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.

BACKGROUND: 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. METHODS: 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 160 mg orally once daily in all patients. RESULTS: The rate of decline of prostate-specific antigen by 50% or more was 72.2%, and median overall survival was 42.05 months. Multivariate analysis revealed that higher pretreatment serum levels of prostate-specific antigen (≥11.3 ng/mL; P = 0.004), neuron-specific enolase (P = 0.014) and interleukin-6 (≥2.15 pg/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. CONCLUSIONS: 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.

Potentiation of flutamide-induced hepatotoxicity in mice by Xian-Ling-Gu-Bao through induction of CYP1A2.

ETHNOPHARMACOLOGICAL RELEVANCE: Xian-Ling-Gu-Bao (XLGB) Fufang is herbal formula widely used to treat osteoporosis and other bone disorders. Because of its commonality in the clinical use, there is a safety concern over the use of XLGB combined with other androgen deprivation therapy (ADT) drugs such as flutamide (FLU) that is associated with reduced bone density. To date, there have been no evaluations on the side effects of the drug-drug interaction between XLGB and FLU. AIM OF THE STUDY: The present study was designed to investigate the hepatotoxicity in the context of the combined treatment of XLGB and FLU in a mouse model, and to determine whether the metabolic activation of FLU through induction of CYP1A2 plays a role in the increased hepatoxicity caused by the combination of XLGB and FLU. MATERIALS AND METHODS: C57 mice were administered with either XLGB (6,160 mg/kg), FLU (300 mg/kg), or with the combination of the two drugs. Animals were treated with XLGB for 5 days before the combined administration of XLGB and FLU for another 4 days. The serum of mice from single or the combined administration groups was collected for biochemical analysis. The mouse liver was collected to examine liver morphological changes, evaluate liver coefficient, as well as determine the mRNA expression of P450 isozymes (Cyp1a2, Cyp3a11 and Cyp2c37). For metabolism analysis, mice were treated with XLGB, FLU, or the combination of XLGB and FLU for 24 h. The urine samples were collected for the analysis of FLU-NAC conjugate by UPLC-Q-Orbitrap MS. The liver microsomes were prepared from fresh livers to determine the activity of metabolizing enzyme CYP1A2. RESULTS: The combined treatment of XLGB and FLU caused loss of mice body weight and elicited significant liver toxicity as evidenced by an increased liver coefficient and serum lactate dehydrogenase (LDH) activity as well as pathological changes of fatty lesion of liver tissue. FLU increased hepatic expression of Cyp1a2 mRNA that was further elevated in the liver of mice when administered with both FLU and XLGB. Treatment of FLU resulted in an increase in the expression of Cyp3a11 mRNA that was negated when mice were co-treated with FLU and XLGB. No significant difference in Cyp2c37 mRNA expression was observed among the different treatment groups as compared to the control. Analysis of metabolic activity showed that the combined administration caused a synergic effect in elevating the activity of the CYP1A2 enzyme. Mass spectrometry analysis identified the presence of FLU reactive metabolite derived FLU-NAC conjugate in the urine of mice treated with FLU. Strikingly, about a two-fold increase of the FLU-NAC conjugate was detected when treated with both FLU and XLGB, indicating an elevated amount of toxic metabolite produced from FLU in the present of XLGB. CONCLUSION: FLU and XLGB co-treatment potentiated FLU-induced hepatoxicity. This increased hepatoxicity was mediated through the induction of CYP1A2 activity which in turn enhanced bioactivation of FLU leading to over production of FLU-NAC conjugate and oxidative stress. These results offer warnings about serious side effects of the FLU-XLGB interaction in the clinical practice.

Antiandrogen Therapy with Hydroxyflutamide or Androgen Receptor Degradation Enhancer ASC-J9 Enhances BCG Efficacy to Better Suppress Bladder Cancer Progression.

