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The effect of finasteride in men with benign prostatic hyperplasia
0022-5347/02]1672-1102/0 THEJOU~'~ALOFUROLOO'~ Copyright© 2002 by AMERICIuNUROLOGICAL ASSOCIATION,INC.@
Vol. 167, 1102-1107,February 20( Printed in U.S,
THE EFFECT OF FINASTERIDE IN MEN WITH BENIGN PROSTATIC HYPERPLASIA GLEEN J. GORMLEY, M.D., PH.D., ELIZABETH STONER, M.D., REGINALD C. BRUSKEWITZ, M.D., JULIANNE IMPERATO-MCGINLEY,M.D., PATRICK C. WALSH, M.D., JOHN D. MCCONNELL, M.D., GERALD L. ANDRIOLE, M.D., JACK GELLER, M.D., BRUCE R. BRACKEN, M.D., JOYCE S. TENOVER, M.D., PH.D.,
E. DARRACOTTVAUGHAN, M.D., FRANCES PAPPAS, M.S., ALICE TAYLOR, M.S., BRUCE BINKOWITZ, M.S., AND JENNIFER NG, S.D., FOR THE FINASTERIDE STUDY GROUP (Reprinted with permission from N Engl J Med, 327: 1185-1191, 1992)
ABSTRACT
Background. Benign prostatic hyperplasia is a progressive, androgen-dependent disease resulting in enlargement of the prostate gland and urinary obstruction. Preventing the conversion of testosterone to its tissue-active form, dihydrotestosterone, by inhibiting the enzyme 5areductase could decrease the action of androgens in their target tissues; in the prostate the result might be a decrease in prostatic hyperplasia and therefore in symptoms of urinary obstruction. Methods. In a double-blind study, we evaluated the effect of two doses offinasteride (1 mg and 5 mg) and placebo, each given once daily for 12 months, in 895 m e n with prostatic hyperplasia. Urinary symptoms, u r i n a r y flow, prostatic volume, and serum concentrations of dihydrotestosterone and prostate-specific antigen were determined periodically during the t r e a t m e n t period. Results. As compared with the men in the placebo group, the men treated with 5 mg of finasteride per day had a significant decrease in total urinary-symptom scores (P <0.001), an increase of 1.6 ml per second (22 percent, P <0.001) in the maximal urinary-flow rate, and a 19 percent decrease in prostatic volume (P <0.001). The men treated with 1 mg of finasteride per day did not have a significant decrease in total urinary-symptom scores, but had an increase of 1.4 ml per second (23 percent) in the maximal urinary-flow rate, and an 18 percent decrease in prostatic volume. The men given placebo had no changes in total urinary-symptom scores, an increase of 0.2 ml per second (8 percent) in the maximal urinary-flow rate, and a 3 percent decrease in prostatic volume. The frequency of adverse effects in the three groups was similar, except for a higher incidence of decreased libido, impotence, and ejaculatory disorders in the finasteride-treated groups. Conclusions. The t r e a t m e n t of benign prostatic hyperplasia with 5 mg of finasteride per day results in a significant decrease in symptoms of obstruction, an increase in urinary flow, and a decrease in prostatic volume, but at a slightly increased risk of sexual dysfunction. Benign prostatic hyperplasia is common in aging men. The resulting enlargement of the prostate gland can lead to urethral obstruction and even complete urinary retention. 1-a The standard treatmefit is surgical resection of the prostate,4 and there has been no effective medical therapy. Androgens are required to maintain the size and function of the prostate in men. The prostate does not become enlarged in boys castrated before puberty, and androgen deprivation leads to a reduction in the size of the prostate.S, GThe androgen primarily responsible for prostatic growth and enlargement is dihydrotestosterone. Men who have 5areductase deficiency7,s and who therefore cannot convert testosterone to dihydrotestosterone have poor prostatic growth, although some other tissues are responsive to testosterone alone. A compound that selectively inhibited 5a-reductase
