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Flutamide

A Review of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Use in Advanced Prostatic Cancer

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Abstract

Synopsis

Flutamide, a nonsteroidal antiandrogenic drug devoid of hormonal agonist activity, is used in the treatment of advanced prostate cancer.

In previously untreated patients, flutamide 750mg daily given alone is of comparable efficacy to diethylstibestrol (stilboestrol) 1 or 3mg daily and estramustine 560 or 840mg daily, but has the potential advantages of fewer cardiovascular effects and maintenance of some sexual potency. Its greatest therapeutic potential is as a component of combination androgen blockade, where administration with an agonist analogue of gonadotrophin-releasing hormone (GnRH) [luteinising hormone-releasing hormone (LH-RH)] in both initial uncontrolled and randomised studies increased survival time relative to GnRH agonist monotherapy or orchidectomy. Subsequent multicentre trials, however, have been unable to confirm an improvement in survival time. Thus, while there seems to be little doubt that flutamide prevents the initial disease flare caused by GnRH agonists, an improvement in remission rate and survival remains contentious.

Flutamide is generally well tolerated and is suitable monotherapy in patients with previously untreated advanced prostatic cancer who wish to preserve sexual potency. However, full assessment of the role of combination androgen blockade awaits publication of the final results of ongoing multicentre trials.

Pharmacodynamic Properties

Flutamide, a nonsteroidal antiandrogenic drug devoid of hormone agonist activity, is often termed a ‘pure’ antiandrogen.

Such activity in intact animals is enhanced by the addition of a GnRH agonist and is associated with more pronounced prostate atrophy than the GnRH analogue alone. These and other findings form the basis of combination androgen blockade used to treat advanced prostatic cancer in men.

Administration of flutamide 750mg daily to healthy male volunteers increases plasma concentrations of testosterone, estradiol, luteinising hormone (LH) and follicle-stimulating hormone (FSH). These effects are prevented by concomitant administration of a GnRH analogue.

It is generally considered that flutamide and its principal active metabolite, 2-hydroxy-flutamide, act mainly by inhibiting the binding of dihydrotestosterone to nuclear androgen receptors, thus decreasing cell proliferation in androgen-dependent tissues. However, a recent study of the proliferative capacity of androgen-sensitive human prostate tumour cells in the presence of steroidal and nonsteroidal antiandrogens found poor correlation between relative binding affinity to androgen receptors and proliferative efficiency. 2-Hydroxy-flutamide appears to be largely responsible for the antiandrogenic activity of flutamide.

Pharmacokinetic Properties

In healthy elderly men (aged 65 to 68 years) and patients with prostate cancer (aged 59 to 82 years), mean maximum concentrations of unchanged flutamide are attained 0.5 to 1.5 hours after a single 250mg oral dose and 1 to 4 hours after a 500mg dose. Plasma flutamide and 2-hydroxy-flutamide concentrations achieve steady-state by the sixth and third day, respectively, of 3 times daily oral administration. At steady-state, mean maximum plasma concentrations are 3- to 5- fold higher than after the first dose. The area under the plasma flutamide concentration-time curve is similar in elderly and younger volunteers, although mean maximum plasma concentrations tend to be lower in the elderly.

Following a single 250mg oral dose, the elimination half-life of 2-hydroxy-flutamide was 8.1 and 4 to 6.6 hours in elderly volunteers and in patients with prostate cancer, respectively.

Therapeutic Efficacy

Comparisons of flutamide and estrogen therapy in generally small numbers of previously untreated patients with advanced prostate cancer have shown flutamide 750mg daily to be of similar efficacy to diethylstilbestrol 1 or 3mg daily. The efficacies of flutamide and estramustine also appeared similar. Uncontrolled trials of flutamide plus a GnRH analogue suggested improved survival with such regimens relative to GnRH analogues alone. Less impressive, though significantly prolonged, survival times relative to medical castration alone were achieved with combination androgen blockade in a subsequent large multicentre randomised trial. However, analyses of several later randomised trials did not find evidence for improved survival time with combined treatment compared with a GnRH agonist alone or orchidectomy.