Recent studies suggest that the androgen receptor (AR) might play important roles in influencing bladder cancer progression, yet its clinical application remains unclear. Here, we developed a new combined therapy with Bacillus Calmette-Guérin (BCG) and the AR degradation enhancer ASC-J9 or antiandrogen hydroxyflutamide (HF) to better suppress bladder cancer progression. Mechanism dissection revealed that ASC-J9 treatment enhanced BCG efficacy to suppress bladder cancer cell proliferation via increasing the recruitment of monocytes/macrophages that involved the promotion of BCG attachment/internalization to the bladder cancer cells through increased integrin-α5ß1 expression and IL6 release. Such consequences might then enhance BCG-induced bladder cancer cell death via increased TNFα release. Interestingly, we also found that ASC-J9 treatment could directly promote BCG-induced HMGB1 release to enhance the BCG cytotoxic effects for suppression of bladder cancer cell growth. In vivo approaches also concluded that ASC-J9 could enhance the efficacy of BCG to better suppress bladder cancer progression in BBN-induced bladder cancer mouse models. Together, these results suggest that the newly developed therapy combining BCG plus ASC-J9 may become a novel therapy to better suppress bladder cancer progress.

High-dose radiotherapy with short-term or long-term androgen deprivation in localised prostate cancer (DART01/05 GICOR): a randomised, controlled, phase 3 trial.

BACKGROUND: The optimum duration of androgen deprivation combined with high-dose radiotherapy in prostate cancer remains undefined. We aimed to determine whether long-term androgen deprivation was superior to short-term androgen deprivation when combined with high-dose radiotherapy. METHODS: In this open-label, multicentre, phase 3 randomised controlled trial, patients were recruited from ten university hospitals throughout Spain. Eligible patients had clinical stage T1c-T3b N0M0 prostate adenocarcinoma with intermediate-risk and high-risk factors according to 2005 National Comprehensive Cancer Network criteria. Patients were randomly assigned (1:1) using a computer-generated randomisation schedule to receive either 4 months of androgen deprivation combined with three-dimensional conformal radiotherapy at a minimum dose of 76 Gy (range 76-82 Gy; short-term androgen deprivation group) or the same treatment followed by 24 months of adjuvant androgen deprivation (long-term androgen deprivation group), stratified by prostate cancer risk group (intermediate risk vs high risk) and participating centre. Patients assigned to the short-term androgen deprivation group received 4 months of neoadjuvant and concomitant androgen deprivation with subcutaneous goserelin (2 months before and 2 months combined with high-dose radiotherapy). Anti-androgen therapy (flutamide 750 mg per day or bicalutamide 50 mg per day) was added during the first 2 months of treatment. Patients assigned to long-term suppression continued with the same luteinising hormone-releasing hormone analogue every 3 months for another 24 months. The primary endpoint was biochemical disease-free survival. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT02175212. FINDINGS: Between Nov 7, 2005, and Dec 20, 2010, 178 patients were randomly assigned to receive short-term androgen deprivation and 177 to receive long-term androgen deprivation. After a median follow-up of 63 months (IQR 50-82), 5-year biochemical disease-free survival was significantly better among patients receiving long-term androgen deprivation than among those receiving short-term treatment (90% [95% CI 87-92] vs 81% [78-85]; hazard ratio [HR] 1·88 [95% CI 1·12-3·15]; p=0·01). 5-year overall survival (95% [95% CI 93-97] vs 86% [83-89]; HR 2·48 [95% CI 1·31-4·68]; p=0·009) and 5-year metastasis-free survival (94% [95% CI 92-96] vs 83% [80-86]; HR 2·31 [95% CI 1·23-3·85]; p=0·01) were also significantly better in the long-term androgen deprivation group than in the short-term androgen deprivation group. The effect of long-term androgen deprivation on biochemical disease-free survival, metastasis-free survival, and overall survival was more evident in patients with high-risk disease than in those with low-risk disease. Grade 3 late rectal toxicity was noted in three (2%) of 177 patients in the long-term androgen deprivation group and two (1%) of 178 in the short-term androgen deprivation group; grade 3-4 late urinary toxicity was noted in five (3%) patients in each group. No deaths related to treatment were reported. INTERPRETATION: Compared with short-term androgen deprivation, 2 years of adjuvant androgen deprivation combined with high-dose radiotherapy improved biochemical control and overall survival in patients with prostate cancer, particularly those with high-risk disease, with no increase in late radiation toxicity. Longer follow-up is needed to determine whether men with intermediate-risk disease benefit from more than 4 months of androgen deprivation. FUNDING: Spanish National Health Investigation Fund, AstraZeneca.

