Alternative Antiandrogen Therapy Research Articles

Determination of enzalutamide long-term safety and efficacy for castration-resistant prostate cancer patients after combined anti-androgen blockade followed by alternative anti-androgen therapy: a multicenter prospective DELC study.

Alternative anti-androgen therapy has been widely used as a first-line treatment for castration-resistant prostate cancer, and it may affect treatment outcome of subsequent agents targeting the androgen receptor axis. We conducted the prospective observational DELC (Determination of Enzalutamide Long-term safety and efficacy for Castration-resistant prostate cancer patients after combined anti-androgen blockade followed by alternative anti-androgen therapy) study to evaluate the efficacy of enzalutamide in patients with castration-resistant prostate cancer who underwent prior combined androgen blockade with bicalutamide and then alternative anti-androgen therapy with flutamide. The DELC study enrolled 163 Japanese patients with castration-resistant prostate cancer who underwent alternative anti-androgen therapy with flutamide following failure of initial combined androgen blockade with bicalutamide in multiple institutions between January 2016 and March 2019. Primary endpoint was overall survival. Administration of enzalutamide was started at 160mg orally once daily in all patients. The rate of decline of prostate-specific antigen by 50% or more was 72.2%, and median overall survival was 42.05months. Multivariate analysis revealed that higher pretreatment serum levels of prostate-specific antigen (≥11.3ng/mL; P=0.004), neuron-specific enolase (P=0.014) and interleukin-6 (≥2.15pg/mL; P=0.004) were independent risk factors for overall survival. Fatigue (30.0%), constipation (19.6%) and appetite loss (17.8%) were the most common clinically relevant adverse events. The enzalutamide dose was not reduced in any patient under the age of 70, but adherence was decreased in those over 70. In the DELC study, the safety of enzalutamide was comparable to that in previous reports. Serum levels of neuron-specific enolase and interleukin-6 were suggested as prognostic factors for castration-resistant prostate cancer with potential clinical utility.

PD05-11 RELEVANCE OF ALTERNATIVE ANTI-ANDROGEN THERAPY FOR CASTRATION-RESISTANT PROSTATE CANCER AFTER COMBINED ANDROGEN BLOCKADE: A PROSPECTIVE OBSERVATIONAL STUDY OF OCCU-CRPC COHORT