Subjective responses (based on symptom control and performance status) were similar in flutamide plus goserelin recipients and surgically castrated patients, although there was evidence of an approximately 8-month longer symptom-free survival in those receiving combination therapy in 1 study. Final judgement on the possible advantages of combination androgen blockade awaits completion of these trials.

Not surprisingly, flutamide, like other systemic treatments affecting the sex hormones, is less effective in patients unresponsive to hormonal manipulation, with response usually limited and short. Nevertheless, substitution of flutamide for cyproterone acetate elicited a positive response in 31% of patients who relapsed during combined androgen blockade, including 58% of those with stage D1 disease. Larger trials are needed to confirm these favourable results and to determine if equally satisfactory results can be achieved with a flutamide-containing regimen started at diagnosis.

Tolerability

Apart from a high incidence of gynaecomastia (34 to 100%) and some gastrointestinal discomfort, flutamide has generally been well tolerated.

Gynaecomastia is less frequent when flutamide is combined with a GnRH analogue, but hot flushes occur in at least 50% of patients treated with such a regimen. Flushing is not associated with flutamide monotherapy, and the incidence of cardiovascular complications may be less than with estrogen treatment. Another favourable feature of treatment with flutamide alone is the maintenance of sexual potency in about 80% of patients, although this advantage over estrogen or estramustine therapy is negated when a GnRH agonist is added. Elevation of liver enzymes has been reported in up to about one-third of patients in some studies. These values often return to normal during continued treatment, although a few instances of reversible liver failure or cholestatic hepatitis have been reported.

Dosage and Administration

When administered alone or combined with a subcutaneous or intranasal GnRH agonist analogue, the oral dosage of flutamide is 250mg 3 times daily in both newly diagnosed patients and those whose disease is refractory to hormonal manipulation.

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References

  • Airhart RA, Barnett TF, Sullivan JW, Levine RL, Schlegel JU. Flutamide therapy for carcinoma of the prostate. Southern Medical Journal 71: 798–801, 1978

    Article  PubMed  CAS  Google Scholar 

  • Ayub M, Levell MJ. Supression of plasma androgens by the antiandrogen flutamide in prostatic cancer patients treated with Zoladex: a GnRH analogue. Clinical Endorcrinology 32: 329–339, 1990

    Article  CAS  Google Scholar 

  • Béland G, Elhilali M, Fradet Y, Laroche B, Ramsey EW. Total androgen blockade for metastatic cancer of the prostate. Am. J. Clin. One. 11(Suppl. 2): S187–S190, 1988

    Article  Google Scholar 

  • Bélanger A, Labrie F, Dupont A, Brochu M, Cusan L. Endocrine effects of combined treatment with a LHRH agonist in association with flutamide in metastatic prostatic carcinoma. Clinical and Investigative Medicine 11: 321–326, 1988

    PubMed  Google Scholar 

  • Boccardo F. Treatment of prostatic cancer with LHRH analogues alone or in combination with pure antiandrogens. Abstract 147. Gynecological Endocrinology 4(Suppl. 2): 84, 1990

    Google Scholar 

  • Brochu M, Bélanger A, Dupont A, Cusan L, Labrie F. Effects of flutamide and aminoglutethimide on plasma 5-reduced steroid glucuronide concentrations in castrated patients with cancer of the prostate. Journal of Steroid Biochemistry 28: 619–622, 1987

    Article  PubMed  CAS  Google Scholar 

  • Brogden RN, Buckley MMT, Ward A. Buserelin: a review of its pharmacodynamic and pharmacokinetic properties, and clinical profile. Drugs 39: 399–437, 1990

    Article  PubMed  CAS  Google Scholar 

  • Brogden RN, Clissold SP. Flutamide: a preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in advanced prostatic cancer. Drugs 38: 185–203, 1989

    Article  PubMed  CAS  Google Scholar 

  • Chrisp P, Goa KL. Goserelin: a review of its pharmacodynamic and pharmacokinetic properties, and clinical use in sex hormone-related conditions. Drugs 41(2): 254–283, 1991