Androgen deprivation by flutamide modulates uPAR, MMP-9 expressions, lipid profile, and oxidative stress: amelioration by daidzein.

The growth and development of prostate gland is governed by testosterone. Testosterone helps in maintaining the adipose tissue stores of the body. It is well documented that with advancing age there has been a gradual decline in testosterone levels. Our aim was to study the protective role of daidzein on flutamide-induced androgen deprivation on matrix degrading genes, lipid profile and oxidative stress in Wistar rats. Sub-chronic (60 days) flutamide (30 mg/kg b.wt) administration resulted in marked increase in expressions of matrix degrading genes [matrix metalloproteases 9 and urokinase plasminogen activation receptor]. Additionally, it increased the levels of low density lipoproteins, total cholesterol, triglycerides, and lowered the levels of high density lipoproteins and endogenous antioxidant levels. Oral administration of daidzein (20 and 60 mg/kg b.wt) restituted the levels to normal. Daidzein administration resulted in amelioration of the prostate atrophy, degeneracy and invasiveness induced by flutamide. Our findings suggest that the daidzein may be given as dietary supplement to patients who are on androgen deprivation therapy, to minimize the adverse effects related to it and also retarding susceptibility of patients to cardiovascular diseases.

Hydroxyflutamide enhances cellular sensitivity to 5-fluorouracil by suppressing thymidylate synthase expression in bicalutamide-resistant human prostate cancer cells.

We investigated the antitumor effects of combination therapy with anti-androgens and 5-fluorouracil (5-FU), and examined the underlying mechanism of the treatment. Initially, we established the bicalutamide-resistant subline CDX25R from the androgen receptor (AR)-positive human prostate cancer cell line LNCaP through continuous exposure to bicalutamide. CDX25R cells lost the ability to respond to androgens, but still expressed AR. They showed significant resistance to bicalutamide, but had high sensitivity to hydroxyflutamide (OH-flutamide) compared with LNCaP cells. The CDX25R subline was thus considered to be a suitable model for prostate cancer that has developed resistance to first-line hormonal therapy but shows sensitivity to an alternative approach. Combined treatment with 5-FU and OH-flutamide had a synergistic effect on CDX25R cells. OH-flutamide decreased expression of the transcription factor E2F1, and subsequently of thymidylate synthase (TS), in CDX25R cells but not in AR-negative DU145 cells. This suggested that OH-flutamide enhanced the growth-inhibitory activity of 5-FU in CDX25R cells by reducing TS expression through the AR pathway. Combined therapy with 5-FU and OH-flutamide may, therefore, be appropriate for patients with prostate cancer that has acquired resistance to initial hormone therapy including bicalutamide.

Antiandrogen withdrawal syndrome and alternative antiandrogen therapy associated with the W741C mutant androgen receptor in a novel prostate cancer xenograft.

BACKGROUND: The mechanisms underlying antiandrogen withdrawal syndrome (AWS) and alternative antiandrogen therapy (AAT) effectiveness were assumed to be mutations in the androgen receptor (AR), which resulted in an altered response to antiandrogens. The aim of the present study was to test this assumption using the novel prostate cancer xenograft model KUCaP-1 harboring the W741C mutant AR (Yoshida et al., Cancer Res 2005; 65(21): 9611-9616). METHODS: Mice bearing xenograft tumors were castrated, and the long-term sequential changes in tumor volume were observed. To determine whether AWS was observed in this model, bicalutamide (BCL) was orally administered to the castrated mice and then withdrawn. The effect of flutamide (FLT) on the W741C mutant AR was examined with transactivation assays in vitro and with the oral administration of FLT to non-castrated mice harboring KUCaP-1 in vivo. The AAT efficacy against KUCaP-1 was evaluated by changing BCL with FLT. RESULTS: KUCaP-1 regressed significantly after castration and did not re-grow. KUCaP-1 treated with BCL continued to grow even after castration and started regressing 2 months after BCL withdrawal, replicating clinically recognized AWS. The antagonistic effect of FLT against the W741C mutant AR was revealed in vitro and in vivo. AAT with FLT suppressed tumor growth after BCL withdrawal. CONCLUSIONS: KUCaP-1 was an entirely androgen-dependent xenograft and mimicked the clinical phenomena of AWS and AAT caused by the agonistic and antagonistic activity of BCL and FLT, respectively. KUCaP-1 could be an in vivo model for screening novel antiandrogens for the treatment of BCL resistant prostate cancer harboring the W741C mutation in the AR.