You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) I (PD05)1 Sep 2021PD05-11 RELEVANCE OF ALTERNATIVE ANTI-ANDROGEN THERAPY FOR CASTRATION-RESISTANT PROSTATE CANCER AFTER COMBINED ANDROGEN BLOCKADE: A PROSPECTIVE OBSERVATIONAL STUDY OF OCCU-CRPC COHORT Taro Iguchi, Minoru Kato, Satoshi Tamada, Sayaka Yasuda, Yuichi Machida, Tetsuji Ohmachi, Keiichi Ishii, Hiroyuki Iwata, Shinji Yamamoto, Tomohiro Kanamaru, Kazuya Morimoto, Taro Hase, Tetsuya Makino, Koji Harimoto, Takashi Deguchi, Takahisa Adachi, Yasuo Yamakoshi, Yoshinori Takegaki, and Tatsuya Nakatani Taro IguchiTaro Iguchi More articles by this author , Minoru KatoMinoru Kato More articles by this author , Satoshi TamadaSatoshi Tamada More articles by this author , Sayaka YasudaSayaka Yasuda More articles by this author , Yuichi MachidaYuichi Machida More articles by this author , Tetsuji OhmachiTetsuji Ohmachi More articles by this author , Keiichi IshiiKeiichi Ishii More articles by this author , Hiroyuki IwataHiroyuki Iwata More articles by this author , Shinji YamamotoShinji Yamamoto More articles by this author , Tomohiro KanamaruTomohiro Kanamaru More articles by this author , Kazuya MorimotoKazuya Morimoto More articles by this author , Taro HaseTaro Hase More articles by this author , Tetsuya MakinoTetsuya Makino More articles by this author , Koji HarimotoKoji Harimoto More articles by this author , Takashi DeguchiTakashi Deguchi More articles by this author , Takahisa AdachiTakahisa Adachi More articles by this author , Yasuo YamakoshiYasuo Yamakoshi More articles by this author , Yoshinori TakegakiYoshinori Takegaki More articles by this author , and Tatsuya NakataniTatsuya Nakatani More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001969.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: In Japan, combined androgen blockade (CAB) with bicalutamide is widely used against advanced hormone-sensitive prostate cancer. Flutamide was widely used in clinical practice as an alternative anti-androgen therapy (AAT) before the era of androgen receptor axis-targeted agents. Enzalutamide has demonstrated benefits in men with metastatic and nonmetastatic castration-resistant prostate cancer (CRPC), and AAT is administered less frequently now. We aimed to determine if AAT is unnecessary for CRPC. METHODS: The OCUU-CRPC study (ClinicalTrials.gov identifier: NCT02346578) is a multicenter open-label phase 2 trial, wherein 103 men with CRPC who experienced disease progression after CAB with bicalutamide, were randomly assigned in 1:1 proportion to enzalutamide (160 mg/day) or flutamide (375 mg/day) treatment groups, stratified by distant metastases. Patients with disease progression using flutamide were recommended enzalutamide treatment as a subsequent therapy. Those who experienced disease progression with enzalutamide were treated based on the physician’s choice. This was a prospective observational study of the OCUU-CRPC cohort, and the endpoints included time to treatment failure of enzalutamide (TTFE) and overall survival (OS) (Figure 1). RESULTS: As of December 31, 2020, the median follow-up time was 45.6 months. The risk of TTFE or OS was not significantly different between enzalutamide and flutamide (TTFE: hazard ratio, 1.07; 95% CI, 0.67-1.69; p=0.78, OS: hazard ratio, 0.91; 95% CI, 0.50-1.66; p=0.77) (Figure 2). CONCLUSIONS: No significant advantage in TTFE and OS was observed between enzalutamide and a sequential therapy of flutamide to enzalutamide. AAT may be an option for patients with financial reasons or difficulties in accessing new drugs. Source of Funding: This study was funded by Astellas Pharma Inc © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e60-e61 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Taro Iguchi More articles by this author Minoru Kato More articles by this author Satoshi Tamada More articles by this author Sayaka Yasuda More articles by this author Yuichi Machida More articles by this author Tetsuji Ohmachi More articles by this author Keiichi Ishii More articles by this author Hiroyuki Iwata More articles by this author Shinji Yamamoto More articles by this author Tomohiro Kanamaru More articles by this author Kazuya Morimoto More articles by this author Taro Hase More articles by this author Tetsuya Makino More articles by this author Koji Harimoto More articles by this author Takashi Deguchi More articles by this author Takahisa Adachi More articles by this author Yasuo Yamakoshi More articles by this author Yoshinori Takegaki More articles by this author Tatsuya Nakatani More articles by this author Expand All Advertisement Loading ...

Editorial Comment to Impact of alternative antiandrogen therapy for Japanese prostate cancer patients in the era of new hormonal therapy.

Editorial Comment to Impact of alternative antiandrogen therapy for Japanese prostate cancer patients in the era of new hormonal therapy.

Impact of alternative antiandrogen therapy for Japanese prostate cancer patients in the era of new hormonal therapy.

Impact of alternative antiandrogen therapy for Japanese prostate cancer patients in the era of new hormonal therapy.

Enzalutamide versus flutamide for castration-resistant prostate cancer after combined androgen blockade therapy with bicalutamide: the OCUU-CRPC study

Before the androgen target therapy era, flutamide was widely used for castration-resistant prostate cancer in Japan. Enzalutamide is currently the recommended treatment; however, the efficacy and safety of enzalutamide and flutamide after combined androgen blockade therapy with bicalutamide, has not been compared. Patients with castration-resistant prostate cancer who received combined androgen blockade therapy with bicalutamide were randomly assigned to receive either enzalutamide or flutamide. The primary endpoint for efficacy was the 3-month prostate-specific antigen response rate. This trial is registered with ClinicalTrials.gov (NCT02346578) and the University hospital Medical Information Network (UMIN000016301). Overall, 103 patients were enrolled. The 3- (80.8% vs. 35.3%; p < 0.001) and 6-month (73.1% vs. 31.4%; p < 0.001) prostate-specific antigen response rates were higher in the enzalutamide than in the flutamide group. The 3-month disease progression rates (radiographic or prostate-specific antigen progression) were 6.4% and 38.8% in the enzalutamide and flutamide groups, respectively [hazard ratio (HR): 0.16; 95% confidence interval (CI): 0.05-0.47; p < 0.001]; the 6-month rates were 11.4% and 51.1%, respectively (HR 0.22; 95% CI 0.09-0.50; p < 0.001). Enzalutamide provided superior prostate-specific antigen progression-free survival compared with flutamide (HR 0.29; 95% CI 0.15-0.54; p < 0.001). Median time to prostate-specific antigen progression-free survival was not reached and was 6.6months in the enzalutamide and flutamide groups, respectively. As an alternative anti-androgen therapy in patients with castration-resistant prostate cancer who fail bicalutamide-combined androgen blockade therapy, enzalutamide provides superior clinical outcomes compared with flutamide. Enzalutamide should be preferred over flutamide in these patients.

