mitoxantrone plus prednisone 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 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 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 A Second Act for Anti and rogens  Men with advanced prostate cancer are often treated with anti and rogens ; drugs that inhibit the activity of male hormones , such as testosterone , that help drive tumor growth . Many of these drugs act by functionally disrupting the and rogen receptor ( AR ) , a transcriptional regulator of cell proliferation , but tumors eventually become resistant to the drugs by expressing higher levels of the AR . Tran et al. ( p. 787 , published online 9 April ) have developed a “ second-generation ” anti and rogen , a thiohydantoin called MDV3100 , which binds the AR with high affinity . MDV3100 retains its anticancer activity in cell culture and in mouse models even when AR levels are elevated . The drug appears to act both by inhibiting translocation of the AR into the nucleus and by reducing its transcriptional activity . MDV3100 is being tested in patients with advanced prostate cancer , the first group of which have shown a decline in blood levels of a marker of cancer growth , prostate-specific antigen . A drug that binds to the and rogen receptor acts by disrupting its activity in the cell nucleus . Metastatic prostate cancer is treated with drugs that antagonize and rogen action , but most patients progress to a more aggressive form of the disease called castration-resistant prostate cancer , driven by elevated expression of the and rogen receptor . Here we characterize the diarylthiohydantoins RD162 and MDV3100 , two compounds optimized from a screen for nonsteroidal anti and rogens that retain activity in the setting of increased and rogen receptor expression . Both compounds bind to the and rogen receptor with greater relative affinity than the clinical ly used anti and rogen bicalutamide , reduce the efficiency of its nuclear translocation , and impair both DNA binding to and rogen response elements and recruitment of coactivators .  RD162 and MDV3100 are orally available and induce tumor regression in mouse models of castration-resistant human prostate cancer . Of the first 30 patients treated with MDV3100 in a Phase I/II clinical trial , 13 of 30 ( 43 % ) showed sustained declines ( by > 50 % ) in serum concentrations of prostate-specific antigen , a biomarker of prostate cancer . These compounds thus appear to be promising c and i date s for treatment of advanced prostate cancer 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 PURPOSE We investigated the efficacy and safety of degarelix treatment and the effects of switching from leuprolide to degarelix in an ongoing extension study with a median 27.5-month followup of a pivotal 1-year prostate cancer trial . MATERIAL S AND METHODS Patients who completed a 1-year pivotal phase III trial continued on the same monthly degarelix maintenance dose ( 160 or 80 mg in 125 each ) ,  or were re-r and omized from leuprolide 7.5 mg to degarelix 240/80 mg ( 69 ) or 240/160 mg ( 65 ) . Data are shown on the approved degarelix 240/80 mg dose . The primary end point was safety/tolerability and the secondary end points were testosterone , prostate specific antigen , luteinizing hormone and follicle-stimulating hormone responses , and prostate specific antigen failure and progression-free survival . RESULTS During followup testosterone and prostate specific antigen suppression were similar to those in the 1-year trial in patients who continued on degarelix or switched from leuprolide . The prostate specific antigen progression-free survival hazard rate was decreased significantly after the switch in the leuprolide/degarelix group while the rate in those who continued on degarelix was consistent with the rate in treatment year 1 . The same hazard rate change pattern occurred in the group with baseline prostate specific antigen greater than 20 ng/ml . Adverse event frequency was similar between the groups and decreased with time . CONCLUSIONS Data support the statistically significant prostate specific antigen progression-free survival benefit for degarelix over leuprolide seen during year 1 and the use of degarelix as first line and rogen deprivation therapy as an alternative to a gonadotropin-releasing hormone agonist 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: Complete and rogen blockade has a small survival benefit of about 5 % .
  Intermittent and rogen deprivation ( IAD ) results in equivalent 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 .
  Zoledronic acid and denusomab can be used in men with CRPC and osseous metastases to prevent skeletal-related complications .
background: OBJECTIVES Our aim is to present a summary of the 2010 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 the levels of evidence ( LEs ) and /or grade s of recommendation ( GR ) were added to the text based on a systematic review of the literature , which included a search of online data bases and bibliographic review s. RESULTS Luteinising hormone-releasing hormone ( LHRH ) agonists are the st and ard of care in metastatic prostate cancer ( PCa ) .
  Although LHRH antagonists decrease testosterone without any testosterone surge , their clinical benefit remains to be determined .
  Treatment of castration-resistant prostate cancer ( CRPC ) includes second-line hormonal therapy , novel agents , and chemotherapy with docetaxel at 75 mg/m(2 ) every 3 wk .