Phase II study of radium-223 dichloride in Japanese patients with symptomatic castration-resistant prostate cancer Efficacy and safety of different interventions in castration resistant prostate cancer progressing after docetaxel-based chemotherapy: Bayesian network analysis of randomized controlled trials Association of AR-V7 on Circulating Tumor Cells as a Treatment-Specific Biomarker With Outcomes and Survival in Castration-Resistant Prostate Cancer. Feasibility study of a randomized controlled trial comparing docetaxel chemotherapy and androgen deprivation therapy with sequential prostatic biopsies from patients with advanced non-castration-resistant prostate cancer. Significant and sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate. Long-term results of a phase II study with neoadjuvant docetaxel chemotherapy and complete androgen blockade in locally advanced and high-risk prostate cancer Phase II multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxel-treated castration-resistant prostate cancer. Combining carboplatin and etoposide in docetaxel-pretreated patients with castration-resistant prostate cancer: a prospective study evaluating also neuroendocrine features. An exploratory analysis of alkaline phosphatase, lactate dehydrogenase, and prostate-specific antigen dynamics in the phase 3 ALSYMPCA trial with radium-223 High toxicity in patients receiving adjuvant docetaxel plus hormone treatment after radical radiotherapy for high-risk prostate cancer: A preplanned safety report of SPCG 13 trial. Phase I trial of weekly docetaxel, total androgen blockade, and image-guided intensity-modulated radiotherapy for localized high-risk prostate adenocarcinoma. Long-term follow-up of a prospective trial of trimodality therapy of weekly paclitaxel, radiation, and androgen deprivation in high-risk prostate cancer with or without prior prostatectomy. Efficacy of Cabazitaxel in Castration-resistant Prostate Cancer Is Independent of the Presence of AR-V7 in Circulating Tumor Cells. 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. EAU guidelines on prostate cancer. part 1: screening, diagnosis, and local treatment with curative intent-update 2013. Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. Salvage radiotherapy with or without short-term hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a randomised, multicentre, open-label phase 3 trial.
Background Radium-223 dichloride ( radium-223 ) is the first targeted alpha therapy approved for the treatment of castration-resistant prostate cancer ( CRPC ) with bone metastases . This study investigated the efficacy and safety of radium-223 in Japanese patients with symptomatic CRPC and bone metastases . Methods In this open-label , multicenter , phase II study , patients with progressive , symptomatic CRPC and bone metastases were treated with radium-223 ( 55 kBq/kg , intravenously ) in a 4-week cycle for six cycles . The primary endpoint was the percent change in total alkaline phosphatase ( ALP ) from baseline at 12 weeks . Secondary endpoints included the percent ALP change from baseline to end of treatment ( EOT ) , ALP response rates , percent change in prostate-specific antigen ( PSA ) from baseline to 12 weeks and EOT , PSA response rates , overall survival ( OS ) , and time to symptomatic skeletal events ( SSEs ) . Adverse events were monitored throughout the study period . Results Of the 49 Japanese patients ( median age 74 years ) , 28 completed all infusions . Mean percent change in total ALP and PSA from baseline to 12 weeks was −19.3 and + 97.4 % , respectively . One-year OS and SSE-free rate at the end of active follow-up were 78 and 89 % , respectively . The ALP response rate was 31 % , while the PSA response rate was 6 % . Grade 3/4 treatment-emergent adverse events observed in ≥10 % of patients included decreased lymphocyte count ( 14 % ) , anemia ( 14 % ) , anorexia ( 10 % ) , and bone pain ( 10 % ) . Conclusions Radium-223 is effective and well tolerated in Japanese patients with CRPC and bone metastases . Results were comparable with the Alpharadin in Symptomatic Prostate Cancer Patients ( ALSYMPCA ) trial . Clinical trial registration Clinical Trials.gov NCT01929655 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 Importance A critical