EAU guidelines on prostate cancer. Part 1: screening, diagnosis, and treatment of clinically localised disease. EAU guidelines on prostate cancer. part 1: screening, diagnosis, and local treatment with curative intent-update 2013. Defining a new testosterone threshold for medical castration: Results from a prospective cohort series. Efficacy and safety of different interventions in castration resistant prostate cancer progressing after docetaxel-based chemotherapy: Bayesian network analysis of randomized controlled trials The gonadotropin-releasing hormone antagonist abarelix depot versus luteinizing hormone releasing hormone agonists leuprolide or goserelin: initial results of endocrinological and biochemical efficacies in patients with prostate cancer. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. Prospective phase I study on testicular castration induced by radiation treatment. Cost–effectiveness analysis comparing degarelix with leuprolide in hormonal therapy for patients with locally advanced prostate cancer Combining carboplatin and etoposide in docetaxel-pretreated patients with castration-resistant prostate cancer: a prospective study evaluating also neuroendocrine features. eRADicAte: A Prospective Evaluation Combining Radium‐223 Dichloride and Abiraterone Acetate Plus Prednisone in Patients With Castration‐Resistant Prostate Cancer Metformin in chemotherapy-naive castration-resistant prostate cancer: a multicenter phase 2 trial (SAKK 08/09). PTEN Protein Loss and Clinical Outcome from Castration-resistant Prostate Cancer Treated with Abiraterone Acetate A phase 3, multicenter, open label, randomized study of abarelix versus leuprolide plus daily antiandrogen in men with prostate cancer. Effects of abiraterone acetate on androgen signaling in castrate-resistant prostate cancer in bone. A Phase II, Randomized, Open-Label Study of Neoadjuvant Degarelix versus LHRH Agonist in Prostate Cancer Patients Prior to Radical Prostatectomy 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. The effect of baseline testosterone on the efficacy of degarelix and leuprolide: further insights from a 12-month, comparative, phase III study in prostate cancer patients. Intermittent LHRH Therapy in the Management of Castrate-resistant Prostate Cancer (CRPCa): Results of a Multi-institutional Randomized Prospective Clinical Trial [CCAFU Recommendations 2013: Prostate cancer]. Bicalutamide 80 mg combined with a luteinizing hormone-releasing hormone agonist (LHRH-A) versus LHRH-A monotherapy in advanced prostate cancer: findings from a phase III randomized, double-blind, multicenter trial in Japanese patients Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3. Neoadjuvant flutamide monotherapy for locally confined prostate cancer. Long-term follow-up of a phase II trial of chemotherapy plus hormone therapy for biochemical relapse after definitive local therapy for prostate cancer.
OBJECTIVE Our aim was to present a summary of the 2010 version of the European Association of Urology ( EAU ) guidelines on the screening , diagnosis , and treatment of clinical ly localised cancer of the prostate ( PCa ) . METHODS The working panel performed a literature review of the new data emerging from 2007 to 2010 . The guidelines were up date d , and level of evidence and grade of recommendation 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 A full version is available at the EAU office or Web site ( www.uroweb.org ) . Current evidence is insufficient to warrant widespread population -based screening by prostate-specific antigen ( PSA ) for PCa . A systematic prostate biopsy under ultrasound guidance and local anaesthesia is the preferred diagnostic method . Active surveillance represents a viable option in men with low-risk PCa and a long life expectancy .  PSA doubling time in <3 yr or a biopsy progression indicates the need for active intervention . In men with locally advanced PCa in whom local therapy is not m and atory , watchful waiting ( WW ) is a treatment alternative to and rogen-deprivation therapy ( ADT ) with equivalent oncologic efficacy . Active treatment is mostly recommended for patients with localised disease and a long life expectancy with radical prostatectomy ( RP ) shown to be superior to WW in a prospect i ve r and omised trial . Nerve-sparing RP represents the approach of choice in organ-confined disease ; neoadjuvant and rogen deprivation demonstrates no improvement of outcome variables . Radiation therapy should be performed with at least 74 Gy and 78 Gy in low-risk and intermediate/high-risk PCa , respectively . For locally advanced disease , adjuvant ADT for 3 yr results in superior disease-specific and overall survival rates and represents the treatment of choice . Follow-up after local therapy is largely based on PSA , and a disease-specific history with imaging is indicated only when symptoms occur . CONCLUSIONS The knowledge in the field of PCa is rapidly changing . These EAU guidelines on PCa summarise the most recent findings and put them into clinical practice CONTEXT The most recent summary of the European Association of Urology ( EAU ) guidelines on prostate cancer ( PCa ) was published in 2011 . OBJECTIVE To present a summary of the 2013 version of the EAU guidelines on screening , diagnosis , and local treatment with curative intent of clinical ly organ-confined PCa . EVIDENCE ACQUISITION A literature review of the new data emerging from 2011 to 2013 has been performed by the EAU PCa guideline group . The guidelines have been up date d , and levels of evidence and grade s of recommendation have been added to the text