Necessary for the Use of Luteinizing Hormone-Releasing Hormone

Proc. Nati. Acad. Sci. USA Vol. 81, pp. 3861-3863, June 1984 Medical Sciences

Simultaneous administration of pure antiandrogens, a combination necessary for the use of luteinizing hormone-releasing hormone agonists in the treatment of prostate cancer (testosterone/prostatic acid phosphatase/androgen dependence/medical castration/disease flare) FERNAND LABRIE*, ANDRE DuPONT*, ALAIN BtLANGER*, JEAN EMONDt, AND GE-RARD MONFETTEt *Departments of Medicine and Molecular Endocrinology, Le Centre Hospitalier de l'Universitd Laval, Quebec G1V 4G2, PQ Canada; tH6tel-Dieu Hospital, Ldvis, PQ Canada; and fHotel-Dieu Hospital, St-Jdr6me, Quebec, PQ Canada

Communicated by Choh Hao Li, February 13, 1984

ABSTRACT Although castration levels of serum andro- increase in serum androgens is accompanied by disease gens are consistently achieved after 2-3 weeks of treatment flare-up in a significant proportion of cases (9), thus serious- with luteinizing hormone-releasing hormone (LHRH) ago- ly limiting the use of LHRH agonists alone in treating pros- nists, the administration of these peptides alone in adult men is tate cancer, at least during the first 2 weeks of treatment. always accompanied by a transient increase in plasma testos- The present study shows that the simultaneous adminis- terone and dihydrotestosterone levels, which lasts for 5-15 tration of a pure antiandrogen neutralizes the influence of days at the beginning of treatment and is accompanied by dis- increased levels of serum androgens induced by the LHRH ease flare-up in some cases, thus seriously limiting the accept- agonist during the first days of treatment, as illustrated by ability of this otherwise efficient and well-tolerated treatment. the rapid and marked decrease in serum prostatic acid phos- The present data show that the simultaneous administration of phatase, a marker of prostate cancer cell activity. a pure antiandrogen neutralizes the influence of the transient increase in serum androgens on prostate cancer, as indicated MATERIALS AND METHODS by the 60% decrease in serum prostatic acid phosphatase ob- Patients. Twenty patients with biopsy-proven prostate served within 5 days of combined treatment with an LHRH adenocarcinoma took part in this study, after written in- agonist and a pure antiandrogen. The addition of a pure anti- formed consent. Eleven patients had bone metastases (stage androgen thus makes fully acceptable the use of LHRH ago- D2 disease); nine patients had stage C disease. After the ap- nists as an advantageous substitute for surgical castration and propriate clinical, urological, biochemical, hematological, estrogens in the treatment of prostate cancer. and radiological tests (7), the patients received a daily subcutaneous injection at 0800 hours of 500 Ag of the LHRH ago- Cancer of the prostate is the second cause of death due to nist [D-Ser(But)6]des-Gly-NH210]-LHRH ethylamide (Buser- cancer in men, with an estimated minimum of 60,000 newly elin); 100 mg of the antiandrogen (5,5-dimethyl-3[4-nitro-3- diagnosed cases annually in the United States. After the pio- (trifluoromethyl)phenyl]-24-imidazolidinedione (Anandron; neering studies of Huggins and Hodges (1), most of the ef- RU-23908) was given orally at 0700, 1500, and 2300 hours. forts during the last 40 years have been aimed at eliminating The antiandrogen was given 1 day before first administration the influence of testicular androgens on the growth of the of the LHRH agonist (day 0). cancer by surgical castration or by treatment with estrogens, Methods. Blood samples were taken at days -2, -1, 0, 1, which causes a decrease in circulating androgens. Such 2, 5, 14, and 30 for measurement of serum levels of testoster- treatments provide a temporary objective and/or subjective one, dihydrotestosterone, and prostatic acid phosphatase by improvement in 60%-70% of cases of advanced prostate can- double-antibody radioimmunoassays (7, 11). Radioim- cer (2, 3). However, surgical castration is not always well munoassay data were analyzed using a program based on accepted by patients, and treatment with estrogens causes model II of Rodbard and Lewald (12). Statistical significance serious cardiovascular complications, which often offset the was measured according to the multiple-range test of Dun- benefits (4). There was thus the need for a more acceptable, can-Kramer (13). Results are shown as the means ± SEM of well-tolerated, and possibly more efficient form of hormonal duplicate determinations of individual samples. A series of therapy. laboratory analyses, including complete and differential The observation that treatment of experimental animals blood count, sequential multiple analyzer (SMA-12), and uri- with luteinizing hormone-relasing hormone (LHRH) ago- nalysis, were performed. No side-effects that could be at- nists causes a marked inhibition of testosterone secretion, tributed to Buserelin or Anandron were noticed, except for accompanied by a decrease in prostate weight (5), offered those related to hypoandrogenecity. the possibility of a new approach in the treatment of prostate Materials. The LHRH agonist Buserelin was supplied by cancer. Fortunately, among the species studied, man is the the Medical Department, Hoechst Canada (Montreal), most sensitive to the inhibitory action of LHRH agonists on through the courtesy of A. T. A. Fazekas; the antiandrogen testicular androgen formation, and thus medical castration Anandron was supplied by J. Gareau (Roussel Canada, Mon- can be easily achieved (5-10). Although the chronic adminis- treal). Material obtained from New England Nuclear was tration of these peptides in adult men completely blocks tes- used for measurement of prostatic acid phosphatase by dou- ticular androgen formation with no secondary effects other ble-antibody radioimmunoassay. than those related to hypoandrogenicity, a serious limitation pertains to the transient increase in serum androgen levels, RESULTS AND DISCUSSION which lasts for 5-15 days at the beginning of treatment. This As illustrated in Fig. 1, increased levels of serum testosterone up to 200% above control are observed during the first days of daily subcutaneous treatment in four representative The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. Abbreviation: LHRH, luteinizing hormone-releasing hormone. 3861 Downloaded by guest on October 1, 2021 3862 Medical Sciences: Labrie et al. Proc. NatL Acad Sci. USA 81 (1984)