Does small-cell phenotype predict the natural history of prostate cancer? A case study in disease behavior.

BACKGROUND: A 52-year-old man presented to his urologist with hematuria and symptoms of frequency and incomplete voiding. The patient received antibiotics without symptom resolution. His prostate-specific antigen (PSA) level was 6.6 ng/ml and digital rectal examination revealed a normal-sized firm prostate gland. Biopsy obtained by transurethral resection revealed poorly differentiated Gleason 9 adenocarcinoma of the prostate with small-cell/neuroendocrine features. Pure small-cell cancer or poorly differentiated prostate cancer may secrete little or no PSA. One should be alerted to this phenotype in a patient with large volume disease on biopsy or examination and a low PSA or PSA not in proportion to tumor burden. INVESTIGATIONS: Digital rectal examination, laboratory tests, cystoscopy, prostatic chips obtained from transurethral resection, prostate biopsy, bone scan, CT scan of the chest, abdomen and pelvis. DIAGNOSIS: Poorly differentiated Gleason 9 adenocarcinoma of the prostate with small-cell/neuroendocrine features. MANAGEMENT: Transurethral resection, androgen blockade with a gonadotropin-releasing hormone analog and antiandrogen flutamide, oral bicalutamide, docetaxel and oral estramustine. Total pelvic exenteration with ileal conduit urinary diversion and permanent end-colostomy formation, percutaneous nephrostomy placement, cisplatin combined with etoposide.

[Administration of 1 alpha-OH vitamin D3 and calcium prevents bone mass loss in patients with advanced prostatic carcinoma after orchidectomy treated with complete androgenic blockade]. / Stosowanie 1alpha-OH witaminy D3 i wapnia zapobiega ubytkowi masy kostnej u pacjentów z zaawansowanym rakiem stercza po orchidektomii leczonych calkowita blokada androgenowa.

UNLABELLED: Complete androgenic blockade used in the treatment of advanced prostatic carcinoma can be attained by administration of antiandrogens in orchidectomized patients or by combined therapy with LH-RH analogs and antiandrogens. The treatment, however, decreases the influence of both androgens end estrogens on bone tissue and may result in bone mass loss and increased propensity to fractures. The purpose of the study was to determine the influence of complete androgenic blockade on bone mass and skeletal metabolism in men with advanced prostatic carcinoma and to assess whether 1alpha-OH vitamin D3 (1alpha-OHD3) together with calcium supplementation is able to prevent bone mass loss in men treated with complete androgenic blockade. 51 patients with advanced prostatic carcinoma, with skeletal metastases, aged 44 - 86, mean 68 ys were included into a 12-month prospective study. All patients were treated with orchidectomy followed by therapy with flutamide in a dose of 750 mg daily. 26 patients were additionally given 1alpha-OHD3 in a dose of 0.5 microg/d and calcium carbonate in an initial dose of 1 g daily. It was found that the 12-month treatment with complete androgenic blockade resulted in a decrease in bone mineral density (BMD) by 8.1% in the lumbar spine, by 6.3% in the femoral neck and by 3.5% in the total skeleton. Therapy with 1alpha-OHD3 and CaCO3 caused complete inhibition of bone tissue loss in the lumbar spine and resulted in an increase in BMD by 2.2% in femoral neck and by 1.9% in the total skeleton. None of the examined patients experienced any skeletal fractures. In both groups of patients a prompt decrease in serum alkaline phosphatase activity - a marker of osteoblast activity and an increase in fasting urine calcium creatinine ratio indicating acceleration of bone resorption were found. CONCLUSIONS: in patients with advanced prostatic carcinoma treated with complete androgenic blockade acceleration of bone mass loss is observed; treatment with 1alpha-OHD3 and CaCO3 is able to prevent both trabecular and compact bone loss.

Evaluation of general behavior, memory, learning performance, and brain sexual differentiation in F1 offspring males of rats treated with flutamide during late gestation.