decision in the management of metastatic castration-resistant prostate cancer ( mCRPC ) is when to administer an and rogen receptor signaling ( ARS ) inhibitor or a taxane . Objective To determine if pretherapy nuclear and rogen-receptor splice variant 7 ( AR-V7 ) protein expression and localization on circulating tumor cells ( CTCs ) is a treatment-specific marker for response and outcomes between ARS inhibitors and taxanes . Design , Setting , and Participants For this cross-sectional cohort study at Memorial Sloan Kettering Cancer Center , 265 men with progressive mCRPC undergoing a change in treatment were considered ; 86 were excluded because they were not initiating ARS or taxane therapy ; and 18 were excluded for processing time constraints , leaving 161 patients for analysis . Between December 2012 and March 2015 , blood was collected and processed from patients with progressive mCRPC immediately prior to new line of systemic therapy . Patients were followed up to 3 years . Main Outcomes and Measures Prostate-specific antigen ( PSA ) response , time receiving therapy , radiographic progression-free survival ( rPFS ) , and overall survival ( OS ) . Results Overall , of 193 prospect ively collected blood sample s from 161 men with mCRPC , 191 were evaluable ( 128 pre-ARS inhibitor and 63 pretaxane ) . AR-V7-positive CTCs were found in 34 sample s ( 18 % ) , including 3 % of first-line , 18 % of second-line , and 31 % of third- or greater line sample s. Patients whose sample s had AR-V7-positive CTCs before ARS inhibition had resistant posttherapy PSA changes ( PTPC ) , shorter rPFS , shorter time on therapy , and shorter OS than those without AR-V7-positive CTCs . Overall , resistant PTPC were seen in 65 of 112 sample s ( 58 % ) without detectable AR-V7-positive CTCs prior to ARS inhibition . There were statistically significant differences in OS but not in PTPC , time on therapy , or rPFS for patients with or without pretherapy AR-V7-positive CTCs treated with a taxane . A multivariable model adjusting for baseline factors associated with survival showed superior OS with taxanes relative to ARS inhibitors when AR-V7-positive CTCs were detected pretherapy ( hazard ratio , 0.24 ; 95 % CI , 0.10 - 0.57 ; P = .035 ) . Conclusions and Relevance The results vali date CTC nuclear expression of AR-V7 protein in men with mCRPC as a treatment-specific biomarker that is associated with superior survival on taxane therapy over ARS-directed therapy in a clinical practice setting . Continued examination of this biomarker in prospect i ve studies will further aid clinical utility BACKGROUND AND OBJECTIVE Sequential tissue biopsies taken during clinical trials of novel systemic anticancer therapies for advanced prostate cancer ( PCa ) may aid pharmacodynamic evaluation and biomarker discovery . We conducted a single institution phase-II open-labeled r and omized study to assess the safety , tolerability , and early efficacy of docetaxel chemotherapy plus and rogen deprivation therapy ( ADT ) vs. ADT alone for patients with advanced non-castration-resistant PCa with sequential prostatic biopsies . PATIENTS AND METHODS We r and omized 30 patients with newly diagnosed high- grade locally advanced or metastatic ( cT3 - 4/N0 - 1/M0 - 1 ) PCa to receive ADT with ( n = 15 ) or without ( n = 15 ) docetaxel . Transrectal ultrasound-guided prostatic biopsies were taken at r and omization and ~22 weeks after treatment initiation . Primary end point : biochemical response rate . Secondary end points : time to progression and tumor profiling . RESULTS Both treatments appear to be well tolerated , and there was no difference in mean nadir prostate-specific antigen and time to prostate-specific antigen relapse between treatment arms ( P>0.05 ) . No adverse effects of pre- and post-treatment prostatic biopsies were observed . The study was neither design ed nor sufficiently powered to demonstrate statistically significant differences in oncological outcomes or safety profiles between the 2 treatment arms . CONCLUSIONS Despite the lack of statistical power , our study suggests that docetaxel and ADT in combination may be well tolerated with apparently similar short-term efficacy compared with ADT alone for high- grade locally advanced or metastatic