Nonsteroidal Antiandrogen Monotherapy Research Articles

Non-steroidal antiandrogen monotherapy compared with luteinizing hormone-releasing hormone agonists or surgical castration monotherapy for advanced prostate cancer: a Cochrane systematic review.

To assess the effects of non-steroidal antiandrogen monotherapy compared with luteinizing hormone-releasing hormone agonists or surgical castration monotherapy for treating advanced hormone-sensitive stages of prostate cancer. We searched the Cochrane Prostatic Diseases and Urologic Cancers Group Specialized Register (PROSTATE), the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Web of Science with Conference Proceedings, three trial registries and abstracts from three major conferences to 23 December 2013, together with reference lists, and contacted selected experts in the field and manufacturers. We included randomized controlled trials comparing non-steroidal antiandrogen monotherapy with medical or surgical castration monotherapy for men in advanced hormone-sensitive stages of prostate cancer. Two review authors independently examined full-text reports, identified relevant studies, assessed the eligibility of studies for inclusion, extracted data and assessed risk of bias as well as quality of evidence according to the GRADE working group guidelines. We used Review Manager 5.2 for data synthesis and the fixed-effect model as primary analysis (when heterogeneity was low with I(2) < 50%); we used a random-effects model when confronted with substantial or considerable heterogeneity (when I(2) ≥50%). A total of 11 studies involving 3060 randomly assigned participants were included in the present review. Use of non-steroidal antiandrogens resulted in lower overall survival times (hazard ratio [HR] 1.24, 95% confidence interval [CI] 1.05-1.48, six studies, 2712 participants) and greater clinical progression (1 year: risk ratio [RR] 1.25, 95% CI 1.08-1.45, five studies, 2067 participants; 70 weeks: RR 1.26, 95% CI 1.08-1.45, six studies, 2373 participants; 2 years: RR 1.14, 95% CI 1.04-1.25, three studies, 1336 participants), as well as treatment failure (1 year: RR 1.19, 95% CI 1.02-1.38, four studies, 1539 participants; 70 weeks: RR 1.27, 95% CI 1.05-1.52, five studies, 1845 participants; 2 years: RR 1.14, 95% CI 1.05-1.24, two studies, 808 participants), compared with medical or surgical castration. The quality of evidence for overall survival, clinical progression and treatment failure was rated as moderate according to GRADE. Use of non-steroidal antiandrogens increased the risk for treatment discontinuation as a result of adverse events (RR 1.82, 95% CI 1.13-2.94, eight studies, 1559 participants), including events such as breast pain (RR 22.97, 95% CI 14.79- 35.67, eight studies, 2670 participants) and gynaecomastia (RR 8.43, 95% CI 3.19-22.28, nine studies, 2774 participants) The risk of other adverse events, such as hot flushes (RR 0.23, 95% CI 0.19-0.27, nine studies, 2774 participants) was decreased when non-steroidal antiandrogens were used. The quality of evidence for breast pain, gynaecomastia and hot flushes was rated as moderate according to GRADE. The effects of non-steroidal antiandrogens on cancer-specific survival and biochemical progression remained unclear. Non-steroidal antiandrogen monotherapy compared with medical or surgical castration monotherapy for advanced prostate cancer is less effective in terms of overall survival, clinical progression, treatment failure and treatment discontinuation resulting from adverse events. Evidence quality was rated as moderate according to GRADE; therefore, further research is likely to have an important impact on results for patients with advanced but non-metastatic prostate cancer treated with non-steroidal antiandrogen monotherapy.

Non-steroidal antiandrogen monotherapy compared with luteinising hormone-releasing hormone agonists or surgical castration monotherapy for advanced prostate cancer.