could therefore provide an effective treatment for benign prostatic hyperplasia while causing less severe androgen de ficiency in other tissues than do less selective approaches. 9,1 Finasteride is a competitive inhibitor of 5a-reductase. 9 Ad ministration of this drug for short periods results in de creased serum dihydrotestosterone concentrations, a reduc tion in the size of the prostate, and improvement in urinary flow rate. 1°-14 The purpose of this study was to evaluate th~ safety and efficacy of the administration of finasteride for 1', months in a large number of men with benign prostati hyperplasia. METHODS
Subjects This was a multicenter, double-blind, placebo-controllec E.S., F.P., A.T., B.B., J.N.); University of Wisconsin, Madison (R.C.B.); New YorkHospital, New York (J.I.-M., E.D.V.); Johns Hop- study conducted at 25 centers in the United States and kins Hospital, Baltimore (P.C.W.); University of Texas, Dallas centers in Canada. The study was approved by the institu (J.D.M.); WashingtonUniversity, St. Louis (G.L.A.);MercyHospital and Medical Center, San Diego, Calif. (J.G.); University of Cincin- tional review board at each center, and all the men gaw nati Medical Center, Cincinnati (B.R.B.); and Harborview Medical written informed consent. A total of 895 men ranging in ag~ Center, Seattle (J.S.T.). Address reprint requests to Dr. Gormleyat from 40 to 83 years who had benign prostatic hyperplasi~ Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065. * The members of the Finasteride Study Group are listed in the were enrolled in the study. All the men had some symptom~ Appendix. of urinary obstruction, an enlarged prostate gland on digita 1102 From the Merck Research Laboratories, Rahway, N.J. (G.J.G.,
1103
FINASTERIDE FOR BENIGN PROSTATIC HYPERPLASIA rectal e x a m i n a t i o n , and m a x i m a l urinary-flow r a t e s o f less t h a n 15 ml p e r second (with a voided volume of 150 m l or more). Men w i t h v e r y low urinary-flow r a t e s were n o t excluded, u n l e s s t h e y were considered to be a t r i s k for total u r i n a r y obstruction. A n y m a n whose rectal e x a m i n a t i o n suggested the p r e s e n c e of prostatic cancer was r e q u i r e d to h a v e a biopsy w i t h negative r e s u l t s for e n t r y into t h e study. Men with a r e s i d u a l u r i n a r y volume of more t h a n 350 ml, a s e r u m prostate-specific-antigen concentration of >-40 p g p e r liter, or evidence of p r o s t a t i c cancer, u r i n a r y t r a c t infection, chronic prostatitis, or neurogenic b l a d d e r were excluded.
Table 1. Reasons for Withdrawal from the Finasteride Study.* R F~S ON FOR
5 MG FINASTERIDE 1 MG FINASTERIDE PLACEBO
~VITIIDIL~WAL
(N = 297)
(N = 298)
(N = 300)
number (percent)
Adverse effects 16 (5) 14 (5) 18 (6) Lack of efficacy 12 (4) 4 (1) 9 (3) Unknownt 3 (1) 2 (1) 4 (1) Other 9 (3) 8 (3) 6 (2) Total 40 (13) 28 (9) 37 (12) * Because ofrounding, the percentages may not add up to the totals. t The patients were lost to follow-up.
Study P r o t o c o l After a two-week period d u r i n g which the m e n received a placebo in single-blind fashion, t h e y were r a n d o m l y a s s i g n e d in a double-blind fashion to one of t h r e e t r e a t m e n t groups: 297 were a s s i g n e d to receive a 5-rag t a b l e t of f i n a s t e r i d e daily, 298 to receive a 1-mg t a b l e t of f i n a s t e r i d e daily, and 300 to receive a placebo t a b l e t each day. The t a b l e t s were t a k e n once each d a y for 12 months. E a c h m a n w a s e v a l u a t e d m o n t h l y by t h e s a m e investigator, a t which t i m e u r i n a r y symptoms, side effects, a n d the degree of compliance w i t h t h e t r e a t m e n t r e g i m e n were a s s e s s e d a n d the urinary-flow r a t e and r e s i d u a l u r i n a r y volume w e r e m e a s u r e d . P r o s t a t i c volu m e was m e a s u r e d at b a s e line a n d a f t e r 6 a n d 12 m o n t h s of t r e a t m e n t . I n addition, each m a n h a d a complete o p h t h a l m o logic e x a m i n a t i o n a t base line a n d after 12 m o n t h s . E v e r y t h r e e m o n t h s , s e r u m a m i n o - t r a n s f e r a s e s , u r e a nitrogen, creatinine, sodium, potassium, calcium, a n d glucose w e