based on a systematic review of the literature , which included a search of online data bases and bibliographic review s. EVIDENCE SYNTHESIS A full version of the guidelines is available at the EAU office or online ( www.uroweb.org ) . Current evidence is insufficient to warrant widespread population -based screening by prostate-specific antigen ( PSA ) for PCa . Systematic prostate biopsies under ultrasound guidance and local anesthesia are the preferred diagnostic method . Active surveillance represents a viable option in men with low-risk PCa and a long life expectancy . A biopsy progression indicates the need for active intervention , whereas the role of PSA doubling time is controversial . In men with locally advanced PCa for whom local therapy is not m and atory , watchful waiting ( WW ) is a treatment alternative to and rogen-deprivation therapy ( ADT ) , with equivalent oncologic efficacy . Active treatment is recommended mostly for patients with localized disease and a long life expectancy , with radical prostatectomy ( RP ) shown to be superior to WW in prospect i ve r and omized trials . Nerve-sparing RP is the approach of choice in organ-confined disease , while neoadjuvant ADT provides no improvement in outcome variables . Radiation therapy should be performed with ≥ 74 Gy in low-risk PCa and 78 Gy in intermediate- or high-risk PCa . For locally advanced disease , adjuvant ADT for 3 yr results in superior rates for disease-specific and overall survival and is the treatment of choice . Follow-up after local therapy is largely based on PSA and a disease-specific history , with imaging indicated only when symptoms occur . CONCLUSIONS Knowledge in the field of PCa is rapidly changing . These EAU guidelines on PCa summarize the most recent findings and put them into clinical practice . PATIENT SUMMARY A summary is presented of the 2013 EAU guidelines on screening , diagnosis , and local treatment with curative intent of clinical ly organ-confined prostate cancer ( PCa ) . Screening continues to be done on an individual basis , in consultation with a physician . Diagnosis is by prostate biopsy . Active surveillance is an option in low-risk PCa and watchful waiting is an alternative to and rogen-deprivation therapy in locally advanced PCa not requiring immediate local treatment . Radical prostatectomy is the only surgical option . Radiation therapy can be external or delivered by way of prostate implants . Treatment follow-up is based on the PSA level BACKGROUND We seek to determine if testosterone levels below the accepted castration threshold ( 50 ng/dL ) have an impact on time to progression to castrate-resistant prostate cancer ( CRPC ) . METHODS This is a prospect i ve cohort series of patients undergoing and rogen deprivation therapy ( ADT ) with luteinizing hormone-releasing hormone agonist or antagonist at a tertiary centre from 2006 to 2011 .  Serum testosterone level  was assessed every 3 months . Patients with any testosterone > 50 ng/dL were excluded . Patients were stratified into groups based on those achieving mean testosterone levels < 20 ng/dL and < 32 ng/dL. Progression to CRPC was assessed with the Kaplan-Meier method and compared with the log-rank test . RESULTS A total of 32 patients were included in this study . Mean patient follow-up was 25.7 months . Patients with a 9-month serum testosterone < 32 ng/dL had a significantly increased time to CRPC compared to patients with testosterone 32 to 50 ng/dL ( p = 0.001 , median progression-free survival ( PFS ) 33.1 months [ < 32 ng/dL ] vs. 12.5 months [ > 32 ng/dL ] ) . Patients with first year mean testosterone < 32 ng/dL also had a significantly increased time to CRPC compared to 32 to 50 ng/dL ( p = 0.05 , median PFS 33.1 months [ < 32 ng/dL ] vs. 12.5 months [ 32 - 50 ng/dL ] ) . A testosterone < 20 ng/dL compared to 20 to 50 ng/dL did not significantly predict with time to CRPC . CONCLUSION This study supports a lower testosterone threshold to define optimal medical castration ( T < 32 ng/dL ) than the previously accepted st and ard of 50 ng/dL. Testosterone levels during ADT serve as an early predictor of disease progression and thus should be measured in conjunction with prostate-specific antigen Background : Most patients receiving docetaxel-based chemotherapy for castration resistant prostate cancer ( CRPC ) will eventually progress , and the optimal interventions for these patients are controversial . The objective of our study is to evaluate the clinical efficacy and safety of pharmacological interventions for CRPC patients progressing after docetaxel-based chemotherapy .  Methods : A systematic review and Bayesian network meta- analysis of the literature was carried out according to st and ard methods . Major electronic data bases including PubMed , Web of Science and Embase were search ed until Jan 2017 . Hazard ratios ( HRs ) and odds ratios ( ORs ) with corresponding 95 % credible intervals ( CrIs ) were used to estimate the association . Results : 17 R and omized Controlled Trials ( RCTs ) comprising 14 different interventions with 12347 patients were enrolled . Compared with control arms , Abiraterone Acetate ( HR : 0.70 , 95%CrI : 0.63 - 0.79 ) , Cabazitaxel ( HR : 0.70 , 95%CrI : 0.51 - 0.95 ) and Enzalutamide ( HR : 0.63 , 95%CrI : 0.53 - 0.75 ) presented similar benefits in term of OS .  