Casodex Overview

I. Pharmacology

Casodex or bicalutamide is a pure anti-androgen. It is an analogue of Flutamide. A comparison of Casodex with Flutamide is shown below.

In animal studies Casodex had a fourfold greater affinity for the androgen receptor (AR) than the active metabolite of Flutamide(2-hydroxy flutamide).[1]

A recent study showed that various growth factors could activate the androgen receptor (AR) in the absence of androgens. In other words, growth factors such as IGF-1 (insulin growth factor), KGF (keratinocyte growth factor) and EGF (epidermal growth factor) were able to directly activate the AR in the absence of androgen. In the LnCaP cell line EGF was able to increase PSA secretion 5-fold. AR activation by EGF, IGF-1 and KGF was completely inhibited by Casodex. This finding may be important in the prevention of progression of PC to an androgen-independent stage since aberrant activation of the androgen receptor may be one of the mechanisms involved in this process.[2]

In another study using LNCaP cell lines investigators were able to show a stimulatory effect of progestins, estrogens and some anti-androgens as a result of their binding to a mutated androgen receptor protein in the ligand binding domain. Interestingly all of these agents were also shown to increase IGF-1 receptor levels. Casodex however did not induce such changes. This may have a bearing on the development of tumor escape from hormone blockade.[3]

II. Clinical Trials

1. Combination Therapy

In a trial of Casodex vs Flutamide combined with an LHRH agonist, Schelhammer et al reported a lower incidence of treatment failure with the Casodex combination. In this trial involving 813 patients, patients were randomized to either Casodex or Flutamide and Lupron or Zoladex. With a median duration of 49 weeks, time to treatment failure was significantly better (P=0.005) for the Casodex + LHRH arm than for the Flutamide + LHRH group. Patients in the Flutamide + LHRH group were 34% more likely to fail treatment over the given time period. All pateints treated had stage D-2 disease. Of interest is that both anti-androgen and LHRH agonist were initiated on the same day despite the published literature indicating the need to start anti-androgens prior to the LHRH agonist. The authors also included in their definition of treatment failure those patients who were withdrawn from the study due to side-effects of the anti-androgen. This resulted in 24 more patients being considered treatment failures solely due to adverse or side-effects, especially diarrhea. 25 patients on Flutamide withdrew from the study compared to 2 using Casodex. Treatment failure also included progression of disease and death. Using these definitions, treatment failure occurred in 168 of 404 patients(42%) in the Casodex + LHRH arm compared to 218 of 409 patients(53%) in the Flutamide + LHRH arm. Significantly there were more treatment failures for progressive events- 98 in the Flutamide arm compared to 73 in the Casodex arm.[4]

2. Monotherapy

Kasimis et al studied 150 patients with stage D-2 PC using monotherapy with 50 mg per day of Casodex. Although 70% of men had an objective response, the median time to treatment failure was only 34 weeks. Breast tenderness occurred in 75% of men and gynecomastia in 55%.[5] In a study of 23 patients receiving 150 mg of Casodex daily as monotherapy, the LH, testosterone and estradiol levels rose with a mean increase after 24 weeks of 102%, 66% and 66% respectively.[6]

III. Side-effects

In a study involving over 3,000 men treated with Casodex, the most commonly reported adverse events (AE) were breast tenderness, gynecomastia and hot flushes. Only 0.3% of patients had to be taken off Casodex for liver function changes. No clinically significant changes in liver function tests was seen. This study used Casodex as monotherapy; therefore the breast tenderness and gynecomastia should decrease or disappear with the addition of a LHRH agonist.[7]

The incidence of diarrhea in patients treated with Casodex + LHRH agonist vs Flutamide + LHRH agonist was 10% compared to 24% respectively.[4]

IV. High-dose Casodex in patients with an anti-androgen withdrawal response

In a very preliminary report [8], high-dose Casodex was used in 3 patients who had shown a response to anti-androgen withdrawal. The anti-androgen that had been used was Flutamide. The dose of Casodex was 200 mg per day. Two patients of the three showed significant declines of PSA i.e. 93% and 98%. The duration of response was not indicated. This response to high-dose Casodex in the setting of AAWR after discontinuation of Flutamide is consistent with the differential effects of Flutamide vs Casodex on induction of mutation of the AR(androgen receptor). Induction of point mutation of the AR appears to be related to Flutamide and not seen with Casodex. Confirmation of these early reports will be important.

REFERENCES

1. Furr BJ: Casodex- a new, pure, peripherally-selective anti-androgen: preclinical studies. Horm Res 32(suppl 1): 69-76, 1989.
2. Culig Z, Hobisch A, Cronauer MV, et.al. Androgen receptor activation in prostatic tumor cell lines by insulin-like growth factor, keratinocyte growth factor, and epidermal growth factor. Ca Res 54(20):5474-8, 1994.
3. Veldscholte J, Berrevoets CA, Ris-Stalpers C, et. al. The androgen receptor in LNCaP cells contains a mutation in the ligand binding domain which affects steroid binding characteristics and response to antiandrogens. J Steroid Bio Mol Biol, 41(3-8):665-9, 1992.
4. Schelhammer P, Sharifi R, Blcok N et al. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate cancer. Urology 45(5):745-52, 1995.
5. Kasimis B, Ahmann R, Schellhammer P, et. al. Phase II evaluation of Casodex in stage D2 prostate cancer. Proc Am Soc Clin Oncol 11:218, 1992.
6. Verhelst J, Denis L, Van Vliet P, Endocrine profiles during administration of the new non-steroidal anti-androgen Casodex in prostate cancer. Clin Endo 41(4):525-30, 1994.
7. Tyrrell CJ: Tolerability and quality of life aspects with the anti-androgen Casodex as monotherapy for prostate cancer. International Casodex Investigators. Eur Urol 26 (1):9-15, 1994.
8. Liebertz Casodex, Kelly WK, Theodoulou M, et. al. High dose Casodex for prostate cancer(PC): PSA declines in patients(PTS) with Flutamide withdrawal responses. Proc Am Soc Clin Oncol 14:232, 1995.
   
    
   
    

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