    Article  PubMed  CAS  Google Scholar 

  • Crawford ED, Eisenberger MA, McLeod DG, Spaulding JT, Benson R, et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. New England Journal of Medicine 321: 419–424, 1989

    Article  PubMed  CAS  Google Scholar 

  • Di Silverio F, Sciarra F, D’Eramo G. Advanced prostatic cancer: clinical and hormonal response to flutamide in patients pretreated with LHRH analogue and cyproterone acetate. European Urology 18: 10–15, 1990

    PubMed  Google Scholar 

  • Donn F, Becker H, Klosterhalfen H, Klein H. Effect of cyproterone acetate in comparison to flutamide on the ventral prostate of adult male castrated Copenhagen-Fisher rats and on Dunning R-3327 H tumors. Andrologia 21: 462–467, 1989

    Article  PubMed  CAS  Google Scholar 

  • El Etreby MF, Habenicht U-F, Louton T, Nishino Y, Schröder HG. Effect of cyproterone acetate in comparison to flutamide and megestrol acetate on the ventral prostate, seminal vesicle, and adrenal glands of adult male rats. Prostate 11: 361–375, 1987

    Article  PubMed  Google Scholar 

  • Ferrari P, Castagnetti G, Pollastri C, Ferrari G, Tavoni F, et al. LHRH analogue buserelin versus buserelin and flutamide in the treatment of advanced metastatic prostatic carcinoma: five years experience. Abstract 154. Gynecological Endrocrinology 4(Suppl.2): 87, 1990

    Google Scholar 

  • Flamm J, Fischer M. Komplette Androgenblockade (Orchiektomie + Flutamid) versus Androgenblockade mit Zytostase (Orchiektomie + Estramustin) in der Behandlung des virginellen fortgeschrittenen Prostatakarzinoms. Wiener Klinische Wochenschrift 100: 589–592, 1988

    PubMed  CAS  Google Scholar 

  • Fourcade RO, Cariou G, Coloby P, Colombel P, Coulange C, et al. Total androgen blockade in advanced prostate carcinoma: interim report of a double-blind study using Zoladex and flutamide. Abstract 158. Gynecological Endocrinology 4(Suppl. 2): 89, 1990

    Google Scholar 

  • Haefliger JM (on behalf of the International Prostate Cancer Study Group). A multicentre randomised trial comparing the LHRH analogue ‘Zoladex’ vs ‘Zoladex’ in combination with flutamide in the treatment of advanced prostate cancer. Abstract 155. Gynecological Endocrinology 4(Suppl. 2): 88, 1990

    Google Scholar 

  • Hart W, Strieker BHCh. Flutamide and hepatitis. Annals of Internal Medicine 110: 943–944, 1989

    PubMed  CAS  Google Scholar 

  • Holdaway I, Altwein JE, Klippel K-F, Lungmayr G, Tyrrell CJ, et al. A multicentre randomised trial comparing the LHRH agonist ‘Zoladex’ with ‘Zoladex’ in combination with flutamide in the treatment of advanced prostate cancer. Journal of Urology 143: 220A, 1990

    Google Scholar 

  • Iversen P (on behalf of the Danish Prostatic Cancer Group). DAPROCA 86 ‘Zoladex’ and flutamide versus orchiectomy for advanced prostatic cancer. Abstract 156. Gynecological Endocrinology 4(Suppl. 2): 88, 1990

    Google Scholar 

  • Iversen P, Christensen MG, Friis E, Hornbol P, Hvidt V, et al. A phase III trial of Zoladex and flutamide versus orchiectomy in the treatment of patients with advanced carcinoma of the prostate. Cancer 66(Suppl.): 1058–1066, 1990a

    PubMed  CAS  Google Scholar 

  • Iversen P, Suciu S, Sylvester R, Christensen I, Denis L. Zoladex and flutamide versus orchiectomy in the treatment of advanced prostatic cancer: a combined analysis of two European studies,EORTC 30853 and DAPROCA 86. Cancer 66(Suppl.): 1067–1073, 1990b

    PubMed  CAS  Google Scholar 

  • Jacobs E, Schmidt JD, Weinstein SH, Flocks RH. Comparison of flutamide (SCH13521) and diethylstilboestrol in untreated advanced prostatic cancer. Urology 8: 231–233, 1976