Enzalutamide showed superiority over PFS and PSA response with a highest probability to rank 1 . Moreover , sensitivity analysis showed that Abiraterone Acetate ( HR : 0.71 , 95%CrI : 0.63 - 0.78 ) exhibited the most efficacious intervention of being rank 1 in term of OS compared with control arms , followed by Cabazitaxel and Cetuximab . On the other h and , Abiraterone Acetate ( OR : 0.86 , 95%CrI : 0.35 - 2.03 ) presented no significant toxicities compared with control arms . Conclusions : Our results demonstrated that Abiraterone Acetate might be the optimal intervention for CRPC patients after docetaxel failure with acceptable tolerability . Future well- design ed RCTs and systematic review s are needed to vali date these findings PURPOSE We contrasted the endocrinological and biochemical efficacies of abarelix depot , a pure gonadotropin-releasing hormone antagonist , with a prospect i ve concurrent control cohort receiving luteinizing hormone releasing hormone ( LH-RH ) agonists with or without anti and rogen for treatment of patients with prostate cancer receiving initial hormonal therapy . MATERIAL S AND METHODS In this phase 2 open label study 242 patients with prostate cancer requiring initial hormonal treatment received abarelix depot ( 209 ) or LH-RH agonists ( 33 ) with or without anti and rogen . A total of 100 mg . abarelix depot was delivered intramuscularly every 28 days with an additional injection on day 15 . LH-RH agonists with or without anti and rogen were administered according to the depot formulation used . Endocrine efficacy was measured by the absence of testosterone surge and rapidity of castration onset . The rate of prostate specific antigen decrease was assessed . RESULTS No patient treated with abarelix depot had testosterone surge during week 1 compared with 82 % of those treated with LH-RH agonists . The concomitant administration of anti and rogen had no effect . During the first week of drug administration , in 75 % of patients treated with abarelix depot and in 0 % of those treated with LH-RH agonist  medical castration was achieved . Prostate specific antigen decrease was faster , with no flare or surge in patients treated with abarelix depot . Abarelix depot was well tolerated . CONCLUSIONS Abarelix depot represents a new class of hormonal therapy , gonadotropin releasing hormone antagonists , that has rapid medical castration and avoids the testosterone surge characteristic of LH-RH agonists PURPOSE Studies indicate that castration-resistant prostate cancer ( CRPC ) remains driven by lig and -dependent and rogen receptor ( AR ) signaling . To evaluate this , a trial of abiraterone acetate-a potent , selective , small-molecule inhibitor of cytochrome P ( CYP ) 17 , a key enzyme in and rogen synthesis -was pursued . PATIENTS AND METHODS Chemotherapy-naïve men ( n = 21 ) who had prostate cancer that was resistant to multiple hormonal therapies were treated in this phase I study of once-daily , continuous abiraterone acetate , which escalated through five doses ( 250 to 2,000 mg ) in three-patient cohorts . RESULTS Abiraterone acetate was well tolerated . The anticipated toxicities attributable to a syndrome of secondary mineralocorticoid excess-namely hypertension , hypokalemia , and lower-limb edema-were successfully managed with a mineralocorticoid receptor antagonist . Antitumor activity was observed at all doses ; however , because of a plateau in pharmacodynamic effect , 1,000 mg was selected for cohort expansion ( n = 9 ) . Abiraterone acetate administration was associated with increased levels of adrenocorticotropic hormone and steroids upstream of CYP17 and with suppression of serum testosterone , downstream and rogenic steroids , and estradiol in all patients . Declines in prostate-specific antigen > or= 30 % , 50 % , and 90 % were observed in 14 ( 66 % ) , 12 ( 57 % ) , and 6 ( 29 % ) patients , respectively , and lasted between 69 to > or= 578 days . Radiologic regression , normalization of lactate dehydrogenase , and improved symptoms with a reduction in analgesic use were documented . CONCLUSION CYP17 blockade by abiraterone acetate is safe and has significant antitumor activity in CRPC . These data confirm that CRPC commonly remains dependent on lig and -activated AR signaling INTRODUCTION Surgery and luteinizing hormone-releasing hormone ( LHRH ) analogs are st and ard and rogen deprivation treatments ( ADT ) for patients with advanced prostate cancer . We performed a phase I study to explore if irradiation to the testes could be used as an alternative to ADT . MATERIAL S AND METHODS All patients had advanced prostate cancer with normal testosterone levels before treatment and indication for long term castration . Treatment started with one LHRH analog injection ( to induce a fast drop of testosterone ) followed by irradiation to the whole scrotum . Two fractionation regimens were tested : 17 Gy in 2 fractions , and 24 Gy in 3 fractions . Hormonal blood evaluation  was performed before and every 3 months after radiotherapy .  