Identification of favorable subgroups for alternative anti-androgen therapy in castration-resistant prostate cancer.

Although alternative anti-androgen therapy (switching to secondary anti-androgens) is no longer recommended in the clinical guidelines of prostate cancer in light of the new hormonal and cytotoxic agents available, this therapy has proven beneficial for some patients with castration-resistant prostate cancer (CRPC). The objective of this study was to identify favorable subgroups for alternative anti-androgen therapy among CRPC patients. Eighty-eight consecutive CRPC patients treated with alternative anti-androgen therapy were included in this study. All patients were treated with bicalutamide in the initial maximum androgen blockade (MAB) and switched to flutamide in the subsequent alternative anti-androgen therapy, combined with a luteinizing hormone-releasing hormone analogue. Several clinical and pathological factors for predicting the prostate-specific antigen (PSA) decline and PSA progression-free survival (PSA-PFS) of alternative anti-androgen therapy were investigated. Of all patients, 45 (51.1%) patients showed ≥50% PSA decline. The median PSA-PFS was 7.5 months [95% confidence interval (CI), 5.7-10.3]. Notably, 15 (17.0%) patients had a PSA-PFS over 2 years. A multivariate analysis showed that ≥3 bone metastatic lesions and a duration <12 months of initial MAB were significant factors shortening the duration of PSA-PFS, with hazard ratios of 2.11 (95% CI, 1.23-3.62; P=0.007) and 2.08 (95% CI, 1.20-3.57; P=0.008), respectively. Patients without any of these factors had a median PSA-PFS of 22.8 months (95% CI, 6.7-48.8). The overall survival in patients with a ≥7.5-month PSA-PFS receiving alternative anti-androgen therapy was significantly longer than that of patients with a <7.5-month PSA-PFS (109.1 vs. 40.8 months; P<0.001). In conclusion, a longer duration of initial MAB and the absence of severe bone metastasis may predict a favorable response to alternative anti-androgen therapies in CRPC patients. Alternative anti-androgen therapy may still be beneficial for these patients, but this needs to be investigated further.

Impact of enzalutamide and sequential flutamide and enzalutamide therapy for castration-resistant prostate cancer after bicalutamide-combined androgen blockade therapy onoverall survival: A follow-up study of randomized phase 2 trial (OCCU-CRPC study).

5042 Background: In Asia, bicalutamide-combined androgen blockade (CAB) is widely used to treat metastatic or locally advanced prostate cancer. Enzalutamide (ENZA) shows benefits in men with metastatic and nonmetastatic castration-resistant prostate cancer (CRPC), although flutamide (FLU) is still used as an alternative anti-androgen therapy after bicalutamide-CAB. Methods: The multicenter open-label phase 2 trial OCUU-CRPC (NCT02346578) randomized patients (1:1) with CRPC after bicalutamide-CAB to ENZA (160 mg/day) or FLU (375 mg/day). Patients were stratified according to distant metastases. The primary endpoint was the prostate-specific antigen (PSA) response rate (≥50% decrease) at 3 months. The endpoints of this follow-up observational study include PSA progression-free survival of ENZA therapy (PSA-PFS-ENZA), time to treatment failure of ENZA therapy (TTF-ENZA), and overall survival (OS). Results: In total, 103 patients were randomized to ENZA (n = 52) and FLU (n = 51). Overall, 67% had distant metastases and 10% had prior radical therapy. Twenty-five (48%) and 38 (75%) patients, respectively, discontinued their assigned treatment because of progressive disease or adverse events (AEs) and were treated by standard of care. Of the 38 patients that discontinued FLU, 34 (89%) received ENZA as subsequent therapy. The median follow-up time was 14 months (ENZA, interquartile range (IQR): 9.5-24.8) and 17.2 months (FLU, IQR: 9.8-24.9). PSA-PFS-ENZA was longer in patients not treated with FLU (hazard ratio (HR), 0.29; 95% confidence interval (CI), 0.14 to 0.63; p &lt; 0.001), but there was no significant difference in TTF-ENZA (HR, 1.27; 95% CI, 0.73 to 2.19; p = 0.397)and OS (HR, 0.77; 95% CI, 0.31 to 1.89; p = 0.567) between the two groups. The AEs of ENZA were consistent with those observed in prior phase 3 trials. Conclusions: ENZA after bicalutamide-CAB resulted in greater PSA-PFS than sequential FLU and ENZA therapy. No differences were observed in TTF-ENZA and OS between ENZA after bicalutamide-CAB and sequential FLU and ENZA therapy. Clinical trial information: NCT02346578. [Table: see text]