Non-steroidal antiandrogens and castration are the main therapy options for advanced stages of prostate cancer. However, debate regarding the value of these treatment options continues. To assess the effects of non-steroidal antiandrogen monotherapy compared with luteinising hormone-releasing hormone agonists or surgical castration monotherapy for treating advanced stages of prostate cancer. We searched the Cochrane Prostatic Diseases and Urologic Cancers Group Specialized Register (PROSTATE), the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Web of Science with Conference Proceedings, three trial registries and abstracts from three major conferences to 23 December 2013, together with reference lists, and contacted selected experts in the field and manufacturers. We included randomised controlled trials comparing non-steroidal antiandrogen monotherapy with medical or surgical castration monotherapy for men in advanced stages of prostate cancer. One review author screened all titles and abstracts; only citations that were clearly irrelevant were excluded at this stage. Then, two review authors independently examined full-text reports, identified relevant studies, assessed the eligibility of studies for inclusion, assessed trial quality and extracted data. We contacted the study authors to request additional information. We used Review Manager 5 for data synthesis and used the fixed-effect model for heterogeneity less than 50%; we used the random-effects model for substantial or considerable heterogeneity. Eleven studies involving 3060 randomly assigned participants were included in this review. The quality of evidence is hampered by risk of bias. Use of non-steroidal antiandrogens decreased overall survival (hazard ratio (HR) 1.24, 95% confidence interval (CI) 1.05 to 1.48, six studies, 2712 participants) and increased clinical progression (one year: risk ratio (RR) 1.25, 95% CI 1.08 to 1.45, five studies, 2067 participants; 70 weeks: RR 1.26, 95% CI 1.08 to 1.45, six studies, 2373 participants; two years: RR 1.14, 95% CI 1.04 to 1.25, three studies, 1336 participants), as well as treatment failure (one year: RR 1.19, 95% CI 1.02 to 1.38, four studies, 1539 participants; 70 weeks: RR 1.27, 95% CI 1.05 to 1.52, five studies, 1845 participants; two years: RR 1.14, 95% CI 1.05 to 1.24, two studies, 808 participants), compared with medical or surgical castration. The quality of evidence for overall survival, clinical progression and treatment failure was rated as moderate according to GRADE. Predefined subgroup analyses showed that use of non-steroidal antiandrogens, compared with castration, was less favourable for overall survival, clinical progression (at one year, 70 weeks, two years) and treatment failure (at one year, 70 weeks, two years) in men with metastatic disease. Use of non-steroidal antiandrogens also increased the risk for treatment discontinuation due to adverse events (RR 1.82, 95% CI 1.13 to 2.94, eight studies, 1559 participants), including events such as breast pain (RR 22.97, 95% CI 14.79 to 35.67, eight studies, 2670 participants), gynaecomastia (RR 8.43, 95% CI 3.19 to 22.28, nine studies, 2774 participants) and asthenia (RR 1.77, 95% CI 1.36 to 2.31, five studies, 2073 participants). The risk of other adverse events, such as hot flashes (RR 0.23, 95% CI 0.19 to 0.27, nine studies, 2774 participants), haemorrhage (RR 0.07, 95% CI 0.01 to 0.54, two studies, 546 participants), nocturia (RR 0.38, 95% CI 0.20 to 0.69, one study, 480 participants), fatigue (RR 0.52, 95% CI 0.31 to 0.88, one study, 51 participants), loss of sexual interest (RR 0.50, 95% CI 0.30 to 0.83, one study, 51 participants) and urinary frequency (RR 0.22, 95% CI 0.11 to 0.47, one study, 480 participants) was decreased when non-steroidal antiandrogens were used. The quality of evidence for breast pain, gynaecomastia and hot flashes was rated as moderate according to GRADE. The effects of non-steroidal antiandrogens on cancer-specific survival and biochemical progression remained unclear. Currently available evidence suggests that use of non-steroidal antiandrogen monotherapy compared with medical or surgical castration monotherapy for advanced prostate cancer is less effective in terms of overall survival, clinical progression, treatment failure and treatment discontinuation due to adverse events. Evidence quality was rated as moderate according to GRADE. Further research is likely to have an important impact on results for patients with advanced but non-metastatic prostate cancer treated with non-steroidal antiandrogen monotherapy. However, we believe that research is likely not necessary on non-steroidal antiandrogen monotherapy for men with metastatic prostate cancer. Only high-quality, randomised controlled trials with long-term follow-up should be conducted. If further research is planned to investigate biochemical progression, studies with standardised follow-up schedules using measurements of prostate-specific antigen based on current guidelines should be conducted.

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.