Toxicity was evaluated at each visit by the CTCv3 scoring system . This was an IRB approved prospect i ve study . RESULTS The first three patients received 17 Gy in 2 fractions . None of them developed acute or late skin toxicity and none became castrated , keeping normal levels of testosterone during the time they were followed at 11 , 24 and 36 months post-radiotherapy . Another four patients received 24 Gy in 3 fractions . Two developed grade 1 temporary acute dermatitis and , again , none of them became castrated during follow up of 11 - 36 months . CONCLUSIONS Prospect i ve studies assessing the effect of the Leydig cells after direct irradiation to the testes are rare . The two radiotherapy regimens used in this study were well tolerated , but not capable of causing castration after 11 - 36 months of follow up . It is not yet clear whether radiation treatment can effectively induce castration in men Degarelix , approved in the USA in 2008 , is a gonadotropin-releasing hormone antagonist , representing one of the latest additions to and rogen deprivation therapy ( ADT ) . ADT is used as first-line therapy for locally advanced or metastatic prostate cancer with the aim to reduce testosterone to castrate levels . Like other gonadotropin-releasing hormone-antagonists , degarelix treatment results in rapid decrease in luteinizing hormone , follicle-stimulating hormone and testosterone levels without the associated risk of flare . Using one registration trial for degarelix with leuprolide as the active control , a cost – effectiveness analysis with a Markov model and a 20-year time horizon found the incremental cost – effectiveness ratio for degarelix to be US$ 245/ quality -adjusted life years . Degarelix provides a cost-effective treatment for ADT among patients with locally advanced prostate cancer BACKGROUND There is currently no st and ard treatment for patients with castration-resistant prostate cancer ( CRPC ) whose disease progresses after docetaxel-based chemotherapy .  The purpose of this study was to prospect ively assess the anticancer activity and tolerance of the carboplatin-etoposide combination in this setting while evaluating neuroendocrine ( NE ) features . PATIENTS AND METHODS Patients with CRPC and metastases who experienced failure after first-line docetaxel-based chemotherapy  were treated with carboplatin ( area under the curve 5 , day 1 ) and etoposide ( 80 mg/m(2)/day from days 1 to 3 ) , repeated every 3 weeks . The association between serum chromogranin A ( CgA ) , neuron-specific enolase ( NSE ) , prostate-specific antigen-doubling time ( PSADT ) , and treatment efficacy was studied . RESULTS Forty patients with CRPC who had received docetaxel with ( n = 20 ) or without ( n = 20 ) estramustine received the  carboplatin-etoposide combination  as second-line chemotherapy . A prostate-specific antigen ( PSA ) response defined as a PSA decline > or = 50 % was achieved in nine patients ( 23 % ) . Median progression-free survival ( PFS ) was 2.1 months ( range 0.6 - 9.6 ) and median overall survival was 19 months ( range 2.1 - 27.7 ) . Pain response was achieved in 15 ( 53 % ) of 28 assessable patients . Toxicity , including mainly grade s 3 - 4 anaemia ( 25 % ) and febrile neutropenia in only 2 % of patients , was manageable . Baseline CgA , NSE , or PSADT were not significant predictors for response or PFS . The PSA response rates were 18 % and 31 % in patients with normal and elevated serum CgA , respectively . It was 25 % and 20 % , respectively , in patients with normal and elevated serum NSE . CONCLUSIONS Combining carboplatin and etoposide as second-line chemotherapy in patients with CRPC is active and well tolerated in spite of a limited PFS . Activity was observed in CRPC with and without NE features Background Multiple castration‐resistant prostate cancer ( CRPC ) therapies are approved by the United States Food and Drug Administration . Radium‐223 dichloride ( Ra‐223 ) with abiraterone acetate plus prednisone have different mechanisms of action and distinct off‐target side‐effect profiles . We prospect ively investigated their combined safety , tolerability , and patient‐reported outcome measures . Patients and Methods eRADicAte , an investigator‐initiated , phase II trial , studied 31 patients with metastatic CRPC , from 5 United States uro‐oncology research sites . Patients completed 6 cycles of Ra‐223 with concurrent abiraterone therapy .  Quality of life and pain were assessed using the Functional Assessment of Cancer Therapy‐Prostate and the Brief Pain Inventory‐Short Form question naires and their subscales ; we reported the number of subjects meeting st and ardized criteria for clinical ly meaningful improvements on each scale . Safety assessment included Eastern Cooperative Oncology Group performance status , laboratory changes , opioid use , radiographic responses , and adverse events ( AEs ) . Results Twenty of 31 ( 65 % ) experienced positive clinical ly meaningful improvement changes on the Functional Assessment of Cancer Therapy‐Prostate , and 25 ( 81 % ) of 31 on the Prostate Cancer Subscale . Eighteen ( 58 % ) of 31 demonstrated reduced pain intensity and 12 ( 39 % ) of 31 demonstrated reduction of pain interference in their lives . At baseline , subjects averaged 11.6 ± 2.8 bone lesions ; at the end of treatment , subjects averaged 5.6 ± 2.4 bone lesions ( P = .0002 ) . The most frequent AEs were diarrhea ( 17 % ) , nausea ( 17 % ) , and fatigue ( 14 % ) . There were 6 serious AEs ; 1 led to study withdrawal . Conclusions Patients experienced clinical ly meaningful improvements in quality of life and pain , without unexpected adverse toxicities . Phase III combination trials of Ra‐223 with novel oral hormonal agents are ongoing to further evaluate radiographic progression and overall survival benefit . Micro‐ Abstract This is the first study to prospect ively evaluate the combined use of radium‐223 dichloride and a novel oral hormonal therapy , abiraterone acetate , in men with metastatic castration‐resistant prostate cancer . The eRADicAte study showed that patients with metastatic castration‐resistant prostate cancer experienced clinical ly meaningful improvements in quality of life with decreased pain , reduction in bone lesions , and an acceptable safety and toxicity profile BACKGROUND There is evidence linking metformin to improved prostate cancer (PCa)-related outcomes . OBJECTIVE To evaluate treatment with metformin