non-castration-resistant PCa , Sequential prostatic biopsies may provide tissue for tumor profiling to yield mechanistic or prognostic insights relating to novel systemic anticancer therapies PURPOSE The principal objective of this trial was to evaluate the antitumor activity of abiraterone acetate , an oral , specific , irreversible inhibitor of CYP17 in docetaxel-treated patients with castration-resistant prostate cancer ( CRPC ) . PATIENTS AND METHODS In this multicenter , two-stage , phase II study , abiraterone acetate 1,000 mg was administered once daily continuously . The primary end point was achievement of a prostate-specific antigen ( PSA ) decline of > or = 50 % in at least seven of 35 patients . Per an attained phase II design , more than 35 patients could be enrolled if the primary end point was met . Secondary objectives included : PSA declines of > or = 30 % and > or = 90 % ; rate of RECIST ( Response Evaluation Criteria in Solid Tumors ) responses and duration on study ; time to PSA progression ; safety and tolerability ; and circulating tumor cell ( CTC ) enumeration . RESULTS Docetaxel-treated patients with CRPC ( N = 47 ) were enrolled .  PSA declines of > or = 30 % , > or = 50 % and > or = 90 % were seen in 68 % ( 32 of 47 ) , 51 % ( 24 of 47 ) , and 15 % ( seven of 47 ) of patients , respectively . Partial responses ( by RECIST ) were reported in eight ( 27 % ) of 30 patients with measurable disease . Median time to PSA progression was 169 days ( 95 % CI , 113 to 281 days ) . The median number of weeks on study was 24 , and 12 ( 25.5 % ) of 47 patients remained on study > or = 48 weeks . CTCs were enumerated in 34 patients ; 27 ( 79 % ) of 34 patients had at least five CTCs at baseline . Eleven ( 41 % ) of 27 patients had a decline from at least five to less than 5 CTCs , and 18 ( 67 % ) of 27 had a > or = 30 % decline in CTCs after starting treatment with abiraterone acetate . Abiraterone acetate was well tolerated . CONCLUSION Abiraterone acetate has significant antitumor activity in post-docetaxel patients with CRPC . R and omized , phase III trials of abiraterone acetate are underway to define the future role of this agent Background Patients with locally advanced and high-risk prostate cancer ( LAPC ) are prone to experience biochemical recurrence despite radical prostatectomy ( RP ) . We evaluated feasibility , safety and activity of a neoadjuvant chemohormonal therapy ( NCHT ) with 3-weekly full dose docetaxel and complete and rogen blockade ( CAB ) in locally advanced and high-risk prostate cancer patients ( LAPC ) undergoing RP . Methods Patients ( n = 30 ) were selected by Kattans ’ preoperative score and received trimestral buserelin 9,45 mg , bicalutamide 50 mg/day and 3 cycles docetaxel ( 75 mg/m2 ) followed by RP . Primary endpoints were biochemical ( PSA ) and local downstaging . Secondary endpoints included toxicity and operability assessment s , pathological complete response ( pCR ) , time to PSA progression , 5-year biochemical recurrence free survival ( bRFS ) and overall survival ( OS ) . Results Median baseline PSA was 25.8 ng/ml ( 2.1–293 ) , and the predicted probability of 5-year bRFS was 10 % ( 0–55 ) . NCHT induced PSA-reduction was 97.3 % ( 81.3 - 99.9 % ; p < 0.001 ) and post-RP 96.7 % of patients were therapy responders , with undetectable PSA-values . Post- vs. pretreatment MRI indicated a median tumor volume reduction of 46.4 % ( −31.3 - 82.8 ; p < 0.001 ) . A pathological downstaging was observed in 48.3 % . Severe hematologic toxicities ( ≥CTC3 ) were frequent with 53.8 % leucopenia , 90 % neutropenia and 13.3 % febrile neutropenia . RP was performed in all patients . While resectability was hindered in 26.7 % , continence was achieved in 96.7 % . Pathologic analyses revealed no pCR . Lymph node- and extracapsular involvement was observed in 36.7 % and 56.7 % with 33.3 % positive surgical margins . After a median of 48.6 ( 19.9 - 87.8 ) months , 55.2 % of therapy responders experienced PSA-recurrence . The estimated median time to PSA-progression was 38.6 months ( 95%CI 30.9 - 46.4 ) and 85.3 months ( 95%CI 39.3–131.3 ) for OS . The 5-year bRFS was improved to 40 % , but limiting for interpretation adjuvant treatment was individualized . Conclusions NCHT is feasible despite