Flutamide is a drug with antiandrogen effects that are mediated through androgen receptors (ARs). In this study, flutamide was subcutaneously administered to female rats (3, 10 or 30 mg/kg/day) on gestation Days 16-21 to evaluate effects on memory and learning performance in F1 offspring. Brain sexual differentiation was also evaluated by measuring the volume of the sexual dimorphic nucleus of the preoptic area (SDN-POA) and analyzing levels of androgen receptor (AR) mRNA expression in the prostate, hypothalamus and hippocampus. In F1 offspring exposed in utero to flutamide, evaluation of motor activity, learning performance and spatial perception showed that flutamide tended to exert a dose-dependent increase on the motor activity in F1 males, but no significant differences were identified in the other measurements. Prominent changes in development of the SDN-POA were apparent in males after maturation. Doses of > or =3 mg/kg/day resulted in significantly decreased length and volume of the SDN-POA compared to controls. These differences tended to become more marked at higher doses. Volumes of the SDN-POA did not differ significantly between F1 males and females exposed to flutamide at 30 mg/kg/day. AR mRNA was assayed using the dot-blotting method in F1 animals. In flutamide dose groups, AR mRNA expression tended to be increased in the prostate gland and decreased in the hippocampus. These results might suggest that exposure to flutamide in utero might affect controlling AR expression on a hormonal signal transduction system mediated by testosterone. However, these changes were not clearly correlated to learning performance in male offspring other than motor activity.

Antiandrogen monotherapy: indications and results.

Many patients with prostate cancer for whom hormonal therapy is indicated are still physically and sexually active; quality of life is therefore a vital issue when considering treatment options. Traditional castration-based therapies, although effective, have implications with respect to quality of life, causing loss of libido, impotence, fatigue, and reduced bone mineral density. Monotherapy with a nonsteroidal antiandrogen is an attractive therapeutic alternative to castration, offering effective therapy with potential quality-of-life benefits. Of the available nonsteroidal antiandrogens, bicalutamide has been most extensively evaluated in the monotherapy setting. Mature combined data (56% mortality) from 2 large randomized studies show no statistically significant difference in overall survival between bicalutamide 150-mg monotherapy and castration in patients with locally advanced, nonmetastatic (stage M0) disease. Survival outcome in patients with metastatic (stage M1) disease (43% mortality) favored castration, although the difference in median survival between the groups was only 6 weeks. Bicalutamide 150-mg monotherapy was associated with significant advantages compared with castration, in terms of sexual interest and physical capacity, in patients with either M0 and M1 stage disease. Data from a small subgroup of patients with stage M0 disease suggest that bicalutamide may also reduce the risk of osteoporosis compared with castration. Long-term therapy with bicalutamide 150-mg monotherapy is generally well tolerated, with a predictable side-effect profile. The most common side effects are male breast pain and gynecomastia. Emerging evidence also supports the use of bicalutamide 150 mg, both as immediate monotherapy and as adjuvant therapy in early stage (localized or locally advanced) prostate cancer.

Clinical efficacy of lower dose flutamide 125 mg/day in the treatment of hirsutism.

Thirty-four patients with moderate-severe hirsutism were enrolled in this study. The patients received 125 mg/day flutamide for a period of 6 months. Hirsutism score and hormone parameters including FSH, LH, T, free T, androstenedione (A), DHEAS, PRL and sex hormone-binding globulin (SHBG) levels were evaluated in all patients before treatment and repeated at every three-monthly intervals. Hirsutism greatly improved during flutamide therapy, and the hirsutism score significantly decreased at month 3 and 6 from a mean (+/-SD) of 17.19+/-4.55 to 10.75+/-3.84 (p<0.001) and 17.19+/-4.55 to 5.91+/-2.53 (p<0.001), respectively. A significant reduction in hirsutism score (mean%+/-SD) as compared to baseline was observed at 3 months (37.78+/-13.30, p<0.001) and at 6 months (65.47+/-13.49, p<0.001). No significant changes in the levels of hormone and no serious side effects were observed in the patients. The lower dose flutamide, 125 mg/day, is a safe and cost-effective drug in the treatment of hirsutism. Lower dose flutamide may be used in place of high dose flutamide, 250 to 750 mg/day.