in patients with castration-resistant PCa ( CRPC ) and the effect of the treatment on progression-free survival ( PFS ) and PSA doubling time ( PSA DT ) . DESIGN , SETTING , AND PARTICIPANTS Forty-four men with progressive metastatic CRPC from 10 Swiss centers were included in this single-arm phase 2 trial between December 2010 and December 2011 . INTERVENTION Patients received metformin 1000 mg twice daily until disease progression . OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary end point was the absence of disease progression at 12 wk . Simon two-stage optimal design was applied . With a 5 % significance level and 90 % power , 44 patients were required to test PFS at 12 wk ≤ 15 % ( H0 ) compared with ≥ 35 % ( H1 ) . RESULTS AND LIMITATIONS Thirty-six percent of patients were progression-free at 12 wk , 9.1 % were progression-free at 24 wk , and in two patients a confirmed ≥ 50 % prostate-specific antigen ( PSA ) decline was demonstrated . In 23 patients ( 52.3 % ) we observed a prolongation of PSA DT after starting metformin . The homeostatic model assessment index fell by 26 % from baseline to 12 wk , indicating an improvement in insulin sensitivity . There was a significant change in insulin-like growth factor-1 and insulin-like growth factor binding protein 3 from baseline to 12 wk . Sample size and lack of a control arm are the limitations of this trial ; analyses are therefore exploratory . CONCLUSIONS Treatment with metformin is safe in nondiabetic patients , and it yields objective PSA responses and may induce disease stabilization . The activity of metformin in PCa , along with its low cost , favorable toxicity profile , and positive effect on metabolic parameters , suggests that further investigation of metformin as therapy for patients with PCa is of interest . PATIENT SUMMARY In this trial we assessed the use of the diabetes mellitus drug metformin in patients with advanced prostate cancer . We found disease stabilization and prolongation of prostate-specific antigen doubling time in some patients as well as effects on metabolic parameters . TRIAL REGISTRATION This study is registered with Clinical Trials.gov with the identifier NCT01243385 . PREVIOUS PRESENTATION The study was presented at ESMO 2012 ( abstract 1460 ) Background Loss of the tumor suppressor phosphatase and tensin homolog ( PTEN ) occurs frequently in prostate cancers . Pre clinical evidence suggests that activation of PI3K/AKT signaling through loss of PTEN can result in resistance to hormonal treatment in prostate cancer . Objective To explore the antitumor activity of abiraterone acetate ( abiraterone ) in castration-resistant prostate cancer ( CRPC ) patients with and without loss of PTEN protein expression . Design , setting , and participants We retrospectively identified patients who had received abiraterone and had hormone-sensitive prostate cancer ( HSPC ) and /or CRPC tissue available for PTEN immunohistochemical analysis . Outcome measurements and statistical analysis The primary end point was overall survival from initiation of abiraterone treatment . Relationship with outcome was analyzed using multivariate Cox regression and log-rank analyses . Results and limitations A total of 144 patients were identified who had received abiraterone post-docetaxel and had available tumor tissue . Overall , loss of PTEN expression was observed in 40 % of patients . Matched HSPC and CRPC tumor biopsies were available for 41 patients .  PTEN status in CRPC correlated with HSPC in 86 % of cases . Loss of PTEN expression was associated with shorter median overall survival ( 14 vs 21 mo ; hazard ratio [ HR ] : 1.75 ; 95 % confidence interval [ CI ] , 1.19–2.55 ; p = 0.004 ) and shorter median duration of abiraterone  treatment ( 24 vs 28 wk ; HR : 1.6 ; 95 % CI , 1.12–2.28 ; p = 0.009 ) . PTEN protein loss , high lactate dehydrogenase , and the presence of visceral metastases were identified as independent prognostic factors in multivariate analysis . Conclusions Our results indicate that loss of PTEN expression was associated with worse survival and shorter time on abiraterone treatment . Further studies in larger and prospect i ve cohorts are warranted . Patient summary PTEN is a protein often lost in prostate cancer cells . In this study we evaluated if prostate cancers that lack this protein respond differently to treatment with abiraterone acetate . We demonstrated that the survival of patients with loss of PTEN is shorter than patients with normal PTEN expression PURPOSE We compared the endocrinological and biochemical efficacy of abarelix depot , a gonadotropin-releasing hormone antagonist , with that of a widely used combination of luteinizing hormone releasing hormone agonist and a nonsteroidal anti and rogen . MATERIAL S AND METHODS A total of 255 patients were r and omized to receive open label 100 mg . abarelix depot or 7.5 mg . leuprolide acetate intramuscularly injection on days 1 , 29 , 57 , 85 , 113 and 141 for 24 weeks . Patients in the abarelix group received an additional injection on day 15 and those in the leuprolide acetate group received 50 mg . bicalutamide daily . Patients could continue treatment with study drug for an additional 28 weeks . The efficacy end points were the comparative rates of avoidance of testosterone surge ( greater than 10 % increase ) within 7 days of the first injection and the rapidity of achieving reduction of serum testosterone to castrate levels ( 50 ng./dl . or less ) on day 8 . Patients were monitored for adverse events and laboratory abnormalities . RESULTS Abarelix was more effective in avoidance of