high hematotoxicity , with excellent functional results . Significant downstaging was observed without pCR . NCHT seems to improve the cohort adjusted 5-year bRFS , but clinical value needs further investigation in r and omized trials PURPOSE Persistence of lig and -mediated and rogen receptor signaling has been documented in castration-resistant prostate cancers ( CRPCs ) . Abiraterone acetate ( AA ) is a potent and selective inhibitor of CYP17 , which is required for and rogen bio synthesis in the testes , adrenal gl and s , and prostate tissue . This trial evaluated the efficacy and safety of AA in combination with prednisone to reduce the symptoms of secondary hyperaldosteronism that can occur with AA monotherapy . PATIENTS AND METHODS Fifty-eight men with progressive metastatic CRPC who experienced treatment failure with docetaxel-based chemotherapy received AA ( 1,000 mg daily ) with prednisone ( 5 mg twice daily ) . Twenty-seven ( 47 % ) patients had received prior ketoconazole . The primary outcome was > or = 50 % prostate-specific antigen ( PSA ) decline , with objective response by Response Evaluation Criteria in Solid Tumors ( RECIST ) criteria , and changes in Eastern Cooperative Oncology Group ( ECOG ) performance status ( PS ) and circulating tumor cell ( CTC ) numbers . Safety was also evaluated . RESULTS A > or = 50 % decline in PSA was confirmed in 22 ( 36 % ) patients , including 14 ( 45 % ) of 31 ketoconazole-naïve and seven ( 26 % ) of 27 ketoconazole-pretreated patients . Partial responses were seen in four ( 18 % ) of 22 patients with RECIST-evaluable target lesions . Improved ECOG PS was seen in 28 % of patients . Median time to PSA progression was 169 days ( 95 % CI , 82 to 200 days ) . CTC conversions with treatment from > or = 5 to < 5 were noted in 10 ( 34 % ) of 29 patients . The majority of  AA-related adverse events were grade 1 to 2 , and no AA-related grade 4 events were seen . CONCLUSION AA plus prednisone was well tolerated , with encouraging antitumor activity in heavily pretreated CRPC patients . The incidence of mineralocorticoid-related toxicities ( hypertension or hypokalemia ) was reduced by adding low-dose prednisone . The combination of AA plus prednisone is recommended for phase III investigations BACKGROUND 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 Baseline clinical variables are prognostic for overall survival ( OS ) in patients with castration-resistant prostate cancer ( CRPC ) . Their prognostic and predictive value with agents targeting bone metastases , such as radium-223 , is not established . Patients and methods The radium-223 ALSYMPCA trial enrolled patients with CRPC and symptomatic bone metastases . Prognostic potential of baseline variables was assessed using Cox models . Percentage changes in biomarker levels from baseline were evaluated during the trial period ; changes from baseline to week 12 were evaluated for association with OS and surrogacy . Results Eastern Cooperative Oncology Group performance status , total alkaline phosphatase ( tALP ) , lactate dehydrogenase ( LDH ) , and prostate-specific antigen ( PSA ) at baseline were associated with OS ( P ≤ 0.0003 ) in the intent-to-treat population ( radium-223 , N = 614 ; placebo , N = 307 ) . tALP declined from baseline within 4 weeks after beginning radium-223 , by week 12 declining in 87 % of radium-223 and 23 % of placebo patients ( P < 0.001 ) . LDH declined in 51 % and 34 % ( P = 0.003 ) , whereas PSA declined in 27 % and 14 % ( P = 0.160 ) . Mean tALP change from baseline was 32.2 % decrease with radium-223 and 37.2 % increase with placebo . Radium-223 patients with tALP decline from baseline to week 12 ( confirmed ≥3 weeks from week 12 ) had 55 % lower risk of death ( hazard ratio = 0.45 ; 95 % CI 0.34–0.61 ) versus those with no confirmed tALP decline . Proportional treatment effect ( PTE ) values for tALP , LDH , and PSA changes from baseline at week 12 as OS surrogate markers were 0.34 ( 95 % CI : 0–0.746 ) , 0.07 ( 95 % CI : 0–0.211 ) , and 0 ( 95 % CI : 0–0.082 ) , respectively . Conclusions Significant tALP declines ( versus placebo ) occurred as early as 4 weeks after beginning radium-223 therapy . tALP or LDH declines at 12 weeks correlated with longer OS , but did not meet statistical surrogacy requirements . Dynamic changes in tALP and LDH during radium-223 treatments may be useful to monitor , but do not serve as surrogates for survival 63 Background : In two r and omized trials a survival benefit has been shown for docetaxel ( T ) in metastatic , hormone refractory prostate cancer PrCa ) . In order to increase the recurrence-free survival and overall survival with adjuvant treatment we conducted a r and omized trial using T in patients ( pts ) with high risk PrCa after radical radiotherapy ( RT ) .  