Current topics and perspectives relating to hormone therapy for prostate cancer

Prostate cancer is androgen-dependent, and hormone therapy, mainly achieved by androgen deprivation, has been one of the main treatment modalities in the clinical management of prostate cancer patients for more than six decades. In the 1980s, luteinizing hormone-releasing hormone agonists, which reduce testosterone to castration levels, were introduced Also, 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 developed. More recently, novel treatment modalities have been developed, such as intermittent androgen suppression, nonsteroidal antiandrogen monotherapy, and alternative antiandrogen therapy after relapse from initial MAB/CAB, The present article focuses on these treatment modalities to review current topics and perspectives with respect to hormone therapy for prostate cancer.

Initial Hormonal Management of Androgen-Sensitive Metastatic, Recurrent, or Progressive Prostate Cancer: 2007 Update of an American Society of Clinical Oncology Practice Guideline

To update the 2004 American Society of Clinical Oncology (ASCO) guideline on initial hormonal management of androgen-sensitive, metastatic, recurrent, or progressive prostate cancer (PCa). The writing committee based its recommendations on an updated systematic literature review. Recommendations were approved by the Expert Panel, the ASCO Health Services Committee, and the ASCO Board of Directors. Seven randomized controlled trials (four new), one systematic review, one meta-analysis (new), one Markov model, and one delta-method 95% CI procedure for active controlled trials (new) informed the guideline update. Bilateral orchiectomy or luteinizing hormone-releasing hormone agonists are recommended initial androgen-deprivation treatments (ADTs). Nonsteroidal antiandrogen monotherapy merits discussion as an alternative; steroidal antiandrogen monotherapy should not be offered. Combined androgen blockade should be considered. In metastatic or progressive PCa, immediate versus symptom-onset institution of ADT results in a moderate decrease (17%) in relative risk (RR) for PCa-specific mortality, a moderate increase (15%) in RR for non-PCa-specific mortality, and no overall survival advantage. Therefore, the Panel cannot make a strong recommendation for early ADT initiation. Prostate-specific antigen (PSA) kinetics and other metrics allow identification of populations at high risk for PCa-specific and overall mortality. Further studies must be completed to assess whether patients with adverse prognostic factors gain a survival advantage from immediate ADT. For patients electing to wait until symptoms for ADT, regular monitoring visits are indicated. For patients with recurrence, clinical trials should be considered if available. Currently, data are insufficient to support use of intermittent androgen blockade outside clinical trials

Gynecomastia in patients with prostate cancer: update on treatment options

Non-steroidal antiandrogen monotherapy offers potential quality of life benefits over other treatment modalities in patients with prostate cancer. Nevertheless, gynecomastia and breast pain still represent the most bothersome side effects during this treatment. In this update article, recent advances in the management options for gynecomastia/breast pain caused by hormonal manipulation are reviewed and critically analyzed.

Endocrine treatment of prostate cancer

Although androgen deprivation as a treatment for patients with prostate cancer was described more than 60 years ago its optimal use remains controversial. The widespread use of prostate-specific (PSA) assay has lead to earlier diagnosis and earlier detection of recurrent disease. This means that the systemic side effects of androgen deprivation and quality of life have become more important. Debates continue regarding the proper use and timing of endocrine therapy with orchiectomy, oestrogen agonists, gonadotropin hormone-releasing hormone (GnRH) agonists, GnRH antagonists, and androgen antagonists. A critical review of the literature was performed. Data support that androgen deprivation is an effective treatment for patients with advanced prostate cancer. However, although it improves survival, it is not curative, and creates a spectrum of unwanted effects that influence quality of life. Castration remains the frontline treatment for metastatic prostate cancer, where orchiectomy, oestrogen agonists and GnRH agonists produce equivalent clinical responses. Maximum androgen blockade (MAB) is not significantly more effective than single agent GnRH agonist or orchiectomy. Nonsteroidal antiandrogen monotherapy is as effective as castration in treatment of locally advanced prostate cancer offering quality of life benefits. Adjuvant endocrine treatment is able to delay disease progression at any stage. There is, however, controversy of the possible survival benefit of such treatment, including patients having PSA relapse after definitive local treatment for prostate cancer. Neoadjuvant endocrine treatment has its place mainly in the external beam radiotherapy setting. Intermittent androgen blockade is still considered experimental. The decision regarding the type of androgen deprivation should be made individually after informing the patient of all available treatment options, including watchful waiting, and on the basis of potential benefits and adverse effects. Several large studies are under way to investigate the role of adjuvant endocrine treatment in the field of early prostate cancer, intermittent androgen deprivation and endocrine therapy alone compared with endocrine therapy with radiotherapy. The real challenge, however, is to develop better means to avert hormone-refractory prostate cancer and better treatments for patients with hormone-refractory disease when it occurs.

