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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Flutamide as an Alternative Anti-androgen Agent and Predictor of the Efficacy of Novel Androgen Receptor-targeted Agents.

BACKGROUND/AIM: There are few reports that verify the relationship between the therapeutic effects of flutamide and novel androgen receptor-targeted agents. We aimed to evaluate the benefits of flutamide as an alternative anti-androgen agent and its effects on the efficacy of novel androgen receptor-targeted agents. PATIENTS AND METHODS: Patients with castration-resistant prostate cancer on novel androgen receptor-targeted agents without prior docetaxel therapy were included. Changes in prostate-specific antigen (PSA) level were recorded. RESULTS: Patients who responded well to flutamide (Flutamide effective) following initial maximum androgen blockade (MAB) showed significantly higher changes in serum PSA levels (p=0.039) and PSA-progression-free survival (PFS) rate (p=0.016) following enzalutamide therapy compared to those who did not respond well to flutamide. Multivariate analysis showed that the factor of Flutamide effective was significantly associated with a good PSA-PFS rate following enzalutamide therapy (HR=7.36, 95%CI=1.4-38.71, p=0.018). CONCLUSION: Patients showing good response to flutamide following initial MAB may achieve a satisfactory PSA-PFS rate with subsequent enzalutamide therapy.

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.

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.

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.

Treatment strategy for metastatic prostate cancer with extremely high PSA level: Reconsidering the value of vintage therapy / 亚洲男科学杂志(英文版)

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.

Treatment strategy for metastatic prostate cancer with extremely high PSA level: reconsidering the value of vintage therapy / 亚洲男科学杂志(英文版)

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.