    Article  Google Scholar 

  • Johansson J-E, Lingärdh G, Andersson S-O, Zador G, Beckman K-W. Clinical evaluation of flutamide and estramustine as initial treatment of metastic carcinoma of prostate. Urology 29: 55–59, 1987

    Article  PubMed  CAS  Google Scholar 

  • Kassem NY, Neri RO. Flutamide in advanced cancer of the prostate. Abstract E1. Clin. Pharmacol. Ther. 31: 238, 1982

    Google Scholar 

  • Kassem NY, Neri RO, Muntol JS. Effect of flutamide, an antiandrogen on stage D cancer of the prostate. Abstract B-27. Clinical Pharmacology and Therapeutics 29: 256, 1981

    Google Scholar 

  • Katchen B, Buxbaum S. Disposition of a new, nonsteroid, antiandrogen, α,α,α-trifluoro-2-methyl-4′-nitro-m-propionotoluidide (flutamide), in men following a single oral 200mg dose. J. Clin. Endo. Metab. 41: 373–379, 1975

    Article  CAS  Google Scholar 

  • Katchen B, Dancik S, Millington G. Percutaneous penetration and metabolism of topical (14C) flutamide in men. Journal of Investigative Dermatology 66: 379–382, 1976

    Article  PubMed  CAS  Google Scholar 

  • de Kernion JN, Murphy GP, Priore R. Comparison of flutamide and emcyt in hormone-refractory metastatic prostatic cancer. Urology 31: 312–317, 1988

    Article  PubMed  Google Scholar 

  • Keuppens F, Denis L, Smith P, Pinto Carvalho A, Newling D, et al. Zoladex and flutamide versus bilateral orchiectomy: a randomised phase III EORTC 30853 study. Cancer 66(Suppl.): 1045–1057, 1990

    PubMed  CAS  Google Scholar 

  • Labrie F, Dupont A, Bélanger A. Complete androgen blockade for the treatment of prostate cancer. In De Vita VT et al. (Eds) Important advances in oncology, pp. 193–217, Lippincott, Philadelphia, 1985

    Google Scholar 

  • Labrie F, Dupont A, Bélanger A, Cusan L, Brochu M, et al. Anti-hormone treatment for prostate cancer relapsing after treatment with flutamide and castration. Addition of aminoglutethimide and low dose hydrocortisone to combination therapy. British Journal of Urology 63: 634–638, 1989b

    Article  PubMed  CAS  Google Scholar 

  • Labrie F, Dupont A, Cusan L, Giguere M, Bergeron N, et al. Combination therapy with flutamide and castration (LHRH agonist or orchiectomy) in previously untreated patients with clinical stage D2 prostate cancer: today’s therapy of choice. Journal of Steroid Biochemistry 30: 107–117, 1988

    Article  PubMed  CAS  Google Scholar 

  • Labrie F, Dupont A, Cusan L, Manhës G, Bergeron N, et al. Combination therapy with castration and flutamide: today’s treatment of choice for prostate cancer. Journal of Steroid Biochemistry 33: 817–821, 1989a

    Article  PubMed  CAS  Google Scholar 

  • Labrie F, Dupont A, Giguere M, Borsanyi J-P, Bélanger A, et al. Combination therapy with flutamide offers a 33% positive objective response in relapsing prostate cancer patients. Abstract. Anticancer Research 6: 338, 1986

    Google Scholar 

  • Labrie F, Dupont A, Giguere M, Borsanyi P, Lacourciere Y, et al. Combination therapy with flutamide and castration (orchiectomy or LHRH agonist): the minimal endocrine therapy in both untreated and previously treated patients. Journal of Steroid Biochemistry 27: 525–532, 1987

    Article  PubMed  CAS  Google Scholar 

  • Lacoste D, Dubé D, Bélanger A, Labrie F. Effect of 2-week combination therapy with the luteinizing hormone-releasing hormone (LHRH) agonist (D-Trp6, des-Gly-NH2 10) LHRH ethylamide and the antiandrogen flutamide on prostate structure and steroid levels in the dog. Molecular and Cellular Endocrinology 67: 131–138, 1989