METHODS Between May 2007 and April 2009 100 pts with PrCa Gleason score ( GS ) 7 ( 4 + 3 ) and cT2 tumors with PSA > 10 to < 70 ng/mL or cT2 tumors with GS 8 - 10 or any cT3 tumors without metastases were r and omized between surveillance ( S ) or six courses of T 75 mg/m2 q21d at the end of RT . Neoadjuvant + adjuvant LHRH-treatment for 9 mo was m and atory . The defined end-point is PSA relapse ( ASTRO-RTOG guidelines ) . The groups were well balanced ; mean age 65 vs 66 years , ECOG ( 0/1 , % ) 90/10 vs 90/10 ; time from diagnosis 262 vs 270 days , GS ( 6 - 7/8 - 10 , % ) 60/40 vs 44/56 ; tumor stage ( T2/T3 , % ) 26/74 vs 28/72 in groups T vs S , respectively . The mean PSA of the 100 pts at the time of diagnosis was 21.9 ng/mL and the nadir PSA after RT was 0.25 ng/mL. By September 2010 227 out of 378 pts have been r and omized to this SPCG 13 trial , NTC 006653848 . RESULTS During T treatment Grade ( G ) 3 adverse event ( AEs ) occurred in 15 pts ( 30 % ) and G 4 AEs in 30 pts ( 60 % ) mainly due to bone marrow toxicity , which was higher than expected ; neutropenia G 3 - 4 in 72 % of the pts . Febrile neutropenia in 24 % of the pts , neutropenic infection in 10 % the pts and G3 infection without neutropenia in 4 % of pts was recorded . Nonhematological G 3 AEs ( pts ) were rare ; anorexia ( 1 ) , diarrhea ( 3 ) , fatigue ( 5 ) , mucositis ( 1 ) , nausea ( 1 ) and pain ( 1 ) . Other severe SAEs related to T were pulmonary embolism and renal failure . However , only three pts stopped T before 6 cycles were completed due to toxicity . No deaths have occurred . In the S arm only one patient experienced G 3 toxicity ( pain ) 12 weeks after the r and omization . CONCLUSIONS Adjuvant T chemotherapy after RT has a higher frequency of neutropenia than previous studies on pts with metastatic disease , but very similar to the SPCG 12 trial of adjuvant T after surgery . Otherwise the treatment was quite well tolerated . [ Table : see text ] BACKGROUND This was a phase I study to find the maximum tolerable dose ( MTD ) of weekly docetaxel combined with high-dose intensity-modulated radiotherapy ( IMRT ) and and rogen deprivation therapy ( ADT ) . PATIENTS AND METHODS Men with localized high-risk prostate cancer ( HRPC ) were treated with weekly docetaxel at 10 to 30 mg/m(2 ) concurrent with IMRT of 77.4 Gy to the prostate and 45 Gy to the seminal vesicles . ADT consisted of a gonadotropin-releasing hormone agonist ( GnRHa ) and bicalutamide beginning 2 months before and during chemoradiation . GnRHa was continued for 24 months . RESULTS Nineteen patients were enrolled .  No dose-limiting toxicity ( DLT ) was seen with docetaxel doses up to 25 mg/m(2 ) . At the 30 mg/m(2 ) level , 2 of 4 patients experienced DLTs of both grade 3 fatigue and dyspepsia . At 41 months ' median follow-up , 2 patients had died--1 from metastatic prostate cancer and the other from heart failure . Two other patients experienced biochemical failure . One patient with bladder invasion at diagnosis experienced late grade 2 urinary hesitancy 9 months after completion of radiotherapy , requiring short-term intermittent catheterization . All patients had erectile dysfunction , but no late toxicities worse than grade 2 were identified . CONCLUSION Weekly docetaxel may be combined with high-dose IMRT and long-term ADT up to a MTD of 25 mg/m(2 ) . Acute toxicities and long-term side effects of this regimen were acceptable . Future studies evaluating the efficacy of docetaxel , ADT , and IMRT for localized HRPC should use a weekly dose of 25 mg/m(2 ) when limiting the irradiated volume to the prostate and seminal vesicles PURPOSE Weekly paclitaxel , concurrent radiation , and and rogen deprivation ( ADT ) were evaluated in patients with high-risk