Effect of nonsteroidal antiandrogen monotherapy versus castration therapy on neuroendocrine differentiation in prostate carcinoma

Objectives To determine whether the administration of the nonsteroidal antiandrogen bicalutamide reduces the risk of an increase in chromogranin A (CgA) levels in patients with prostate cancer who experienced biochemical failure after radical retropubic prostatectomy (RRP) compared with pharmacologic castration therapy. It has been hypothesized that continuous androgen suppression for the treatment of prostate cancer results in hyperactivation of neuroendocrine cells and an increase in CgA levels. Methods Forty-eight patients with pT3pN0M0 prostate cancer and biochemical (prostate-specific antigen) progression after RRP were randomized to bicalutamide monotherapy or pharmacologic castration. The serum levels of CgA and prostate-specific antigen were measured at 1, 3, 6, 12, 18, and 24 months of therapy. The changes in serum CgA levels were compared for patients who successfully responded to the first 24 months of therapy. Results In both treatment groups, a statistically significant trend was noted for CgA levels to increase from baseline to 24 months. This trend was lower in the bicalutamide group (slope = 0.60, 95% confidence interval 0.28 to 0.92; P = 0.004) than in the castration group (slope = 0.29, 95% confidence interval 0.08 to 0.50; P = 0.01). Conclusions The results of this study provide the first evidence to show that in patients with prostate cancer undergoing hormonal therapy, nonsteroidal antiandrogen monotherapy produces a significantly lower increase in serum CgA compared with castration.

Tolerability of Antiandrogens in the Treatment of Prostate Cancer

This article presents and discusses data on the tolerability of the antiandrogens, both steroidal (cyproterone acetate; CPA) and non-steroidal (bicalutamide, flutamide, nilutamide), across all stages of hormone-responsive prostate cancer. Steroidal and non-steroidal antiandrogens have different endocrine effects and therefore different pharmacological side effects during monotherapy, with CPA generally resulting in loss of sexual interest and erectile dysfunction, whereas the majority of men retain some sexual interest and function during non-steroidal antiandrogen monotherapy. The most common side effects of the non-steroidal agents are gynaecomastia and breast pain. Although the incidence of these events varies considerably between studies, there is no evidence that there is a true difference in incidence between the three non-steroidal agents. Important differences exist between the antiandrogens with respect to non-pharmacological side effects. CPA has been linked to adverse changes in serum lipids as well as significant, and in some cases fatal, cardiovascular events. CPA can also cause hepatotoxicity. Nilutamide is associated with delayed adaptation to darkness, alcohol intolerance and interstitial pneumonitis. Flutamide is associated with a greater risk of serious hepatotoxicity than bicalutamide or nilutamide. Diarrhoea is also more likely to occur during therapy with flutamide than the other antiandrogens. In contrast, no specific non-pharmacological complications have been linked to bicalutamide, while diarrhoea and abnormal liver function occur less frequently than with flutamide. Thus, when considering antiandrogen therapy at any stage of prostate cancer, bicalutamide appears to have advantages over the other antiandrogens.

Effect of non-steroidal antiandrogen monotherapy versus castration therapy on neuroendocrine differentiation in prostate carcinoma

Effect of non-steroidal antiandrogen monotherapy versus castration therapy on neuroendocrine differentiation in prostate carcinoma

Is there a role for antiandrogen monotherapy in patients with metastatic prostate cancer?

