Intermittent LHRH Therapy in the Management of Castrate-resistant Prostate Cancer (CRPCa): Results of a Multi-institutional Randomized Prospective Clinical Trial Efficacy and safety of different interventions in castration resistant prostate cancer progressing after docetaxel-based chemotherapy: Bayesian network analysis of randomized controlled trials Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. Phase II study of radium-223 dichloride in Japanese patients with symptomatic castration-resistant prostate cancer Phase I trial of weekly docetaxel, total androgen blockade, and image-guided intensity-modulated radiotherapy for localized high-risk prostate adenocarcinoma. 2-Weekly versus 3-weekly docetaxel to treat castration-resistant advanced prostate cancer: a randomised, phase 3 trial. Significant and sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate. Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3. Association of AR-V7 on Circulating Tumor Cells as a Treatment-Specific Biomarker With Outcomes and Survival in Castration-Resistant Prostate Cancer. Concurrent and adjuvant docetaxel with three-dimensional conformal radiation therapy plus androgen deprivation for high-risk prostate cancer: preliminary results of a multicentre phase II trial. 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. Combining carboplatin and etoposide in docetaxel-pretreated patients with castration-resistant prostate cancer: a prospective study evaluating also neuroendocrine features. Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. A phase 2 study of estramustine, docetaxel, and bevacizumab in men with castrate‐resistant prostate cancer Initial biopsy Gleason score as a predictive marker for survival benefit in patients with castration-resistant prostate cancer treated with docetaxel: data from the TAX327 study. An exploratory analysis of alkaline phosphatase, lactate dehydrogenase, and prostate-specific antigen dynamics in the phase 3 ALSYMPCA trial with radium-223 Intense androgen-deprivation therapy with abiraterone acetate plus leuprolide acetate in patients with localized high-risk prostate cancer: results of a randomized phase II neoadjuvant study.
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 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 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 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 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 BACKGROUND Docetaxel administered every 3 weeks is a st and ard treatment for castration-resistant advanced prostate cancer . We hypothesised that 2-weekly administration of docetaxel would be better tolerated than 3-weekly docetaxel in patients with castration-resistant advanced prostate cancer , and did a prospect i ve , multicentre , r and omised , phase 3 study to compare efficacy and safety . METHODS Eligible patients had advanced prostate cancer ( metastasis , a prostate-specific-antigen test result of more than 10·0 ng/mL , and WHO performance status score of 0 - 2 ) , had received no chemotherapy ( except with estramustine ) , had undergone surgical or chemical castration , and had been referred to a treatment centre in Finl and , Irel and , or Sweden . Enrolment and treatment were done between March 1 , 2004 , and May 31 , 2009 . R and omisation was done central ly and stratified by centre and WHO performance status score of 0 - 1 vs 2 . Patients were assigned 75 mg/m(2 ) docetaxel intravenously on day 1 of a 3-week cycle , or 50 mg/m(2 ) docetaxel intravenously on days 1 and 15 of a 4-week cycle . 10 mg oral prednisolone was administered daily to all patients . The primary endpoint was time to treatment failure ( TTTF ) . We assessed data in the per- protocol population . This study is registered with Clinical Trials.gov , number NCT00255606 . FINDINGS 177 patients were r and omly assigned to the 2-weekly docetaxel  group and 184 to the 3-weekly group . 170 patients in the 2-weekly group and 176 in the 3-weekly group were included in the analysis . The 2-weekly administration was associated with significantly longer TTTF than was 3-weekly administration ( 5·6 months , 95 % CI 5·0 - 6·2 vs 4·9 months , 4·5 - 5·4 ; hazard ratio 1·3 , 95 % CI 1·1 - 1·6 , p=0·014 ) . Grade 3 - 4 adverse events occurred more frequently in the 3-weekly than in the 2-weekly administration group , including neutropenia ( 93 [ 53 % ] vs 61 [ 36 % ] ) , leucopenia ( 51 [ 29 % ] vs 22 [ 13 % ] ) , and febrile neutropenia ( 25 [ 14 % ] vs six [ 4 % ] ) . Neutropenic infections were reported more frequently in patients who received docetaxel every 3 weeks ( 43 [ 24 % ] vs 11 [ 6 % ] , p=0·002 ) . INTERPRETATION Administration of docetaxel every 2 weeks seems to be well tolerated in patients with castration-resistant advanced prostate cancer and could be a useful option when 3-weekly single-dose administration is unlikely to be tolerated . FUNDING Sanofi 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 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 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 PURPOSE We evaluate the feasibility of concomitant and adjuvant docetaxel combined with three-dimensional conformal radiotherapy ( 3D-CRT ) and and rogen deprivation in high-risk prostate carcinomas . METHODS Fifty men with high-risk localized prostate cancer ( 16 ) , locally advanced ( 28 ) or very high-risk prostate cancer ( 6 ) were included . Seventy Gy were delivered on prostate