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0 0 0 1 8 1'5 22 29 1 8 15 22 29 Days of treatment FIG. 1. Representative changes in serum testosterone (-) and prostatic acid phosphatase (----) concentrations during the first month of combined treatment with an LHRH agonist and a pure antiandrogen in four patients having stage D2 prostate cancer. Note the rapid and marked decrease in serum prostatic acid phosphatase in the presence of increased serum testosterone levels, thus indicating the efficiency of the antiandrogen. Blood samples were obtained at 0800 hours, 24 hr after last administration of the LHRH agonist. patients receiving 500 ,pg of the LHRH agonist. A maximal 100- increase in serum androgen levels is usually found 3-5 days after starting treatment. After this initial increase in serum testosterone, near-castration levels are then achieved 2-4 80- weeks after treatment. At time intervals >4 weeks, castra- Li ztion levels of serum testosterone and dihydrotestosterone are maintained for up to 3 years, the longest time interval ° -o 60 - studied. C o At The important finding in the present study is that the serum prostatic acid phosphatase concentration, which was el- < 40- evated before treatment in these 20 patients showed a very C\ rapid and marked decrease after initiation of the combined 0to therapy. In fact, serum prostatic acid phosphatase levels are 20- decreased by 60% as early as 5 days after starting treatment, at a time when serum testosterone levels are maximally increased (Figs. 1 and 2). 0- l It is now well recognized that chronic treatment with LHRH agonists is an efficient and extremely well-tolerated 10- + way to achieve medical castration, thus offering an advantageous alternative to surgical castration and estrogens. The 8- rationale for treatment of prostatic carcinoma with LHRH agonists is to mimic the effects of castration or DES on serum androgen levels. However, it was observed in an adult C 2 \ man treated with a high dose of an LHRH agonist (6), and 6 1 P \ confirmed in subsequent studies (7-10), that increased levels oC \ of serum testosterone and dihydrotestosterone are always a, o 4- \ found during the first days of treatment. Unfortunately, these high levels of serum androgens can cause disease flare- H - up in a significant proportion of patients having advanced 2- prostate cancer (9). The well-known high androgen sensitiv- ity of prostate cancer and the risk of a disease flare-up at the