prostate cancer ( PC ) with or without prior prostatectomy ( RP ) . METHODS AND MATERIAL S Eligible post-RP patients included : pathological T3 disease , or rising prostate-specific antigen ( PSA ) ≥ 0.5 ng/mL post-RP . Eligible locally advanced PC ( LAPC ) patients included : 1 ) cT2b-4N0N+ , M0 ; 2 ) Gleason score ( GS ) 8 - 10 ; 3 ) GS 7 + PSA 10 - 20 ng/mL ; or 4 ) PSA 20 - 150 ng/mL. Treatment included ADT ( 4 or 24 months ) , weekly paclitaxel ( 40 , 50 , or 60 mg/m(2)/wk ) , and pelvic radiation therapy ( total dose : RP = 64.8 Gy ; LAPC = 70.2 Gy ) . RESULTS Fifty-nine patients were enrolled ( LAPC , n = 29 ; RP , n = 30 ; ADT 4 months , n = 29 ; 24 months , n = 30 ; whites n = 29 , African Americans [ AA ] , n = 28 ) . Baseline characteristics ( median [ range ] ) were : age 67 ( 45 - 86 years ) , PSA 5.9 ( 0.1 - 92.1 ng/mL ) , GS 8 ( 6 - 9 ) . At escalating doses of paclitaxel , 99 % , 98 % , and 95 % of doses were given with radiation and ADT , respectively , with dose modifications required primarily in RP patients . No acute Grade 4 toxicities occurred . Grade 3 toxicities were diarrhea 15 % , urinary urgency/incontinence 10 % , tenesmus 5 % , and leukopenia 3 % . Median follow-up was 75.3 months ( 95 % CI : 66.8 - 82.3 ) . Biochemical progression occurred in 24 ( 41 % ) patients and clinical progression in 11 ( 19 % ) patients . The 5- and 7-year OS rates were 83 % and 67 % . There were no differences in OS between RP and LAPC , 4- and 24-month ADT , white and AA patient categories . CONCLUSIONS In addition to LAPC , to our knowledge , this is the first study to evaluate concurrent chemoradiation with ADT in high-risk RP patients . With a median follow-up of 75.3 months , this trial also represents the longest follow-up of patients treated with taxane-based chemotherapy with EBRT in high-risk prostate cancer . Concurrent ADT , radiation , and weekly paclitaxel at 40 mg/m(2)/week in RP patients and 60 mg/m(2)/week in LAPC patients is feasible and well-tolerated BACKGROUND And rogen receptor splice variant 7 ( AR-V7 ) in circulating tumor cells ( CTCs ) from patients with metastatic castration-resistant prostate cancer ( mCRPC ) was recently demonstrated to be associated with resistance to abiraterone and enzalutamide . Cabazitaxel might , however , remain effective in AR-V7-positive patients . OBJECTIVE To investigate the association between AR-V7 expression in CTCs and resistance to cabazitaxel . DESIGN , SETTING , AND PARTICIPANTS We selected patients with mCRPC from the multicenter , r and omized , phase 2 , r and omized , open-label , multicenter study in mCRPC on the pharmacodynamic effects of budesonide on cabazitaxel ( Jevtana ) ( CABARESC )  . Before the start of the first and third cabazitaxel cycle , CTCs were enumerated using the Cell Search System . In patients with ≥10 CTCs in 7.5 ml blood at baseline , the expression of AR-V7 was assessed by quantitative polymerase chain reaction . OUTCOME MEASURES AND STATISTICAL ANALYSIS The primary end point was the association between the AR-V7 status and the CTC response rate ( decrease to fewer than five CTCs in 7.5 ml blood during treatment ) . Secondary end points were the prostate-specific antigen ( PSA ) response rate ( RR ) and overall survival ( OS ) . Analyses were performed using chi-square and log-rank tests . RESULTS AND LIMITATIONS AR-V7 was detected in 16 of 29 patients ( 55 % ) with ≥10 CTCs and was more frequently found in  abiraterone  pretreated patients ( 5 of 5 [ 100 % ] treated vs 7 of 20 [ 35 % ] untreated ; p=0.009 ) . We found no differences in CTC and PSA RRs . The presence of AR-V7 in CTCs was not associated with progression-free survival ( hazard ratio [ HR ] : 0.8 ; 95 % confidence interval [ CI ] , 0.4 - 1.8 ) or overall survival ( HR 1.6 ; 95 % CI , 0.6 - 4.4 ) . CONCLUSIONS The response to cabazitaxel seems to be independent of the AR-V7 status of CTCs from mCRPC patients . Consequently , cabazitaxel might be a valid treatment option for patients with AR-V7-positive CTCs . PATIENT SUMMARY Tools are needed to select specific treatments for specific patients at specific times . The presence of the gene AR-V7 in CTCs has been associated with resistance to anti- and rogen receptor treatments . We investigated whether this holds true for