and seminal vesicles in 35 fractions , concurrently with weekly docetaxel ( 20mg/m(2 ) ) . Three weeks after the completion of 3D-CRT , docetaxel was given for 3 cycles ( 60mg/m(2 ) ) , every 3 weeks . Patients had to receive LHRH agonist  during 3 years . RESULTS The intent to treat analysis shows that four patients out of 15 stopped prematurely the chemotherapy due to grade 3 - 4 acute toxicity . In the per protocol analysis , 46 patients completed a full-dose chemoradiation regimen representing 413 cycles : five patients experienced a grade 3 toxicity , and 15 patients experienced a grade 2 toxicity . With a median follow-up of 54 months , the 5-year clinical disease-free survival was 66.72 % and the 5-year survival was 92.15 % . CONCLUSIONS 3D-CRT with and rogen deprivation and concurrent weekly docetaxel , followed by three cycles of adjuvant docetaxel may be considered as feasible in high-risk prostate cancer and deserved to be evaluated in a phase III r and omized trial 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 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 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 The use of docetaxel prolongs survival for patients with castrate‐resistant prostate cancer ( CRPC ) . Inhibition of vascular endothelial growth factor ( VEGF ) with bevacizumab may further enhance the antitumor effect of docetaxel and estramustine in patients with CRPC BACKGROUND Since 2004 , docetaxel has been the st and ard first-line systemic therapy for patients with metastatic castration-resistant prostate cancer ( mCRPC ) . With abiraterone recently becoming available in the predocetaxel setting , it is warranted to identify subgroups of patients who may obtain the greatest benefit from docetaxel and particularly qualify for receiving docetaxel as first-line treatment for mCRPC . OBJECTIVE We aim ed to identify factors that could characterize subgroups of patients who obtain the greatest benefit from the use of docetaxel . DESIGN , SETTING , AND PARTICIPANTS TAX327 was multinational , r and omized , phase 3 study that was conducted from 2000 to 2002 in 1006 men with mCRPC . INTERVENTION Patients were r and omized to receive docetaxel every 3 wk ( D3 ) , weekly docetaxel ( D1 ) , or mitoxantrone every 3 wk ( M3 ) , each with prednisone . OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS We investigated whether patients with poorly differentiated tumors ( Gleason score ≥7 ) at diagnosis had greater benefit from D3 compared with M3 than patients with better differentiated tumors ( Gleason score ≤6 ) . Using a Cox model , we compared overall survival ( OS ) between the treatment groups within each subgroup of Gleason score . RESULTS AND LIMITATIONS The TAX 327 data showed that the OS benefit of D3 versus M3 was greater in patients with high- grade tumors ( median OS : 18.9 vs 14.5 mo ; p=0.009 ) than in patients with low- grade tumors ( median OS : 21.6 vs 20.7 mo ; p=0.674 ) . Limitations of a retrospective analysis apply . CONCLUSIONS The survival benefit obtained with docetaxel is most pronounced in patients with high-Gleason-score tumors ( Gleason ≥7 ) . In a time of shifting paradigms in mCRPC , with abiraterone becoming available prior to docetaxel chemotherapy , Gleason score may help in selecting patients who obtain the greatest benefit from docetaxel as first-line treatment for mCRPC . Prospect i ve validation of these findings is warranted 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 PURPOSE Cure rates for localized high-risk prostate cancers ( PCa ) and some intermediate-risk PCa are frequently suboptimal with local therapy . Outcomes are improved by concomitant and rogen-deprivation therapy ( ADT ) with radiation therapy , but not by concomitant ADT with surgery . Luteinizing hormone-releasing hormone agonist ( LHRHa ; leuprolide acetate ) does not reduce serum and rogens as effectively as abiraterone acetate ( AA ) , a prodrug of abiraterone , a CYP17 inhibitor that lowers serum testosterone ( < 1 ng/dL ) and improves survival in metastatic PCa . The possibility that greater and rogen suppression in patients with localized high-risk PCa will result in improved clinical outcomes makes paramount the re assessment of neoadjuvant ADT with more robust and rogen suppression . PATIENTS AND METHODS A neoadjuvant r and omized phase II trial of LHRHa with AA was conducted in patients with localized high-risk PCa ( N = 58 ) . For the first 12 weeks , patients were r and omly assigned to LHRHa versus LHRHa plus AA . After a research prostate biopsy , all patients received 12 additional weeks of LHRHa plus AA followed by prostatectomy .  RESULTS The levels of intraprostatic and rogens from 12-week prostate biopsies , including the primary end point ( dihydrotestosterone/testosterone ) , were significantly lower ( dehydroepi and rosterone , Δ(4)- and rostene-3,17-dione , dihydrotestosterone , all P < .001 ; testosterone , P < .05 ) with LHRHa plus AA compared with LHRHa alone . Prostatectomy pathologic staging demonstrated a low incidence of complete responses and minimal residual disease , with residual T3- or lymph node-positive disease in the majority . CONCLUSION LHRHa plus AA treatment suppresses tissue and rogens more effectively than LHRHa alone . Intensive intratumoral and rogen suppression with LHRHa plus AA before prostatectomy for localized high-risk PCa may reduce tumor burden
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 .