testosterone surge ( p < 0.001 ) and the rapidity of reduction of testosterone to castrate levels on day 8 ( p < 0.001 ) than combination therapy . No significant difference was seen between the groups in the initial rate of decline of serum prostate specific antigen or the ability to achieve and maintain castrate levels of testosterone . No unusual or unexpected adverse events were reported . CONCLUSIONS Abarelix as monotherapy achieves medical castration significantly more rapidly than combination therapy and avoids the testosterone surge characteristic of agonist therapy . Both treatments were equally effective in reducing serum prostate specific antigen , and achieving and maintaining castrate levels of testosterone PURPOSE Persistent and rogen signaling is implicated in castrate-resistant prostate cancer ( CRPC ) progression . This study aim ed to evaluate and rogen signaling in bone marrow-infiltrating cancer and testosterone in blood and bone marrow and to correlate with clinical observations . PATIENTS AND METHODS This was an open-label , observational study of 57 patients with bone-metastatic CRPC who underwent transiliac bone marrow biopsy between October 2007 and March 2010 . Patients received oral abiraterone acetate ( 1 g ) once daily and prednisone ( 5 mg ) twice daily . And rogen receptor ( AR ) and CYP17 expression were assessed by immunohistochemistry , testosterone concentration by mass spectrometry , AR copy number by polymerase chain reaction , and TMPRSS2-ERG status by fluorescent in situ hybridization in available tissues . RESULTS Median overall survival was 555 days ( 95 % CI , 440 to 965 + days ) . Maximal prostate-specific antigen decline ≥ 50 % occurred in 28 ( 50 % ) of 56 patients . Homogeneous , intense nuclear expression of AR , combined with ≥ 10 % CYP17 tumor expression , was correlated with longer time to treatment discontinuation ( > 4 months ) in 25 patients with tumor-infiltrated bone marrow sample s. Pretreatment CYP17 tumor expression ≥ 10 % was correlated with increased bone marrow aspirate testosterone . Blood and bone marrow aspirate testosterone concentrations declined to less than picograms-per-milliliter levels and remained suppressed at progression . CONCLUSION The observed pretreatment and rogen-signaling signature is consistent with persistent and rogen signaling in CRPC bone metastases . This is the first evidence that abiraterone acetate  achieves sustained suppression of testosterone in both blood and bone marrow aspirate to less than picograms-per-milliliter levels . Potential admixture of blood with bone marrow aspirate limits our ability to determine the origin of measured testosterone Purpose : Degarelix , a new gonadotropin-releasing hormone ( GnRH ) receptor antagonist with demonstrated efficacy as first-line treatment in the management of high-risk prostate cancer , possesses some theoretical advantages over luteinizing hormone – releasing hormone ( LHRH ) analogues in terms of avoiding “ testosterone flare ” and lower follicle-stimulating hormone ( FSH ) levels . We set out to determine whether preoperative degarelix influenced surrogates of disease control in a r and omized phase II study . Experimental Design : Thirty-nine patients were r and omly assigned to one of three different neoadjuvant arms : degarelix only , degarelix/bicalutamide , or LHRH agonist/bicalutamide . Treatments were given for 3 months before prostatectomy . Patients had localized prostate cancer and had chosen radical prostatectomy as primary treatment . The primary end point was treatment effect on intratumoral dihydrotestosterone levels . Results : Intratumoral DHT levels were higher in the degarelix arm than both the degarelix/bicalutamide and LHRH agonist/bicalutamide arms ( 0.87 ng/g vs. 0.26 ng/g and 0.23 ng/g , P < 0.01 ) . No significant differences existed for other intratumoral and rogens , such as testosterone and dehydroepi and rosterone . Patients in the degarelix-only arm had higher AMACR levels on immunohistochemical analysis ( P = 0.01 ) . Serum FSH levels were lower after 12 weeks of therapy in both degarelix arms than the LHRH agonist/bicalutamide arm ( 0.55 and 0.65 vs. 3.65 , P < 0.01 ) , and inhibin B levels were lower in the degarelix/bicalutamide arm than the LHRH agonist/bicalutamide arm ( 82.14 vs. 126.67 , P = 0.02 ) . Conclusions : Neoadjuvant degarelix alone , compared with use of LHRH agonist and bicalutamide , is associated with higher levels of intratumoral dihydrotestosterone , despite similar testosterone levels . Further studies that evaluate the mechanisms behind these results are needed . Clin Cancer Res ; 23(8 ) ; 1974–80 . © 2016 AACR 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 OBJECTIVE To investigate the effects of baseline testosterone on testosterone control and prostate-specific antigen ( PSA ) suppression using data from a phase III trial ( CS21 ) comparing degarelix and leuprolide in prostate cancer . METHODS In CS21 , patients with histologically confirmed prostate cancer ( all stages ) were r and omized to degarelix 240 mg for 1 month followed by monthly maintenance doses of 80 or 160 mg , or leuprolide 7.5 mg/month . Patients receiving leuprolide could receive anti and rogens for flare protection . Treatment effects on testosterone and PSA reduction , testosterone surge , and microsurges were investigated in 3 baseline testosterone subgroups : < 3.5 , 3.5 - 5.0 , and > 5.0 ng/mL. Data are presented for the groups receiving degarelix 240/80 mg ( the approved dose ) and leuprolide 7.5 mg . RESULTS Higher baseline testosterone delayed castration with both