Castration is the most widely used form of androgen ablation employed in the treatment of metastatic (M1) prostate cancer. Non-steroidal antiandrogen monotherapy is a potential alternative treatment option for men for whom castration is unacceptable or not indicated. Of the three non-steroidal antiandrogens, bicalutamide ('Casodex'), flutamide and nilutamide, only bicalutamide has been compared with castration in large, controlled, randomised, Phase III trials in M1 patients. A post-hoc analysis of these studies indicated that bicalutamide 150 mg/day monotherapy may be of benefit to M1 patients with a prostate specific antigen (PSA) level </=400 ng/ml. Significant advantages for M1 patients treated with bicalutamide were observed in subjective response rate, maintenance of sexual interest and physical capacity. Patients with a higher disease burden (PSA >400 ng/ml) may decide that quality of life and symptomatic benefits outweigh the slight survival disadvantage seen in clinical trials and opt for bicalutamide monotherapy as an alternative to castration.Prostate Cancer and Prostatic Diseases (2001) 4, 196-203.

BICALUTAMIDE MONOTHERAPY COMPARED WITH CASTRATION IN PATIENTS WITH NONMETASTATIC LOCALLY ADVANCED PROSTATE CANCER: 6.3 YEARS OF FOLLOWUP

Nonsteroidal antiandrogen monotherapy may be a treatment option for some patients with advanced prostate cancer. We report a survival and safety update from an analysis of 2 studies in which patients with nonmetastatic (M0) locally advanced disease were treated with either 150 mg. bicalutamide monotherapy or castration. Data from 2 open label, multicenter studies of identical design were pooled according to protocol. Patients with stage T3/4 prostate cancer were randomized to receive 150 mg. bicalutamide daily or castration (orchiectomy or 3.6 mg. goserelin acetate every 28 days) in a 2:1 ratio. A total of 480 patients with locally advanced prostate cancer were randomized to treatment. After a median followup of 6.3 years mortality was 56%. There was no statistically significant difference between the 2 groups in overall survival (hazard ratio 1.05, upper 1-sided 95% confidence limit 1.31, p = 0.70) or time to progression (1.20, 1.45, p = 0.11). There were statistically significant benefits in the bicalutamide monotherapy group in the 2 quality of life parameters of sexual interest (p = 0.029) and physical capacity (p = 0.046). The highest incidences of adverse events were the pharmacological side effects of hot flashes in the castration group, and breast pain and gynecomastia in the bicalutamide group. The incidences of other types of adverse events were low. Bicalutamide was well tolerated, with few drug related withdrawals from study, and no new safety issues were identified during this longer followup. Monotherapy with 150 mg. bicalutamide is an attractive alternative to castration in patients with locally advanced prostate cancer for whom immediate hormone therapy is indicated.

Are Non-Steroidal Anti-Androgens Appropriate as Monotherapy in Advanced Prostate Cancer?

Objectives: To evaluate the efficacy of non-steroidal anti-androgen monotherapy in the treatment of advanced prostate cancer. Methods: The pertinent literature regarding the use of nilutamide, flutamide, and bicalutamide as monotherapy in the treatment of prostate cancer has been reviewed. Results: The clinical utility of non-steroidal antiandrogen monotherapy is currently under investigation. As with other endocrine therapies, this approach appears to provide effective palliation of symptoms, but offers certain quality-of-life benefits, including preservation of libido and sexual potency, issues which may be important in certain patients, particularly younger men. Available data indicate that flutamide may be as effective as orchidectomy in terms of prolonging progression-free survival in selected patients. Nilutamide has been less extensively investigated, but the clinical utility of this agent, except for use in combined therapy, would appear to be somewhat limited by a high incidence of drug-related side effects. Bicalutamide, however, is well tolerated as monotherapy and appears to be as effective as castration in patients with locally advanced non-metastatic disease. In metastatic disease, the improved subjective response and quality of life gains with bicalutamide may outweigh the slightly inferior survival. Conclusion: These promising preliminary findings, a number of issues remain to be determined before non-steroidal antiandrogen monotherapy can be considered to be routine clinical practice. These include optimum indication and dosage, long-term clinical efficacy and tolerability, and response to second-line therapy.

Non-steroidal anti-androgen monotherapy of advanced prostate cancer ??? A reasonable option

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