Enzalutamide versus flutamide for castration-resistant prostate cancer after combined androgen blockade therapy with bicalutamide: study protocol for a multicenter randomized phase II trial (the OCUU-CRPC study)

BackgroundEnzalutamide is an oral androgen receptor targeted agent that has been shown to improve survival in PREVAIL trials and has been approved for patients with chemo-naïve metastatic castration-resistant prostate cancer (CRPC). Meanwhile, flutamide is a non-steroidal oral anti-androgen that was commonly used before the approval of bicalutamide. The objective of the OCUU-CRPC study is to compare the efficacy and safety between second-line hormonal therapy of enzalutamide and flutamide as alternative anti-androgen therapy (AAT) after combined androgen blockade (CAB) therapy that included bicalutamide in patients with CRPC.MethodsA total of 100 patients with CRPC with or without distant metastases after disease progression who received CAB therapy with bicalutamide were randomly assigned at a 1:1 ratio according to distant metastases to the enzalutamide (160 mg/day, 4 × 40 mg capsules once daily) and flutamide (375 mg/day; 3 × 125 mg tablets thrice daily) groups. The primary endpoint for the drug efficacy is the response rate of prostate-specific antigen (PSA) (i.e., the ratio of patients whose PSA declined by ≥50% from baseline) at 3 months. Meanwhile, the secondary endpoints are PSA progression rate at 3 and 6 months, PSA response rate at 6 months, change in quality of life, PSA progression-free survival, and safety. The patient registration started in January 2015 and will end in March 2018, and the follow-up period is 6 months after the last patient registration. The main result will be reported in March 2019.DiscussionIn the OCUU-CRPC study, we compare the efficacy and safety of enzalutamide or alternative AAT with flutamide in participants with CRPC who were previously treated with a CAB therapy with bicalutamide. The expected results of this study will be that enzalutamide is superior to flutamide in terms of PSA response. A longer time to disease progression with enzalutamide over flutamide may translate to better overall survival. However, flutamide may be more accessible for patients owing to its lower cost than enzalutamide.Trial registrationThe OCUU-CRPC study was prospectively registered at clinicaltrials.gov (NCT02346578, January 2015) and University Hospital Medical Information Network (UMIN000016301, January 2015).

Enzalutamide versus flutamide for castration-resistant prostate cancer after combined androgen blockade therapy with bicalutamide: A multicenter randomized phase II trial (OCUU-CRPC study).

168 Background: In Asia, including Japan, combined androgen blockade (CAB) therapy with bicalutamide is widely administered for metastatic prostate cancer. Alternative anti-androgen therapy (AAT) with flutamide after CAB therapy with bicalutamide was common before the androgen receptor-targeted therapy era. The objective of the OCUU-CRPC study was to compare the efficacy and safety between second-line hormonal therapy of enzalutamide and flutamide as alternative AAT after CAB therapy that included bicalutamide in patients with CRPC. Methods: A total of 104 patients with CRPC with or without distant metastases after disease progression who received CAB therapy with bicalutamide were randomly assigned at a 1:1 ratio according to distant metastases to the enzalutamide (160 mg/day) and flutamide (375 mg/day) groups. The primary endpoint for the drug efficacy was the response rate of prostate-specific antigen (PSA; i.e., declined by ≥50%) at 3 months. Results: Between January 2015 and February 2018, 103 patients were randomly assigned, 52 to enzalutamide and 51 to flutamide. 25 (48%) and 38 (75%) patients, respectively, discontinued their assigned treatment before study end, mainly due to progressive disease. Median follow-up time was 13.4 months (IQR 9.6–23.8) in the enzalutamide group and 17.0 months (9.7–24.4) in the flutamide group. Enzalutamide resulted in significant improvements in the response rate of PSA at 3 months (84.6% vs 31.4%; p&lt; 0.001). Enzalutamide significantly improved in all secondary endpoints: the PSA progression rate at 3 months (HR, 0.17; 95% CI, 0.05 to 0.47; p&lt; 0.01) and at 6 months (HR, 0.22; 95% CI, 0.09 to 0.50; p&lt; 0.01); and PSA response rate at 6 months (75.0% vs 29.4%; p&lt; 0.01); and time to PSA progression (median: not reached vs 6.6 months; HR, 0.29; 95% CI, 0.15 to 0.54; p&lt; 0.01). The observed adverse event profile was consistent with that from phase III enzalutamide trials. Conclusions: Enzalutamide significantly reduced risk of progression compared with flutamide in patients with CRPC after CAB therapy with bicalutamide. This trial is registered with ClinicalTrials.gov, number. Clinical trial information: NCT02346578.