    Article  PubMed  CAS  Google Scholar 

  • Leuprolide Study Group. Leuprolide versus diethylstilbestrol for metastatic prostate cancer. New England Journal of Medicine 311: 1281–1286, 1984

    Google Scholar 

  • Lund F, Rasmussen F. Flutamide versus stilboestrol in the management of advanced prostatic cancer: a controlled prospective study. British Journal of Urology 61: 140–142, 1988

    Article  PubMed  CAS  Google Scholar 

  • Lunglmayr G (on behalf of the International Prostate Cancer Study Group). ‘Zoladex’ versus ‘Zoladex’ plus flutamide in the treatment of advanced prostate cancer: first interim analysis of an international trial. Therapeutic Progress in Urological Cancers, pp. 145–151, 1989

    Google Scholar 

  • Mahler C, Pinto de`Carvalho A, Smith Ph, Newling D, Bono A, et al. Randomised study of orchietomy versus ‘Zoladex’ and flutamide in metastatic prostatic cancer. Abstract 142. Gynecological Endocrinology 4(suppl.2): 81, 1990

    Google Scholar 

  • McLeod DG, Blumenstein BA, Spicer D, Crawford ED, Eisenberger MA, et al. The use of flutamide in hormone-refractory metastatic prostate cancer. Abstract 130. Journal of Urology 143: 221A, 1990

    Google Scholar 

  • Millard OH, Givner ML. Preliminary results in thirty patients with stage D2 prostatic cancer treated by total androgen blockade. Journal of Drug Development 1(Suppl. 1): 26–33, 1987

    Google Scholar 

  • Møller S, Iversen P, Franzmann M-B. Flutamide-induced liver failure. Journal of Hepatology 10: 346–349, 1990

    Article  PubMed  Google Scholar 

  • Neri R. Pharmacology and pharmacokinetics of flutamide. Urology 34(Suppl.): 19–56, 1989

    Article  PubMed  CAS  Google Scholar 

  • Neri B, Bartalucci S, Pieri A, Gemelli MT, Rizzo M, et al. Complete androgen blockade as treatment for advanced prostate cancer: clinical response and side effects. Anticancer Research 9: 13–16, 1989

    PubMed  CAS  Google Scholar 

  • Neri R, Kassem N. Biological and clinical properties of antiandrogens. In Bresciani et al. (Eds) Progress in cancer research and therapy, Vol. 31, pp. 507–518, Raven Press, New York, 1984

    Google Scholar 

  • Neumann F, Gräf K-J, Hasan SH, Schenck B. Steinbeck H. Central actions of antiandrogens. In Martini & Motta (Eds) Androgrens and antiandrogens, pp. 163–177, Raven Press, New York, 1977

    Google Scholar 

  • Newling DWW. Use of flutamide as monotherapy in the treatment of advanced prostate cancer. Therapeutic Progress in Urological Cancers, pp.117–121, 1989

    Google Scholar 

  • Olea N, Sakabe K, Soto AM, Sonnenschein C. The proliferative effect of ‘anti-androgens’ on the androgen-sensitive human prostate tumor cell line LNCaP. Endocrinology 126: 1457–1463, 1990

    Article  PubMed  CAS  Google Scholar 

  • Pinto Carvalho A, Carneiro de Moura JL, Denis L, Newling D, Smith Ph. “Zoladex” and flutamide vs orchidectomy: a phase III EORTC 30853 trial. In Therapeutic progress in urological cancers, pp. 129–143, Alan R. Liss Inc., 1990

    Google Scholar 

  • Prout GR, Keating MA, Griffen PP, Schiff SF. Long-term experience with flutamide in patients with prostatic carcinoma. Urology 34(Suppl.): 37–45, 1989

    Article  PubMed  Google Scholar 

  • Radwanski E, Perentesis G, Symchowicz S, Zampaglione N. Single and multiple dose pharmacokinetic evaluation of flutamide in normal geriatric volunteers. Journal of Clinical Pharmacology 29: 554–558, 1989