r e m e a s u r e d a n d a complete blood count was performed. A f t e r m o n t h 12, t h e m e n could e n t e r a n open s t u d y in which t h e y received 5 m g of f i n a s t e r i d e daily. Compliance w i t h t r e a t m e n t was excellent as d e t e r m i n e d b y counting t h e n u m b e r of t a b l e t s r e m a i n i n g a t each visit a n d by periodic m e a s u r e m e n t s of s e r u m d i h y d r o t e s t o s t e r e n e concentrations. D u r i n g t h e study, 40 (13 percent) of t h e m e n in t h e group receiving 5 m g o f f i n a s t e r i d e , 28 (9 percent) of those receiving 1 m g of f i n a s t e r i d e , and 37 (12 percent) of those receiving placebo w i t h d r e w from t h e s t u d y for t h e reasons shown in Table 1. Evaluation Procedures T h e p a t i e n t s ' s y m p t o m s were a s s e s s e d on t h e basis of t h e i r responses to a q u e s t i o n n a i r e m o d i f e d from t h a t of B o y a r s k y et al. is T h e total s y m p t o m score was calculated from t h e responses to n i n e questions a b o u t u r i n a r y h e s i t a n c y , t e r m i n a l dribbling, i m p a i r m e n t of~the size a n d force of t h e u r i n a r y s t r e a m , i n t e r r u p t i o n of u r i n a t i o n , incomplete e m p t y i n g , urgency, d y s u r i a , clothes wetting, a n d s t r a i n i n g or p u s h i n g to s t a r t u r i n a r y flow. Each s y m p t o m was scored according to a five-point scale, w i t h a score of 0 i n d i c a t i n g t h e a b s e n c e of a s y m p t o m a n d a score of 4 t h e presence of a severe s y m p t o m , so t h a t the w o r s t possible score was 36. The total score was divided into two subgroups: one covering changes due to obstructive u r o p a t h y and t h e o t h e r covering changes involving n o n o b s t r u c t i v e u r o p a t h y . The o b s t r u c t i v e - u r o p a t h y score w a s c a l c u l a t e d from the r e s p o n s e to t h e first five questions, a n d t h e n o n o b s t r u c t i v e - u r o p a t h y score was c a l c u l a t e d from t h e r e s p o n s e to t h e l a s t four questions. T h e s y m p t o m score was v a l i d a t e d in studies of n o r m a l m e n a n d m e n w i t h benign p r o s t a t i c h y p e r p l a s i a before a n d after t r a n s u r e t h r a l resection of t h e prostate. The m e a n ( ± S D ) score in t h e 20 n o r m a l m e n was 0.9 --- 1.8 ( u n p u b l i s h e d data). The m e a n score among 20 m e n s t u d i e d in t h e office of a urologist before a n d 1 to 3 m o n t h s a f t e r s u r g e r y d e c r e a s e d from 10.9 - 5.9 to 3.7 - 3.8, a n d it decreased from a preoperative m e a n of 8.1 -+ 3.5 to 4.4 ± 3.6 among 7 m e n who responded to a questionnaire mailed 12 months after surgery. U r i n a r y - o u t f l o w obstruction w a s m e a s u r e d w i t h a u r i n a r y
flow-meter (Urodyn 1000, Dantec, Mahwah, N.J.). I n n o r m a l men, the m a x i m a l u r i n a r y flow exceeded 15 ml p e r second and t h e i r m e a n u r i n a r y flow was more t h a n 6.9 ml p e r second. 16 M e a s u r e m e n t s of m a x i m a l a n d m e a n urinary-flow r a t e s were used in t h e a n a l y s e s only if a t l e a s t 150 ml of u r i n e was excreted. A p p r o x i m a t e l y 9 percent of t h e urinary-flow m e a s u r e m e n t s w e r e excluded on this basis. R e s i d u a l u r i n a r y volume was m e a s u r e d b y t r a n s a b d o m i n a l u l t r a s o n o g r a p h y . P r o s t a t i c volume was m e a s u r e d by m a g n e t i c r e s o n a n c e i m a g i n g a t base line a n d after 3, 6, a n d 12 m o n t h s of t r e a t ment. M e a s u r e m e n t s were m a d e in t h e axial, sagittal, a n d coronal planes, a n d t h e volume of the p r o s t a t e was c a l c u l a t e d according to the following formula: volume (in milliliters) = ( 4 / 3 ) ~ a x i a l value/2)(coronal value/2)(sagittal value/2). W i t h the use of this a p p r o a c h t h e m e a n (-+SD) p r o s t a t i c volume in 23 m e n r a n g i n g in age from 31 to 50 y e a r s (mean, 41) with no u r i n a r y s y m p t o m s w a s 25 ± 19 ml. Laboratory Tests S e r u m t e s t o s t e r o n e a n d d i h y d r o t e s t o s t e r o n e were m e a s u r e d by r a d i o i m m u n o a s s a y a f t e r c h r o m a t o g r a p h i c s e p a r a tion a t Endocrine Sciences (Tarzana, Calif.). 