Enzalutamide versus flutamide for castration-resistant prostate cancer after combined androgen blockade therapy with bicalutamide: A retrospective study.

293 Background: In Asia, including Japan, combined androgen blockade (CAB) therapy with bicalutamide is widely used for metastatic prostate cancer. Alternative anti-androgen therapy (AAT) with flutamide (FLU) after CAB therapy with bicalutamide was common before the androgen receptor-targeted therapy era. The AAT response rate was 20–30%, and there is no evidence of prolonged overall survival (OS), but we have encountered effective clinical cases. Currently, two prospective clinical studies are ongoing, but this is the first retrospective study comparing FLU and enzalutamide (ENZ) for castration-resistant prostate cancer (CRPC). Methods: In our hospital, 55 patients were diagnosed with CRPC after CAB therapy and administered FLU or ENZ between May 2014 and December 2017. Patients with FLU failure then received ENZ. The study evaluation included 1) prostate-specific antigen (PSA) best response with initial therapy, 2) PSA progression-free survival with initial therapy (PSA-PFS), 3) PSA best response with ENZ therapy, 4) PSA-PFS of ENZ therapy (PSA-PFS-ENZ), and 5) OS. Results: As first-line CRPC therapy, patients received ENZ (n=29) or FLU (n=26). In the FLU group, 18 patients showed disease progression and then received ENZ. The PSA best response was statistically higher in the ENZ group. PSA-PFS was significantly statistically longer in the ENZ group (hazard ratio (HR) 1.85, 95% confidence interval (CI) 0.53–0.64, p=0.02). However, there was no significant difference in PSA best response with ENZ therapy and PSA-PFS-ENZ between the ENZ and post-FLU ENZ groups (HR 0.80, 95% CI 0.33–1.94, p=0.62) or in OS between the ENZ and post-FLU ENZ groups (HR 1.85, 95% CI 0.53–6.42, p=0.33). Conclusions: AAT with subsequent FLU after CAB therapy with bicalutamide may be suitable for some CRPC patients. (NCT02346578 and NCT02918968).

Treatment strategy for metastatic prostate cancer with extremely high PSA level: reconsidering the value of vintage therapy.

The prognostic significance of initial prostate-specific antigen (PSA) level for metastatic prostate cancer remains uncertain. We investigated the differences in prognosis and response to hormonal therapies of metastatic prostate cancer patients according to initial PSA levels. We analyzed 184 patients diagnosed with metastatic prostate cancer and divided them into three PSA level groups as follows: low (<100 ng ml−1), intermediate (100–999 ng ml−1), and high (≥1000 ng ml−1). All patients received androgen deprivation therapy (ADT) immediately. We investigated PSA progression-free survival (PFS) for first-line ADT and overall survival (OS) within each of the three groups. Furthermore, we analyzed response to antiandrogen withdrawal (AW) and alternative antiandrogen (AA) therapies after development of castration-resistant prostate cancer (CRPC). No significant differences in OS were observed among the three groups (P = 0.654). Patients with high PSA levels had significantly short PFS for first-line ADT (P = 0.037). Conversely, patients in the high PSA level group had significantly longer PFS when treated with AW than those in the low PSA level group (P = 0.047). Furthermore, patients with high PSA levels had significantly longer PFS when provided with AA therapy (P = 0.049). PSA responders to AW and AA therapies had significantly longer survival after CRPC development than nonresponders (P = 0.011 and P < 0.001, respectively). Thus, extremely high PSA level predicted favorable response to vintage sequential ADT and AW. The current data suggest a novel aspect of extremely high PSA value as a favorable prognostic marker after development of CRPC.