0- cancer receiving the combined therapy with an LHRH agonist and a -4 0 4 8 12 16 20 24 28 32 pure antiandrogen. Data are presented as means + SEM of duplicate Days of treatment determinations of 20 individual samples. No disease flare-up was observed in any of the patients and subjective improvement, espe- FIG. 2. Time course of changes of serum testosterone and pros- cially decrease of pain, was observed within the first 2-5 days of tatic acid phosphatase levels in 20 patients with advanced prostate treatment. Downloaded by guest on October 1, 2021 Medical Sciences: Labrie et al. Proc. Natl. Acad. Sci. USA 81 (1984) 3863

initiation of treatment seriously limit the use of LHRH ago- 3. Resnick, M. I. & Grayhack, J. T. (1975) Urol. Clin. North Am. nists alone in patients with advanced prostate cancer, at 2, 141-161. least during the first 2 weeks of treatment. 4. Byar, D. P. (1973) Cancer 32, 1126-1130. A solution is offered by the present study, which clearly 5. Labrie, F., Auclair, C., Cusan, L., Kelly, P. A., Pelletier, G. & Ferland, L. (1978) Int. J. Androl., Suppl. 2, 303-318. demonstrates that simultaneous administration of a pure an- 6. Labrie, F., B61anger, A., Cusan, L., Sdguin, C., Pelletier, G., tiandrogen at a relatively low dose completely blocks the in- Kelly, P. A., Lefebvre, F. A., Lemay, A. & Raynaud, J. P. fluence of the transient increase in serum androgens on the (1980) J. Androl. 1, 209-228. activity of prostate cancer, as reflected by serum prostatic 7. Labrie, F., Dupont, A., Bdlanger, A., Cusan, L., Lacourciere, acid phosphatase levels as well as by parallel changes of the Y., Monfette, G., Laberge, J. G., Emond, J. P., Fazekas, clinical response. No secondary effects other than those re- A. T. A., Raynaud, J. P. & Husson, J. M. (1982) J. Clin. In- lated to hypoandrogenicity (loss of libido and hot flashes in vest. Med. 5, 267-275. 50% of cases) were noted. The rapid and marked decrease in 8. Labrie, F., Dupont, A. & Belanger, A. (1984) in Important Ad- serum prostatic acid phosphatase observed during the first vances in Oncology, eds. De Vita, V. T., Jr., Hellman, S. & Rosenberg, S. A. (Lippincott, Scranton, PA), in press. days of combined therapy with the antiandrogen and the 9. Trachtenberg, J. (1983) J. Urol. 129, 1149-1152. LHRH agonist clearly indicates that the antiandrogen effi- 10. Tolis, G., Ackman, D., Stellos, A., Mehta, A., Labrie, F., Fa- ciently neutralizes the elevated levels of serum testosterone zekas, A. T. A., Comaru-Schally, A. M. & Schally, A. V. and dihydrotestosterone induced by the LHRH agonist on (1982) Proc. Natl. Acad. Sci. USA 79, 1658-1662. the cancer. 11. B6langer, A., Caron, S. & Picard, V. (1980) J. Steroid Bio- chem. 13, 185-190. 12. Rodbard, D. & Lewald, J. E. (1970) in Second Karolinska 1. Huggins, C. & Hodges, C. V. (1941) Can Res. 1, 293-297. Symposium on Research Methods in Reproductive Endocrinol- 2. Nesbit, R. M. & Baum. W. C. (1950) J. Am. Med. Assoc. 143, ogy (Bogtrykleriet Forum, Copenhagen), pp. 79-103. 1317-1320. 13. Kramer, C. Y. (1956) Biometrics 12, 307-310. Downloaded by guest on October 1, 2021