12 The s e n s i t i v i t y of t h e a s s a y was 5 ng p e r deciliter (0.17 nmol p e r liter) for t e s t o s t e r o n e and 2 ng p e r deciliter (0.07 nmol p e r liter) for dihydrotestosterone, a n d t h e i n t e r - a s s a y v a r i a t i o n s were 9.6 p e r c e n t a n d 11.7 percent, respectively. The r a n g e of s e r u m t e s t o s t e r o n e in n o r m a l m e n w a s 344 to 1029 n g p e r deciliter (12 to 36 nmol p e r liter), a n d of s e r u m dihydrotestosterone, 30 to 88 ng per deciliter (1.0 to 2.9 nmol p e r liter). S e r u m luteinizing h o r m o n e w a s m e a s u r e d by r a d i o i m m u n o a s s a y with h u m a n p i t u i t a r y s t a n d a r d s obtained from t h e World H e a l t h Organization. S e r u m prostate-specific a n t i g e n w a s m e a s u r e d by MRL L a b o r a t o r i e s (Cincinnati) w i t h a solidphase, two-site i m m u n o r a d i o m e t r i c a s s a y (Hybritech, L a Jolla, Calif.). The normal concentration was less t h a n 4 p g p e r liter, the sensitivity of the a s s a y was 0.2 p g p e r liter, and the i n t e r a s s a y variation was 3.8 percent. The m e a s u r e m e n t s were m a d e as the samples were collected, and the results were not released from the central laboratory until the end of the study. Statistical Analysis A n i n t e n t i o n - t o - t r e a t a n a l y s i s was used in e v a l u a t i n g t h e results. T h e l a s t r e s u l t s in m e n who did not complete t h e s t u d y were carried f o r w a r d t h r o u g h month 12. An a n a l y s i s of the d a t a b a s e d only on r e s u l t s in m e n for w h o m d a t a w e r e available a t each t i m e p o i n t (per protocol analysis) produced r e s u l t s t h a t were s i m i l a r to those of t h e i n t e n t i o n - t o - t r e a t analysis. A n a n a l y s i s of v a r i a n c e was used to compare t h e effects of t r e a t m e n t on t h e total, obstructive-uropathy, a n d n o n o b s t r u c t i v e - u r o p a t h y s y m p t o m scores; p r o s t a t i c volume; m a x i m a l urinary-flow rate; a n d s e r u m h o r m o n e a n d p r o s t a t e - s p e c i f c - a n t i g e n v a l u e s a t each time point. The a n a l ysis of v a r i a n c e model a n a l y z e d the effects of i n t e r a c t i o n s b e t w e e n t r e a t m e n t groups, b e t w e e n s t u d y centers, and bet w e e n t r e a t m e n t groups a n d s t u d y centers. No significant q u a l i t a t i v e i n t e r a c t i o n w a s found. All a n a l y s e s of v a r i a n c e
1104
FINASTERIDE FOR BENIGN PROSTATIC HYPERPLASIA
Table 2. Base-Line Characteristics of Men with Benign Prostatic Hyperplasia, According to Treatment-Group Assignment.* ~ILa.RACTERISTIC
PLACEBO
i MG FINASTERIDE
5 Me FXNASTERIDE
No. randomized
300
298
297
No. completing study 263 270 257 Age (yr) Mean 64 64 64 Range 45-82 41-83 40-80 Race White 288 282 286 Black 8 13 6 Other 4 3 5 Mean urinary flow (ml/sec) 5.6 +- 2.1 5.3 -+ 2.2 5.6 ± 2.1 Total voided volume (ml) 260 ± 114 244 ± 94t 258 ± 112 Residual volume (ml) 73 ± 91 76 -+ 94 73 ± 69 Serum prostate-specific 4.1 -+ 4.8 3.8 ± 7.2 3.6 -+ 4.2 antigen (t~g/liter) Serum dihydrotestosterone 42 ± 18 41 ± 17 42 ± 18 (ng/dl)~ Serum testosterone (ng/dl)§ 436 ± 145 452 ± 148 446 ± 161 Serum luteinizing hormone 6.8 ± 2.8 6.8 ± 2.7 6.6 ± 2.6 (U]liter) * Base-line measurements were made just before treatment was begun (mouth 0). Plus--minus values are means ± SD. t P <0.05 for the comparison with the placebo group. To convert values for dihydrotestosterone to nanomoles per liter, multiply by 0.033. § To convert values for testosterone to nanomoles per liter, multiply by 0.035.