Predictors of poor response to secondary alternative antiandrogen therapy with flutamide in metastatic castration-resistant prostate cancer.

In Japan, flutamide had been commonly used as second-line alternative antiandrogen hormonal therapy for metastatic castration-resistant prostate cancer that relapses after initial hormone therapy before new androgen pathway inhibitors became available. In this study, we attempted to identify predictive factors for efficacy of alternative antiandrogen as second-line hormone therapy. We identified consecutive 65 patients with metastatic castration-resistant prostate cancer who were treated with alternative antiandrogen as second-line hormonal therapy (bicalutamide to flutamide). All patients were treated with combined androgen blockade initially. We analyzed correlations between progression-free survival of alternative antiandrogen and clinicopathological characteristics, including patients' ages, initial prostate-specific antigen levels, prostate-specific antigen levels at flutamide induction, Gleason scores, T stage, N stage, extent of disease grades on bone scan and previous duration of prostate cancer response to combined androgen blockade. In univariate analysis, T stage, N stage and previous duration of response to combined androgen blockade were correlated with shorter progression-free survival. We found four significant risk factors for shorter progression-free survival in multivariate analysis: initial prostate-specific antigen level, clinical N stage, extent of disease grades and previous duration of response to combined androgen blockade. Initial prostate-specific antigen, N stage, extent of disease grades on bone scan and previous duration of response to combined androgen blockade were the significant predictors for efficacy of alternative antiandrogen as second-line hormone therapy in patients with metastatic castration-resistant prostate cancer. These findings might support that decision-making of when to start the new androgen receptor pathway inhibitors.

Clinical outcomes of anti-androgen withdrawal and subsequent alternative anti-androgen therapy for advanced prostate cancer following failure of initial maximum androgen blockade

The present study aimed to investigate the significance of anti-androgen withdrawal and/or subsequent alternative anti-androgen therapy in patients with advanced prostate cancer (PC) who relapsed after initial maximum androgen blockade (MAB). The present study evaluated the clinical outcomes of 272 consecutive advanced PC patients undergoing anti-androgen withdrawal and/or subsequent alternative anti-androgen therapy with flutamide following the failure of initial MAB using bicalutamide. With the exception of 41 patients (15.1%) who did not undergo anti-androgen withdrawal due to the characteristics of PC suggesting aggressive diseases, prostate-specific antigen (PSA) declined from the baseline value in 83 patients (35.9%), including 18 (7.8%) with PSA decline >50%, but not in the remaining 148 (64.1%). No significant difference in the overall survival (OS) or cancer-specific survival (CSS) among the three groups was observed based on the response to anti-androgen withdrawal. Following the introduction of alternative anti-androgen therapy with flutamide, PSA decline was observed in 185 patients (68.0%), including 103 (37.9%) who achieved a PSA reduction of >50%; however, the PSA level continued to elevate in the remaining 87 (32.0%). Furthermore, of the numerous factors examined, only the duration of the initial MAB therapy was shown to be significantly correlated with the PSA decline following alternative anti-androgen therapy. Multivariate analysis of several factors identified revealed that only PSA decline following alternative anti-androgen therapy was an independent predictor of CSS and OS. If initial MAB is effective, the introduction of alternative anti-androgen therapy may be considered; however, anti-androgen withdrawal should be omitted, irrespective of the characteristics of advanced PC.

Identification of a predictive factor of metastatic castration-resistant prostate cancer patients’ response to alternative antiandrogen therapy with flutamide.