The effect of combined androgen blockade on bone turnover and bone mineral densities in men treated for prostate carcinoma: longitudinal evaluation and response to intermittent cyclic etidronate therapy.

BACKGROUND: Androgen receptor blocking agents have become an established form of therapy for men with disseminated prostate carcinoma. The purpose of this study was to evaluate markers of bone turnover and to measure bone mineral densities (BMD) in men with disseminated prostate carcinoma treated with combined androgen blockade prior to and after 6 months of intermittent cyclic etidronate therapy. METHODS: Twelve consecutive men with disseminated prostate carcinoma were evaluated at 0, 6, and 12 months after treatment with a long acting gonadotropin-releasing hormone agonist (goserelin acetate) and an androgen antagonist (flutamide). During the 6-12 month period, patients were treated with adjuvant intermittent cyclic etidronate therapy and calcium supplementation. Lumbar spine BMD was measured by spinal quantitative computed tomography (QCT) and femoral neck BMD by dual energy X-ray absorptiometry (DXA). RESULTS: Combined androgen blockade resulted in all men achieving serum free testosterone concentrations of <2.2 pmol/L (normal range, 38-114 pmol/ L). The mean serum prostate specific antigen activities decreased from 130.8+/-46 to 6.9+/-4.4 ng/mL (P < 0.05). Although serum calcium, parathyroid hormone, and 25-hydroxyvitamin D measurements remained unchanged, serum bone Gla-protein concentrations and urinary deoxypyridinolene excretion rates increased significantly (P < 0.01, respectively). Mean lumbar spine QCT decreased by 6.6+/-1.5% from 76.5 mg/cm3 (95% confidence interval [95% CI, 57-96 mg/cm3) to 73.9 mg/cm3 (95% CI, 55-93 mg/cm3) (P < 0.001) and mean femoral neck DXA decreased by 6.5+/-1.3% from 0.94 g/cm2 (95% CI, 0.81-1.07 g/cm2) to 0.91 g/cm2 (95% CI, 0.79-1.04 g/cm2) (P < 0.001). After treatment with adjuvant intermittent cyclic etidronate, mean lumbar spine QCT increased by 7.8+/-3.7% to a final value of 75 mg/cm3 (95% CI, 48.7-101 mg/cm3) (P=0.001 compared with the initial 6 months without intermittent cyclic etidronate therapy). Significant increases in BMD also were observed in the femoral neck and Ward's triangle. CONCLUSIONS: Androgen receptor blocking agents have an established role in the treatment of disseminated prostate carcinoma. However, combined androgen blockade in elderly men with disseminated prostate carcinoma results in high bone turnover with significant cancellous bone loss. The results of this study show that adjuvant therapy with intermittent cyclic etidronate may prevent these changes and decrease the risk of spinal fractures.

Daily dosing with flutamide or Casodex exerts maximal antiandrogenic activity.

OBJECTIVES: Because the large increase in luteinizing hormone secretion induced by flutamide in the intact rat is not found in men, we have used castrated rats and mice supplemented with androstenedione (4-dione) instead of intact animals to measure the activity of the pure antiandrogens flutamide and Casodex. METHODS: We first compared the effect of different schedules of administration of various doses of the two antiandrogens on prostate and seminal vesicle weights in the castrated rat and mice models. RESULTS: For both flutamide and Casodex, no consistent difference was found between the effects of once daily and thrice daily oral dosing in the rat. It was observed, however, that flutamide, especially at the high and therapeutically more effective doses, is about three times more potent than Casodex under both schedules of dosing. When flutamide was administered subcutaneously three times a day, twice a day, once a day, or once every second day in rats and mice, no difference was observed in the degree of inhibition achieved on prostate and seminal vesicle weights. CONCLUSIONS: The present data show that Casodex is about three times less potent than flutamide on the well-recognized parameters of androgen responsiveness in the rat, namely prostate and seminal vesicle weights. Another finding is that once daily dosing with flutamide exhibits an effectiveness comparable to thrice daily dosing; such data may have potential significance in facilitating compliance by administration of flutamide once daily instead of the current thrice daily schedule in men. Moreover, these data, if obtained in a reliable in vivo model, should be helpful in determining the choice of an appropriate dose of Casodex for the treatment of prostate cancer.