treatments . However , castrate testosterone levels and PSA suppression occurred more rapidly with degarelix irrespective of baseline testosterone . With leuprolide , the magnitude of testosterone surge and microsurges increased with increasing baseline testosterone . There was no overall correlation between baseline testosterone and initial PSA decrease in either treatment group , although PSA suppression tended to be slowest with leuprolide and fastest with degarelix in the high baseline testosterone subgroup . CONCLUSION Patients with high baseline testosterone may have greater risk of tumor stimulation ( clinical flare ) and mini-flares during gonadotrophin-releasing hormone agonist treatment and so the need for flare protection with anti and rogens in these patients is obvious , especially in metastatic disease . Although higher baseline testosterone delays castration , castrate testosterone and PSA suppression occur more rapidly with degarelix , irrespective of baseline testosterone , without the need for flare protection Background : Patients who develop castration-resistant prostate cancer ( CRPCa ) typically continue on and rogen deprivation therapy ( ADT ) . Whether these patients need to remain on ADT has not been well studied . We conducted a multicenter r and omized trial to compare an intermittent versus continuous approach to ADT in CRPCa patients .  Overall survival , health-related quality of life ( QOL ) , and cost were the main endpoints . Methods : CRPCa patients were r and omized 2:1 to intermittent or continuous luteinizing hormone-releasing hormone agonists ( LHRHa ) .  Patients were followed with clinical assessment s , laboratory investigations , and QOL question naires ( EORTC QLQ-C30 or PROSQOLI ) every 2 months . If the serum testosterone rose above castrate levels ( 1.75 nmol/L ) , LHRHa were reinitiated . The study was design ed to close if > 50 % of patients needed to restart ADT in the intermittent arm . Results : Thirty-one patients were followed with a median follow-up of 26.8 months—18 in the intermittent arm and 13 in the continuous . Twelve of 18 patients on the intermittent arm were reinitiated on LHRHa at a median time of 17.9 months . There was no difference in overall or cancer-specific survival between the 2 arms . There was no statistically significant difference in QOL between the 2 arms at 0 and 12 months . The total mean costs at 24 months were significantly lower in the intermittent arm ( $ 3135 vs. $ 8253 Canadian dollars , P=0.0167 ) compared with the continuous . The main limitation of this study is the small sample size . Conclusions : We have observed that intermittent ADT in patients with CRPCa , using a testosterone of > 1.75 ngmol/L as a trigger to reinitiate LHRHa , results in a substantial cost savings with no negative impact on oncologic and QOL outcomes INTRODUCTION The sub Comittee prostate of the CCAFU established guidelines for diagnostic , treatment , evaluation and st and art of care of prostate cancer . METHODS Guidelines 2010 were up date d based on systematic literature search performed by the sub-Comittee in Medline and PubMed data bases to evaluate references , levels of evidence and grade of recomm and ation . RESULTS Pathological examination of the tissue specimens was defined specifically for Gleason score according to ISP 2005 recomm and ations . Prostate and pelvis RMN became the reference in terms of radiological exam . Individual and early diagnosis of prostate cancer was defined and role of PSA was precised . Active surveillance became one of the st and art of care of low-risk tumors , radical prostatectomy remained one of the options for all risk group tumors , length of hormonotherapy in association with radiotherapy was precised according to the risk group . Side effects of  hormonotherapy  treament needed specific supervision ; hormonotherapy had no indication in case of non metastatic tumors and intermittent hormonotherapy in metastatic tumors . New hormonal drugs in pre and post chemotherapy and bone target drugs opened new therapeutics pathways . CONCLUSION From 2010 to 2013 , st and arts of care of prostate cancer were modified because of results of prospect i ve studies and new therapeutics . They allowed precise treatments for each specific clinical situation . In the future , multidisciplinary treatments for high risk tumors , time of adjuvant treatment and sequencies of new hormonal treatment had to be defined To compare combination therapy with bicalutamide 80 mg and a luteinizing hormone-releasing hormone agonist ( LHRH-A ) versus LHRH-A alone in Japanese men with untreated advanced prostate cancer . A total of 205 patients with stage C/D prostate cancer were r and omized to either LHRH-A+once-daily oral bicalutamide 80 mg or placebo . Primary study variables have been reported previously . Secondary variables included : time to achieve prostate-specific antigen⩽4 ng/ml , time-to-treatment failure ( TTTF ) , time-to-disease progression ( TTP ) , overall survival ( OS ) , adverse events and adverse drug reactions . Following combination therapy with bicalutamide 80 mg , there were significant ( P<0.001 ) advantages over LHRH-A alone in terms of TTTF and TTP , but the difference in the interim OS was not statistically significant . First-line combination therapy with bicalutamide 80 mg in Japanese patients with advanced prostate cancer offers significant benefits over LHRH-A alone , with respect to TTTF and TTP . Follow-up for OS continues PURPOSE Evolving treatments , disease phenotypes , and biology , together with a changing drug development environment , have