    PubMed  CAS  Google Scholar 

  • Schulz M, Schmeldt A, Donn F, Becker H. The pharmacokinetics of flutamide and its major metabolites after a single oral dose and during chronic treatment. European Journal of Clinical Pharmacology 34: 633–636, 1988

    Article  PubMed  CAS  Google Scholar 

  • Secreto G, Recchione C, Zambetti M, Fariselli G, Ballerini P. Hormonal changes induced by the pure antiandrogen flutamide in postmenopausal women with advanced breast cancer. Europ. J. Cancer Clin. One. 24: 867–872, 1988

    Article  CAS  Google Scholar 

  • Simard J, Luthy I, Guay J. Belanger A, Labrie F. Characteristics of interaction of the antiandrogen flutamide with the androgen receptor in various target tissues. Molecular and Cellular Endocrinology 44: 261–270, 1986

    Article  PubMed  CAS  Google Scholar 

  • Smith Ph, Denis L, Carneiro De Moura JL, Newling D, Bono A, et al. ZoladexR and flutamide versus bilateral orchiectomy: a randomised phase III trial 30853 study. Abstract 19. European Journal of Cancer 143: 151, 1990

    Google Scholar 

  • Snycerski A. Polarographic determination of flutamide. Journal of Pharmaceutical and Biomedical Analysis 7: 1513–1518, 1989

    Article  PubMed  CAS  Google Scholar 

  • Soret JY, Verine JL, Daver A, Labrie F. Levels of intraprostatic androgen receptors and intraprostatic testosterone following orchiectomy with or without addition of an antiandrogen (flutamide) in the treatment of advanced prostatic cancer. Journal of Drug Development 1(Suppl. 1): 23–25, 1987

    Google Scholar 

  • Symes EK, Milroy EJG, Mainwaring WIP. The nuclear uptake of androgen by human benign prostate in vitro: action of antiandrogens. Journal of Urology 120: 180–183, 1978

    PubMed  CAS  Google Scholar 

  • Tyrrell CJ. A multicentre randomised trial comparing the LHRH agonist ‘Zoladez’ with ‘Zoladex’ in combination with flutamide in the treatment of advanced prostate cancer. European Journal of Cancer 143: 151, 1990

    Google Scholar 

  • Waxman J. Short term anti-androgen therapy and very long-acting depot gonadotrophin-releasing hormone agonist for prostatic cancer. Therap. Prog. Urolog. Cancer, pp. 61–68, 1989

    Google Scholar 

  • Waxman J, Man A, Hendry WF, Whitfield HN, Besser GM, et al. Importance of early tumour exacerbation in patients treated with long acting analogues of gonadotrophin releasing hormone for advanced prostatic cancer. British Medical Journal 291: 1387–1388, 1985

    Article  PubMed  CAS  Google Scholar 

  • Yagoda A. Flutamide-induced diarrhea secondary to lactose intolerance. Correspondence. J. Nat. Cancer Ins. 81: 1989

    Google Scholar 

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    Rex N. Brogden & Paul Chrisp

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Various sections of the manuscript reviewed by: G. Bonadonna, Divison of Medical Oncology, Istituto Nazionale per lo Studio e la Cura Dei Tumori, Milan, Italy; E.D. Crawford, Division of Urology, University of Colorado Health Sciences Center, Denver, Colorado, USA; B.J. Cusack, Veterans Administration Medical Center, Boise, Idaho, USA; I.M. Holdaway, Section of Endocrinology, Auckland Hospital, Auckland, New Zealand; R.P. Hubert, Department of Urologic Oncology, Roswell Park Memorial Institute, Buffalo, New York, USA; G.P. Murphy, American Cancer Society, Atlanta, Georgia, USA; S.D. Perrapato, Department of Urologic Oncology, Roswell Park Memorial Institute, Buffalo, New York, USA; J.E. Phister, Veterans Administration Medical Center, Boise, Idaho, USA; F. Rasmussen, Department of Urology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.

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Brogden, R.N., Chrisp, P. Flutamide. Drugs & Aging 1, 104–115 (1991). https://doi.org/10.2165/00002512-199101020-00003

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