were performed with both parametric methods (with use of the actual c h a n g e from b a s e line) a n d n o n p a r a m e t r i c m e t h ods (a r a n k t r a n s f o r m a t i o n o f t h e s e v a l u e s a c r o s s t r e a t m e n t g r o u p s a n d c e n t e r s ) to e n s u r e t h e c o n s i s t e n c y o f i n f e r e n c e s . B e c a u s e of a g e n e r a l lack of s y m m e t r y in the d i s t r i b u t i o n s , t h e m e d i a n v a l u e s a r e g i v e n for p r o s t a t i c v o l u m e a n d s e r u m p r o s t a t e - s p e c i f i c a n t i g e n , e x c e p t i n t a b l e s 2 a n d 3. T h e v a l u e s for all o t h e r v a r i a b l e s a r e g i v e n a s m e a n c h a n g e s . W i t h i n group tests were done with a paired t-test or with Puri's e x t e n s i o n of t h e s i g n e d - r a n k test, w i t h d a t a s t r a t i f i e d accordi n g to c e n t e r . T h e C o c h r a n - M a n t e l - H a e n s z e l t e s t w a s u s e d to analyze categorical variables, with data stratified according to c e n t e r . All t e s t s o f s i g n i f i c a n c e w e r e t w o - t a i l e d , a n d all P v a l u e s o f 0.05 o r l e s s w e r e c o n s i d e r e d to i n d i c a t e s i g n i f i c a n c e . N o a d j u s t m e n t w a s m a d e for t h e p e r f o r m a n c e o f m u l t i p l e tests. RESULTS
The base-line char~teristics of the men enrolled in the study are shown in Tables 2 and 3. The three treatment groups were similar except that the total voided volume was significantly lower (P <0.05) and the obstructive-symptom scores significantly higher (P <0.05) in the men who received 1 mg of finasteride than in those who received placebo. Changes In Hormone Secretion Speclfic-Antlgen Levels
and Prostate-
The mean base-line concentrations of serum dihydrotestosterone, testosterone, luteinizing hormone, and prostatespecific a n t i g e n w e r e s i m i l a r in t h e t h r e e groups. The m e a n s e r u m d i h y d r o t e s t o s t e r o n e c o n c e n t r a t i o n s d e c r e a s e d significantly in t h e two f i n a s t e r i d e - t r e a t e d groups (P <0.001) during the first two weeks of treatment and did not change t h e r e a f t e r (fig. 1A). T h e d e c r e a s e i n s e r m n d i h y d r o t e s t o s t e r ° one concentrations among the men who received 5 mg of finasteride daily was significantly greater than that among t h e m e n w h o r e c e i v e d 1 m g o f f i n a s t e r i d e d a i l y ( P -<0.01) a t all t i m e s f r o m 2 w e e k s to 12 m o n t h s . I n b o t h f i n a s t e r i d e - t r e a t e d g r o u p s , s e r u m t e s t o s t e r o n e conc e n t r a t i o n s i n c r e a s e d a p p r o x i m a t e l y 8 to 10 p e r c e n t a f t e r t w o weeks of treatment, and they remained increased thereafter.