321 Background: Recently, new androgen pathway inhibitors, abiraterone and enzalutamide, are demonstrated to improve overall survival for metastatic castration-resistant prostate cancer (mCRPC). In Japan, alternative antiandrogen (AA) as second-line hormonal therapy for mCRPC that relapses after initial hormone therapy have been commonly used before new androgen pathway inhibitors. In this study, we attempted to identify the predictive factors for efficacy of AA as second-line hormone therapy. Methods: We identified consecutive 65 mCRPC patients treated with AA as second-line hormonal therapy. All patients were treated with maximum androgen blockade (MAB) initially and evaluated antiandrogen withdrawal syndrome after relapse. We analyzed the correlations between progression-free survival (PFS) of AA and clinicopathological characteristics, including patients’ age, initial PSA levels, PSA levels at flutamide induction, Gleason scores, T stage, N stage, extent of disease (EOD) classifications on bone scan, and the previous duration of prostate cancer sensitivity to MAB. Results: The median duration of prostate cancer sensitivity to MAB was 11.3 months (range: 1.5-53.0 months). In multivariate analysis, four significant risk factors for poor PFS were identified; initial PSA levels ( &gt; 263 ng/mL vs ≤ 263; HR 0.53, p = 0.038), N stage (1 vs 0; HR 3.00, p = 0.001), EOD classifications (3-4 vs 1-2; HR 2.50, p = 0.007), and the previous duration of prostate cancer sensitivity to MAB ( &lt; 12 months vs ≥ 12; HR 2.16, p = 0.026). We stratified the patients into two cohorts with low risk (0-2 risk factor present) and high risk (3-4 risk factors present). We found a significant difference in PFS among risk groups (median PFS 7.3 months vs 1.5, p &lt; 0.000). Conclusions: Initial PSA, N stage, EOD classifications on bone scan, and the previous duration of prostate cancer sensitivity to MAB were the significant predictive factors for efficacy of AA as second-line hormone therapy in patients with mCRPC. These findings might support that decision-making of when to start the new AR pathway inhibitors.

245P Predictive factor of metastatic castration-resistant prostate cancer patients' poor response to secondary alternative antiandrogen therapy with flutamide

245P Predictive factor of metastatic castration-resistant prostate cancer patients' poor response to secondary alternative antiandrogen therapy with flutamide

Efficacy of tegafur–uracil (UFT) administration in castration-resistant prostate cancer patients with a history of both alternative antiandrogen therapy and estramustine phosphate sodium hydrate therapy

The purpose of this study was to evaluate the efficacy of tegafur-uracil (UFT) administration as a fourth-line therapy in patients with castration-resistant prostate cancer (CRPC) who had already received combined androgen blockade (CAB) therapy (first-line), alternative antiandrogen therapy (second-line), and estramustine phosphate sodium hydrate (EMP) therapy (third-line), in order to determine who would benefit from UFT therapy. UFT was administered at a daily dose of 300 mg/m(2) to 26 patients, and the response to UFT 4 weeks after its induction and its toxicity were evaluated. A reduction in the serum prostate-specific antigen (PSA) value was observed in 12 patients (46.2 %), while two cases (7.7 %) achieved more than 50 % reduction in PSA. Two patients (7.7 %) required discontinuation of UFT administration because of side effects (grade 2 exanthema in one patient and grade 2 nausea in one patient). A PSA response to UFT was observed, especially in patients older than 75 years and/or whose Gleason score was 8 or less. Our data indicate that UFT administration as a fourth-line therapy was tolerable and effective to some degree in patients with CRPC who had already received CAB therapy, alternative antiandrogen therapy, and EMP therapy. It can be used, even in patients aged more than 75 years old, without any loss of efficacy or effect on their activities of daily life, and can be regarded as a treatment option for patients with advanced prostate cancer.

Efficacy of estramustine phosphate sodium hydrate (EMP) monotherapy in castration-resistant prostate cancer patients: report of 102 cases and review of literature

This retrospective chart review study was conducted to evaluate the efficacy of estramustine phosphate sodium hydrate (EMP) monotherapy in patients with castration-resistant prostate cancer (CRPC) and to determine who would benefit from EMP therapy. EMP was administered at a daily dose of 560 mg to 102 patients as a third-line therapy, who had already received combined androgen blockade (CAB) and subsequent alternative antiandrogen therapy. The responses to EMP after its induction and its toxicity were evaluated. We also analyzed the association between the clinicopathological factors of the patients and their responses to EMP therapy. A reduction in the serum prostate-specific antigen (PSA) 4 weeks after induction was observed in 70 patients (68.6%), while 30 cases (29.4%) achieved more than 50% reduction of PSA. Long-term reduction of PSA from baseline for more than 6 months was observed in 31 patients (30.4%). EMP treatment was discontinued in 11 patients (10.8%) because of side effects (nausea in six patients, gynecomastia in three patients, eruption in one patient, and liver dysfunction in one patient). Multivariate analysis demonstrated that long duration of prior hormonal therapy was an independent favorable factor for reduced PSA levels, long responses, and overall survival. The data suggest that oral EMP administration as a third-line monotherapy is well tolerated and effective to some degree in patients with CRPC who have already received CAB and subsequent alternative antiandrogen therapy. Thus, EMP can be regarded as one treatment option, especially for patients whose prior duration of hormonal therapy was long.