cabazitaxel , but we found cabazitaxel to be effective independent of the presence of AR-V7 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 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 PURPOSE It has been postulated that castration-resistant prostate cancer ( CRPC ) commonly remains hormone dependent . Abiraterone acetate is a potent , selective , and orally available inhibitor of CYP17 , the key enzyme in and rogen and estrogen bio synthesis . PATIENTS AND METHODS This was a phase I/II study of abiraterone acetate in castrate , chemotherapy-naive CRPC patients ( n = 54 ) with phase II expansion at 1,000 mg ( n = 42 ) using a two-stage design to reject the null hypothesis if more than seven patients had a prostate-specific antigen ( PSA ) decline of > or = 50 % ( null hypothesis = 0.1 ; alternative hypothesis = 0.3 ; alpha = .05 ; beta = .14 ) . Computed tomography scans every 12 weeks and circulating tumor cell ( CTC ) enumeration were performed . Prospect i ve reversal of resistance at progression by adding dexamethasone 0.5 mg/d to suppress adrenocorticotropic hormone and upstream steroids was pursued . RESULTS A decline in PSA of > or = 50 % was observed in 28 ( 67 % ) of 42 phase II patients , and declines of > or = 90 % were observed in eight ( 19 % ) of 42 patients . Independent radiologic evaluation reported partial responses ( Response Evaluation Criteria in Solid Tumors ) in nine ( 37.5 % ) of 24 phase II patients with measurable disease . Decreases in CTC counts were also documented . The median time to PSA progression ( TTPP ) on abiraterone acetate alone for all phase II patients was 225 days ( 95 % CI , 162 to 287 days ) . Exploratory analyses were performed on all 54 phase I/II patients ; the addition of dexamethasone at disease progression reversed resistance in 33 % of patients regardless of prior treatment with dexamethasone , and pretreatment serum and rogen and estradiol levels were associated with a probability of > or = 50 % PSA decline and TTPP on abiraterone acetate and dexamethasone . CONCLUSION CYP17 blockade by abiraterone acetate results in declines in PSA and CTC counts and radiologic responses , confirming that CRPC commonly remains hormone driven BACKGROUND How best to treat rising prostate-specific antigen ( PSA ) concentration after radical prostatectomy is an urgent clinical question . Salvage radiotherapy delays the need for more aggressive treatment such as long-term and rogen suppression , but fewer than half of patients benefit from it . We aim ed to establish the effect of adding short-term and rogen suppression at the time of salvage radiotherapy on biochemical outcome and overall survival in men with rising PSA following radical prostatectomy . METHODS This open-label , multicentre , phase 3 , r and omised controlled trial , was done in 43 French study centres . We enrolled men ( aged ≥18 years ) who had received previous treatment for a histologically confirmed adenocarcinoma of the prostate ( but no previous and rogen deprivation therapy or pelvic radiotherapy ) , and who had stage pT2 , pT3 , or pT4a ( bladder neck involvement only ) in patients who had rising PSA of 0·2 to less than 2·0 μg/L following radical prostatectomy , without evidence of clinical disease . Patients were r and omly assigned ( 1:1 ) central ly via an interactive web response system to st and ard salvage radiotherapy ( three-dimensional [ 3D ] conformal radiotherapy or intensity modulated radiotherapy , of 66 Gy in 33 fractions 5 days a week for 7 weeks ) or radiotherapy plus short-term and rogen suppression using 10·8 mg goserelin by subcutaneous injection on the first day of irradiation and 3 months later . R and omisation was stratified using a permuted block method according to investigational site , radiotherapy modality , and prognosis . The primary endpoint was progression-free survival , analysed in the intention-to-treat population . This trial is registered with Clinical Trials.gov , number NCT00423475 . FINDINGS Between Oct 19 , 2006 , and March 30 , 2010 , 743 patients were r and omly assigned , 374 to radiotherapy  alone and 369 to radiotherapy plus goserelin . Patients assigned to radiotherapy plus goserelin were significantly more likely than patients in the radiotherapy alone group