The mean (_+SD) values in the men who received 5 mg el finasteride were 484 - 173 ng per deciliter (17 - 6 nmol Pez liter) after 2 weeks and 488 -+ 173 ng per deciliter (17 _+£ nmol per liter) after 12 months, as compared with 492 __. 161 ng per deciliter (17 - 6 nmol per liter) and 489 _+ 161 ng pel deciliter (17 _+6 nmo] per liter), respectively, in the men who received i mg of finasteride. Despite the increases, all value~ were within the normal range at all times. The values in th~ two finasteride-treated groups were significantly higher (} <0.001) than those in the placebo group at all times, bul there was no significant difference between the two finasteride-treated groups. Serum luteinizing hormone concentrations increased in all three groups during the first two months. However, the in creases in both finasteride-treated groups were significantb higher than those in the placebogroup (P <0.05). Amongthe men who received 5 mg of finasteride, the mean (-+SD)serurr ]uteinizing hormone concentration increased from 6.6 _+ 2.( U per liter to 7.4 _ 2.7 U per-literafter 2 months and to 7.6 _+ 2.9 U per liter after 12 months. Amongthe men who received 1 mg of finasteride, the serum luteinizing hormone coneen. tration increased from 6.8 _ 2.7 U per liter to 7.7 +- 3.3 U pc, liter after 2 months and to 7.8 -+ 3.4 U per liter after 12 months, and in the men who receivedplacebo, the concentra. tion increased from 6.8 _ 2.8 U per liter to 7.2 _ 3.1 U pel liter and 7.3 --- 3.4 U per liter, respectively. The median serum prostate-specifc-antigen concentra. tions in the placebo group did not change during the 12. month treatment period (Fig. 1B). In contrast the men in b o t h f i n a s t e r i d e - t r e a t e d g r o u p s h a d s i g n i f i c a n t r e d u c t i o n s i~ s e r u m p r o s t a t e - s p e c i f i c a n t i g e n ( P < 0 . 0 0 1 for t h e c o m p a r i s o ~ w i t h t h e p l a c e b o g r o u p ) a t all t i m e s f r o m m o n t h 3 througl7 m o n t h 12 o f t r e a t m e n t (Fig. 1B). T h e m e d i a n d e c r e a s e w a s 5£ p e r c e n t a m o n g t h e m e n w h o r e c e i v e d 5 m g o f f i n a s t e r i d e and 48 p e r c e n t a m o n g t h o s e w h o r e c e i v e d 1 m g o f f i n a s t e r i d e .
Table 3. Symptom Scores, Maximal Urinary-Flow Rates, and Prostatic Volume in Men with Benign Prostatic Hyperplasia Treated with Finasteride or Placebo.*
GROUP
BASZLIXE
12 Mom~ts
PERCENT CHANGEAT
12 hIo.'crHst Total symptom score Placebo 1 mg finasteride 5 mg finasteride Obstructive-symptom
9.8 ± 5.3 10.6 ± 5.7 10.2 ± 5.5
8.8 ± 6.1 8.8 ± 5.9 7.5 ± 5.25
-2 -9 -21
score
Placebo 6.7 -+ 3.5 5.9 -+ 3.8 -2 1 mg finasteride 7.4 ± 3.85 6.0 ± 3.85 -12 5 mg finasteride 7.0 -+ 3.6 5.1 ± 3.6§ -23 Nonobstructive-symptom score Placebo 3.4 ± 2.1 3.1 ± 2.6 +3 1 mg finasteride 3.6 ± 2.4 3.1 -+ 2.5 0 5 mg finasteride 3.6 ± 2.3 2.6 -+ 2.09 -18 Maximal urinary flow (mYsee) Placebo 9.6 ± 3.5 9.8 ± 3.7 +8 1 mg finasteride 9.2 ± 3.4 10.6 ± 4.0§ +23 5 mg finasteride 9.6 ± 3.7 11.2 ± 4.7§ +22 Prostatic volume (ml) Placebo 61.0 ± 36.5 59.8 -+ 39.4 -3 1 mg finasteride 60.9 ± 34.3 49.1 ± 26.6§ -18 5 mg finasteride 58.6 -+ 30.5 47.5 ± 23.6§ -19 * Base-line values were obtained just before treatment was begun (month 0). Plus--minus values are means ± SD. t Values are the means of the percent changes from base line in each man and therefore cannot be derived from the base-line and 12-month results shown. * P <=0.05for the comparisou with the placebo group at the same time. § P <=0.001 for the comparison with the placebo group at the same time. P <=0.01 for the comparison with the placebo group at the same time.
