Phase II multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxel-treated 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 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. Significant and sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate. 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. 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. Efficacy of Cabazitaxel in Castration-resistant Prostate Cancer Is Independent of the Presence of AR-V7 in Circulating Tumor Cells. Association of AR-V7 on Circulating Tumor Cells as a Treatment-Specific Biomarker With Outcomes and Survival in Castration-Resistant Prostate Cancer. Combining carboplatin and etoposide in docetaxel-pretreated patients with castration-resistant prostate cancer: a prospective study evaluating also neuroendocrine features. 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. 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. Phase 3 randomized trial evaluating second-line hormonal therapy versus docetaxel-estramustine combination chemotherapy on progression-free survival in asymptomatic patients with a rising prostate-specific antigen level after hormonal therapy for prostate cancer: an Eastern Cooperative Oncology Grou Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. 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. Long-term results of a phase II study with neoadjuvant docetaxel chemotherapy and complete androgen blockade in locally advanced and high-risk prostate cancer
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 : 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 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 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 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 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 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 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 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 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 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 Despite improvements in early detection of prostate cancer when it is clinical ly localized-- and therefore most amenable to curative local therapies-- approximately 33 % of men with early prostate cancer will develop biochemical failure with a rising prostate-specific antigen ( PSA ) during follow-up . The early use of and rogen suppression in this group of men has changed the clinical picture of and rogen-independent disease . Now , there are men on and rogen suppression who will develop biochemical failure and remain free of clinical or radiographic evidence of metastatic disease for a period of time . There is no st and ard approach to this group of men , who have a rising PSA on and rogen deprivation , because there are little or no data about strategies that may improve survival , delay time to progression , or improve quality of life . Therefore , current management of this population remains controversial . In an effort to determine which of these 2 approaches -- second-line hormone therapy or chemotherapy -- is optimal in delaying the time to progression , the Eastern Cooperative Oncology Group ( ECOG ) developed protocol E1899 . Although both approaches offer the potential for response ( reduction in PSA and prolonging the time to clinical progression ) , they have very different toxicity profiles , making impact on quality of life another important end point . This r and omized trial evaluating second-line hormonal therapy using ketoconazole and hydrocortisone versus docetaxel and estramustine combination chemotherapy on progression-free survival in asymptomatic men with a rising PSA on and rogen ablation for prostate cancer is the subject of this article 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 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 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
Zoledronic acid and denosumab can be used in men with mCRPC and osseous metastases to prevent skeletal-related complications .
PATIENT SUMMARY In men with a rise in their PSA levels after prior local treatment for prostate cancer only , it is important to balance overtreatment against further progression of the disease since survival and quality of life may never be affected in many of these patients .
OBJECTIVE To present a summary of the 2016 version of the European Association of Urology ( EAU ) - European Society for Radiotherapy & Oncology ( ESTRO ) - International Society of Geriatric Oncology ( SIOG ) Guidelines on the treatment of relapsing , metastatic , and castration-resistant prostate cancer ( CRPC ) .
EVIDENCE SYNTHESIS Relapse after local therapy is defined by a rising prostate-specific antigen ( PSA ) level > 0.2ng/ml following radical prostatectomy ( RP ) and > 2ng/ml above the nadir after radiation therapy ( RT ) .
And rogen deprivation therapy ( ADT ) remains the basis for treatment of men with metastatic prostate cancer ( PCa ) .
Level 1 evidence for the treatment of metastatic CRPC ( mCRPC ) includes , abiraterone acetate plus prednisone ( AA/P ) , enzalutamide , radium 223 ( Ra 223 ) , docetaxel at 75 mg/m2 every 3 wk and sipuleucel-T. Cabazitaxel , AA/P , enzalutamide , and radium are approved for second-line treatment of CRPC following docetaxel .
CONCLUSIONS The knowledge in the field of advanced and metastatic PCa and CRPC is changing rapidly .