Efficacy of alternative antiandrogen therapy for prostate cancer that relapsed after initial maximum androgen blockade.

PurposeWe evaluated the effectiveness of second-line maximum androgen blockade (MAB) with an alternative antiandrogen in patients who relapsed after initial MAB.Materials and MethodsWe retrospectively analyzed 47 patients with prostate cancer who relapsed after initial MAB, including surgical or medical castration combined with antiandrogens, from January 1998 to December 2009. When the serum prostate-specific antigen (PSA) level was increased on three consecutive occasions, we discontinued the antiandrogen and then administered an alternative antiandrogen. Seven patients were assessed for antiandrogen withdrawal syndrome (AWS). The effect of the second-line MAB was evaluated by the serum PSA level, and response was subdivided into ≥50% and <50% PSA reductions from the baseline PSA at the start of second-line MAB.ResultsPSA reduction was observed in 32 patients (68.1%). Among them, 23 (48.9%) achieved ≥50% PSA reductions with a mean response duration of 13.4±5.4 months. Nine (19.2%) patients reached <50% PSA reductions with a mean response duration of 12.2±6.2 months. The time to nadir PSA level after first-line MAB in the ≥50% PSA reduction group, <50% PSA reduction group, and PSA elevation group was 15.6±12.9 months, 11.8±6.0 months, and 8±6.5 months, respectively. That is to say, it was significantly longer in the responder groups (p=0.038).ConclusionsSecond-line MAB using an alternative antiandrogen is an effective treatment option before cytotoxic chemotherapy in patients who relapse after initial MAB.

Alternative antiandrogen therapy in patients with castration‐resistant prostate cancer: A single‐center experience

Outcomes of alternative (second-line) antiandrogen therapy in 112 patients with relapsing prostate cancer after first-line hormonal therapy were analyzed. A good response (prostate-specific antigen [PSA] decrease 50%) and a partial response (PSA decrease of 0–50%) by switching from bicalutamide (BCL) to flutamide (FLT) and from FLT to BCL were achieved in 35.4% (28/79) and 30.4% (24/79), and in 45.0% (9/20) and 20.0% (4/20) of cases, respectively. A good response and a partial response with the change from chlormadinone acetate (CMA) to a non-steroidal antiandrogen (FLT or BCL)and from a non-steroidal antiandrogen to CMA were obtained in 25.0% (2/8) and 37.5% (3/8), and in 20.0% (1/5) and 0% (0/5)of cases, respectively. In multivariate analyses, a second-line good response was significantly predictive of cause-specific survival from first therapy relapse to cancer death in all patients. Patients (52/112, 46.4%) with 30% decrease in PSA levels were associated with significantly better cause-specific survival as measured from the start of first-line treatment and first-line relapse.

Current Medical and Surgical Options for Androgen Deprivation in Prostate Cancer Patients

The growth of prostate cancer cells is driven by androgens. Thus, androgen deprivation, is one of the main treatment modalities in the management of prostate cancer. Historically, bilateral orchiectomy, which achieves 95% reduction of testosterone levels within 3 hours, was the only effective androgen deprivation therapy (ADT). In the 1980s, luteinizing hormone-releasing hormone agonists (LHRH-A) were introduced to reduce testosterone to castration levels. After the 1980s, nonsteroidal antiandrogens were developed in addition to steroidal antiandrogens. Since then, so-called maximum androgen blockade (MAB)/combined androgen blockade (CAB), which is a combination of surgical or medical castration and oral antiandrogens, has been suggested. More recently, novel treatment modalities have been developed, such as intermittent androgen suppression (IAS), nonsteroidal antiandrogen monotherapy, and alternative antiandrogen therapy after relapse from the initial MAB/CAB. ADT, whether surgical or medical, provides important quality of life (QOL) benefits in patients with advanced and metastatic prostate cancer. While the principle of the therapy has remained unchanged, the role, type and timing of these therapies is continuously evolving. This review will focus on the current medical and surgical options for ADT in advanced and metastatic prostate cancer, summarizing the results of several recent clinical trials and discuss their implications for clinical practice and for future research in this disease.