Response to flutamide, as second-line therapy after bicalutamide, predicts efficacy of abiraterone, not that of enzalutamide

Nakai, Yasushi; Tanaka, Nobumichi; Miyake, Makito; Inoue, Takeshi; Anai, Satoshi; Fujimoto, Kiyohide

doi:10.1186/s13104-018-3453-z

Cited by 3 publications

(6 citation statements)

References 13 publications

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“…Nakai et al, have reported that patients using abiraterone as the first novel androgen receptor targeted agent and showing a good response to flutamide therapy following initial MAB using bicalutamide therapy, had a significantly higher PSA-PFS rate and % PSA change compared to those without such response. However, multivariate analysis for the predictive factor of PSA-PFS was not performed in this study (12). From the above results, it was considered that the efficacy of alternative antiandrogen therapy using flutamide in CRPC patients could be a predictor of subsequent enzalutamide therapy.…”

Section: During Therapy With Novel Androgen Receptortargeted Agents (Enzalutamide or Abiraterone) Waterfall Plots In Patients Who Receivementioning

confidence: 92%

“…using flutamide affect the efficacy of novel androgen receptor-targeted agents. Only a few reports have evaluated the relationship between the therapeutic effects of alternative anti-androgen therapy using flutamide and the subsequent treatment effect of novel androgen receptor-targeted agents (12,13). In the present study, we reviewed the clinical characteristics of 79 patients and examined the clinical benefits of flutamide as an alternative anti-androgen agent and as an effective predictor of novel androgen receptortargeted agents.…”

Section: During Therapy With Novel Androgen Receptortargeted Agents (Enzalutamide or Abiraterone) Waterfall Plots In Patients Who Receivementioning

confidence: 99%

“…Furthermore, patients having a good response to alternative anti-androgen therapy demonstrate a significantly better cancer-specific survival (CSS) rate compared to those without a good response to alternative anti-androgen therapy (9)(10)(11). There exist a few reports showing the effects of novel androgen receptor-targeted agents following anti-androgen therapy using flutamide (12,13). In this study, we evaluated the clinical benefits of flutamide as an alternative anti-androgen agent and examined whether the therapeutic effects of flutamide affect the efficacy of novel androgen receptortargeted agents.…”

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confidence: 99%

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

et al. 2019

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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 receptortargeted agents. Patients and Methods: Patients with castrationresistant 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, p=0.018). Conclusion: Patients showing good response to flutamide following initial MAB may achieve a satisfactory PSA-PFS rate with subsequent enzalutamide therapy.Prostate cancer is the second leading cause of cancer-related deaths in western industrialized countries (1). Similarly, the number of prostate cancer patients is increasing in Japan (2). Patients with advanced prostate cancer with lymph node and/or distant organ metastasis typically receive hormone therapy, undergo medical or surgical castration, and/or receive antiandrogen agents, such as bicalutamide. However, most prostate cancers acquire resistance to initial hormone therapy and 3879

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Section: During Therapy With Novel Androgen Receptortargeted Agents (Enzalutamide or Abiraterone) Waterfall Plots In Patients Who Receivementioning

confidence: 92%

Section: During Therapy With Novel Androgen Receptortargeted Agents (Enzalutamide or Abiraterone) Waterfall Plots In Patients Who Receivementioning

confidence: 99%

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confidence: 99%

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

et al. 2019

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“…Zhao et al (4) reported that switching to flutamide did not influence the OS of abiraterone acetate in patients with metastatic CRPC, which suggests that the OS of patients with CRPC may be prolonged based on the response duration of alternative anti-androgen therapy. Nakai et al (28) showed that patients for whom second-line flutamide was effective had a better response to subsequent abiraterone acetate than those for who the treatment proved to be ineffective. In a preclinical setting, Prekovic et al (29) showed that the combination of the androgen receptor (AR) F877L mutation, which leads to enzalutamide resistance, and the AR T878A mutation, which is often found in flutamide-treated patients, causes enzalutamide to have strong agonistic activity, but that only the F877L mutation has a weak effect on enzalutamide binding, which suggests that the prior administration of flutamide may enhance enzalutamide resistance.…”

Section: Any Psa Decline ≥50% Psa Decline ---------------------------mentioning

confidence: 99%

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

et al. 2019

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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.

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“…One potential suppressive agent is nonsteroidal antiandrogen flutamide, which exerts effects by interfering with the binding of dihydrotestosterone or testosterone to the androgen receptor 4 . Currently, there are indications that flutamide as a second‐line hormonal therapy decreases adrenal androgens and is effective for bicalutamide‐refractory prostate cancer 5 …”

Section: Introductionmentioning

confidence: 99%

Proteoglycans orchestrate remodeling of prostatic cytoarchitecture after androgenic blockade in old gerbils

et al. 2022

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Background: The aim of this study was to evaluate modifications in proteoglycan morphology and composition in the prostatic stroma of 18-month-old gerbils after surgical castration, in association or not with an androgenic blockade. Methods:The animals (n = 5) were sorted into groups subjected or not to antiandrogen treatment (flutamide 10 mg/kg/day) administered for the total postsurgery period and euthanized at 7-or 30-day postcastration; the control group consisted of intact animals. Tissue analysis included immunohistochemical assessment (perlecan and chondroitin sulfate) and proteoglycan morphology was analyzed by transmission electron microscopy.Results: Chondroitin sulfate frequency was increased 7 days postcastration with an androgenic blockade. The presence of these carbohydrates was rare after 30 days of androgenic blockade treatment. There was a significant increase in the amount of perlecan in the prostate stroma from groups subjected to castration plus flutamide for 7 or 30 days. Ultrastructural analysis showed that the incidence of areas occupied by proteoglycans and basement membrane was altered by treatment. In addition, androgenic blockade results in changes in the amount, thickness, and morphology of these structures. At 30 days postcastration, with or without flutamide treatment, larger proteoglycans were common.Conclusions: In this study, in particular, the decrease in chondroitin sulfate after the longer period might be understood as a prostatic response to androgenic deprivation, while the high frequency and permanence of perlecan led to the assumption that its modulation could be androgen-independent. Length and form alterations in proteoglycans as well as associations among them and with the basement membrane were dynamic events in the prostate microenvironment.

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Response to flutamide, as second-line therapy after bicalutamide, predicts efficacy of abiraterone, not that of enzalutamide

Cited by 3 publications

References 13 publications

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

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

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

Proteoglycans orchestrate remodeling of prostatic cytoarchitecture after androgenic blockade in old gerbils

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