created the need to revise  castration-resistant prostate cancer ( CRPC ) clinical trial recommendations to succeed those from prior Prostate Cancer Clinical Trials Working Groups . METHODS An international expert committee of prostate cancer clinical investigators ( the Prostate Cancer Clinical Trials Working Group 3 [ PCWG3 ] ) was reconvened and exp and ed and met in 2012 - 2015 to formulate up date d criteria on the basis of emerging trial data and validation studies of the Prostate Cancer Clinical Trials Working Group 2 recommendations . RESULTS PCWG3 recommends that baseline patient assessment include tumor histology , detailed records of prior systemic treatments and responses , and a detailed reporting of disease subtypes based on an anatomic pattern of metastatic spread . New recommendations for trial outcome measures include the time to event end point of symptomatic skeletal events , as well as time to first metastasis and time to progression for trials in the nonmetastatic CRPC state . PCWG3 introduces the concept of no longer clinical ly benefiting to underscore the distinction between first evidence of progression and the clinical need to terminate or change treatment , and the importance of documenting progression in existing lesions as distinct from the development of new lesions . Serial biologic profiling using tumor sample s from biopsies , blood-based diagnostics , and /or imaging is also recommended to gain insight into mechanisms of resistance and to identify predictive biomarkers of sensitivity for use in prospect i ve trials . CONCLUSION PCWG3 moves drug development closer to unmet needs in clinical practice by focusing on disease manifestations most likely to affect prognosis adversely for therapeutics tested in both nonmetastatic and metastatic CRPC population s. Consultation with regulatory authorities is recommended if a trial is intended to seek support for drug approval BACKGROUND We compared the clinical effects and impact on quality of life ( QOL ) of patients who received a 3-month course of flutamide monotherapy before radical prostatectomy with those who received a 3-month course of luteinizing hormone-releasing hormone ( LHRH ) agonist monotherapy .  METHODS Thirty-seven patients with non-metastatic prostate cancer were enrolled in this study ( 19 , flutamide ; 18 , LHRH agonist ) . The rates of change of serum prostate-specific antigen ( PSA ) and testosterone levels , downsizing of prostate volume , the rate of organ confined disease , adverse effects and perioperative scores measured using the European Organization for Research and Treatment of Cancer Prostate Cancer Quality of Life Question naire ( EORTC-P ) and the Sapporo Medical University Sexual Function Question naire ( SMUF ) were analyzed . RESULTS At radical prostatectomy , pathological variables were not significantly different in the two groups . Serum testosterone level was significantly higher ( mean 359.2 compared to 10.5 , P < 0.001 ) , complete response rate of PSA ( 13 % compared to 57 % , P = 0.028 ) and rate of downsizing of prostate volume ( mean , -17.7 % compared to -35.4 % , P = 0.038 ) were significantly lower in the flutamide group than in the LHRH group . After neoadjuvant hormone therapy , the scores on the sexual problem domain of EORTC-P ( P = 0.033 ) and sexual desire score of SMUF ( P = 0.021 ) were significantly higher in the flutamide group than in the LHRH group . At a median follow-up of 34 months after prostatectomy , biochemical failure-free survival rate in the flutamide group did not differ from that in the LHRH group . CONCLUSION This study suggests that flutamide monotherapy can be an acceptable modality as an option for neoadjuvant hormone therapy OBJECTIVE To evaluate long-term follow-up of a phase II trial of chemohormonal therapy in 62 men with prostate cancer biochemical relapse ( BR ) . METHODS Treatment was 4 cycles of docetaxel ( 70 mg/m(2 ) ) every 3 weeks and estramustine 280 mg three times a day ( days 1 - 5 ) followed by 15 months of goserelin acetate/bicalutamide . The primary endpoint was the proportion with prostate-specific antigen ( PSA ) < 0.1 with recovered testosterone 5 years after completion of therapy . Secondary endpoints included time to progression ( TTP ) , time to reinitiate and rogen deprivation therapy ( ADT ) , the proportion with castration-resistant prostate cancer ( CRPC ) , and overall survival ( OS ) . RESULTS Median follow-up was 8.6 years ( range 1.3 - 11.1 years ) . At 5 year follow-up , 7 patients ( 11 % ) had PSA < 0.1 ( 5 undetectable ) ; 8 ( 13 % ) had PSA > 0.1 but without reinitiation of ADT ( median PSA 0.37 ) . Of the 15 ( 24 % ) men without reinitiation of ADT , and 14 have recovered testosterone to normal range . Median TTP for the complete cohort was 35.0 months ( 95 % confidence interval [ CI ] 31.7 - 39.2 ) . Baseline PSA < 3.0 ng/dL , no prior ADT , and prostatectomy ( vs radiation ) were associated with longer TTP ( P = .0001 , P = .0055 , and P = .0398 , respectively ) . At the time of analysis , 42 men ( 68 % ) had restarted ADT , 23 men had CRPC ( 37 % ) , and 11 ( 18 % ) had chemotherapy . Median time to reinitiation of ADT was 32.6 months ( range 0 - 107.6 months ) . Median OS has not been reached ; there were 15 deaths . CONCLUSION Chemotherapy plus ADT for BR result ed in durable ( > 5 years ) complete responses ( < 0.1 ng/mL ) in 7 men ( 11 % ) . Twenty-four percent of men have not re-initiated ADT 5 years from completion of protocol therapy
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 .
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 .