to be free of biochemical progression or clinical progression at 5 years ( 80 % [ 95 % CI 75 - 84 ] vs 62 % [ 57 - 67 ] ; hazard ratio [ HR ] 0·50 , 95 % CI 0·38 - 0·66 ; p<0·0001 ) . No additional late adverse events occurred in patients receiving short-term and rogen suppression compared with those who received radiotherapy alone . The most frequently occuring acute adverse events related to goserelin were hot flushes , sweating , or both ( 30 [ 8 % ] of 366 patients had a grade 2 or worse event ; 30 patients [ 8 % ] had hot flushes and five patients [ 1 % ] had sweating in the radiotherapy plus goserelin group vs none of 372 patients in the radiotherapy alone group ) . Three ( 8 % ) of 366 patients had grade 3 or worse hot flushes and one patient had grade 3 or worse sweating in the radiotherapy plus goserelin group versus none of 372 patients in the radiotherapy alone group . The most common late adverse events of grade 3 or worse were genitourinary events ( 29 [ 8 % ] in the radiotherapy alone group vs 26 [ 7 % ] in the radiotherapy plus goserelin group ) and sexual disorders ( 20 [ 5 % ] vs 30 [ 8 % ] ) . No treatment-related deaths occurred . INTERPRETATION Adding short-term and rogen suppression to salvage radiotherapy benefits men who have had radical prostatectomy and whose PSA rises after a postsurgical period when it is undetectable . Radiotherapy combined with short-term and rogen suppression could be considered as a reasonable option in this population . FUNDING French Ministry of Health , AstraZeneca , and La Ligue Contre le Cancer
LHRH antagonists decrease testosterone without any testosterone surge , and they may be associated with an oncologic benefit compared with LHRH analogues .
Complete and rogen blockade has a small survival benefit of about 5 % .
Intermittent and rogen deprivation results in noninferior oncologic efficacy when compared with continuous and rogen-deprivation therapy ( ADT ) in well-selected population s. In locally advanced and metastatic PCa , early ADT does not result in a significant survival advantage when compared with delayed ADT .
LHRH antagonists decrease testosterone without any testosterone surge , and they might be associated with an oncologic benefit compared with LHRH analogues .
Complete and rogen blockade has a small survival benefit of about 5 % .
Intermittent and rogen deprivation results in noninferior oncologic efficacy when compared with continuous and rogen-deprivation therapy ( ADT ) in well-selected population s. In locally advanced and metastatic PCa , early ADT does not result in a significant survival advantage when compared with delayed ADT .
OBJECTIVE To present a summary of the 2013 version of the European Association of Urology ( EAU ) guidelines on the treatment of advanced , relapsing , and castration-resistant prostate cancer ( CRPC ) .
The guidelines were up date d , and levels of evidence and /or grade s of recommendation were added to the text based on a systematic review of the literature that included a search of online data bases and bibliographic review s. EVIDENCE SYNTHESIS Luteinising hormone-releasing hormone ( LHRH ) agonists are the st and ard of care in metastatic prostate cancer ( PCa ) .
Treatment of CRPC includes sipuleucel-T , abiraterone acetate plus prednisone ( AA/P ) , or chemotherapy with docetaxel at 75mg/m(2 ) every 3 wk .
Cabazitaxel , AA/P , enzalutamide , and radium-223 are available for second-line treatment of CRPC following docetaxel .
CONCLUSIONS The knowledge in the field of advanced , metastatic , and castration-resistant PCa is rapidly changing .
PATIENT SUMMARY We present a summary of the 2013 version of the European Association of Urology guidelines on treatment of advanced , relapsing , and castration-resistant prostate cancer ( CRPC ) .
Luteinising hormone-releasing hormone ( LHRH ) agonists are the st and ard of care in metastatic prostate cancer ( PCa ) .
Relapse after local therapy is defined by prostate-specific antigen ( PSA ) values > 0.2 ng/ml following radical prostatectomy ( RP ) and > 2 ng/ml above the nadir and after radiation therapy .
Therapy for PSA relapse after RP includes salvage radiation therapy at PSA levels < 0.5 ng/ml and salvage RP or cryosurgical ablation of the prostate in radiation failures .