FINASTERIDE FOR BENIGN PROSTATIC HYPERPLASIA Changes
in Symptom
Scores
0
The symptom scores at base line and at 12 months are shown in Table 3, and the results of t r e a t m e n t at each time point are shown in Figure 2. In the placebo group the total symptom scores decreased during the first four months, indicating t h a t these patients h a d fewer or less severe symptoms, but then increased gradually toward base-line values. In contrast, the men treated with 5 mg of finasteride had a significant decrease in total symptom scores at several points from week 2 through month 12 (P <0.02 at months 2 and 7, P <0.01 at months 10 and 11, and P <0.001 at month 12), as compared with the placebo group. The maximal decrease in the scores at 12 months was 2.7 points in the group given 5 mg of finasteride (Table 3). The men treated with 1 mg of finasteride h a d no significant changes in the symptom scores. The changes in the obstructive-symptom scores were similar to those in the total scores. The mean obstructivesymptom score at base line was approximately 7 (table 3). At 12 months, the scores were lower by 1.9 points in the group given 5 mg of finasteride, by 1.4 in the group given 1 mg of finasteride, and by 0.8 in the group given placebo. The scores decreased in all three groups during the first nine months of treatment. The scores continued to decrease in the group given 5 mg of finasteride but increased in the group given placebo, such t h a t the scores in these two groups were significantly different (P <0.001) at 12 months. The scores in the group given 1 mg of finasteride did not change after 9 months, but they were significantly different from the scores in the group given placebo at 12 months (P <0.05). The nonobstructive-symptom scores decreased in the group given 5 mg of finasteride but not in the other two groups. The
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Figure 1. Effect of Treatment with Placebo (Circles), 1 mg of Finasteride (Triangles), or 5 mg of Finasteride (Squares) on Mean (±SE) Serum Dihydrotestosterone (Panel A) and Median (---95 Percent Confidence Interval) Serum Prostate-Specific-Antigen (Panel B) Concentrations in Men with Benign Prostatic Hyperplasia. The stippled area in Panel A indicates the normal range in men. To convert values for dihydrotestosterone to nanomoles per liter, multiply by 0.033. Month 0 represents the base line. Values before month 0 were obtained during the two-week placebo run-in period.
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Figure 2. Mean (-SE) Change in the Total Symptom Score in Men with Benign Prostatic Hyperplasia during Treatment with Placebo (Circles), 1 mg of Finasteride (Triangles), or 5 mg of Finasteride (Squares). The asterisks (P <0.05), the pound symbols (P <0.01), and the dagger (P <0.001)--indicate significant differences between the finasteride-treated groups and the placebo group. Month 0 represents the base line.
scores in the group given 5 mg of finasteride were significantly lower t h a n those in the placebo group at 10 months (P = 0.05) and 12 months (P <0.01) (Table 3). Changes
in Urinary
Flow Rate
The maximal urinary-flow rates increased slightly during the two-week p r e t r e a t m e n t period in all three groups. During the 12 months of treatment, the maximal urinary-flow rates increased progressively in both finasteride-treated groups, but not in the group given placebo (Table 3, Fig. 3). At 6 and 12 months the maximal flow rates in both finasteride-treated groups were significantly greater than both the" base-line values and the values in the placebo group (P <0.05 to P <0.001). After 12 months of t r e a t m e n t the maximal urinaryflow rate had increased by at least 3 ml per second in 31 percent of the men who received 5 mg of finasteride, 30 percent of those who received 1 mg of finasteride, and 17 percent of those who received placebo. The differences between the placebo group and the two finasteride-treated groups were significant (P ~0.001). The maximal urinaryflow rates at base line were not significantly different between the men who had increases in maximal urinary flow of at least 3 ml per second and the men who did not have Such increases. At each measurement from 5 to 12 months, the mean urinary-flow rates increased slightly but significantly more in the men treated with 5 mg of finasteride than in the men given placebo. The mean values at base line and after 12 months were 5.6 - 2.1 and 6.4 _ 2.7 ml per second in the group given 5 mg of finasteride, 5.3 +- 2.2 and 6.1 --- 2.4 ml per second in the group given i mg of finasteride, and 5.6 + 2.1 and 5.8 - 2.3 ml per second in the group given placebo. There were no significant differences in residual u r i n a r y volume between the groups at any time. Changes
in the Size of the Prostate
During the first six months, the median size of the prostate decreased progressively in both finasteride-treated groups (Fig. 4), after which it did not change significantly, and it was significantly smaller in both finasteride-treated groups than in the placebo group at all times (P <0.001). After 12 months of treatment, the prostate h a d shrunk by 19 percent from base line in the group given 5 mg of finasteride, by 18 percent in the group given 1 mg offinasteride, and by 3 percent in the group given placebo (Table 3). The prostatic volume had decreased by at least 20 percent in 43 percent of the men
FINASTERIDE FOR BENIGN PROSTATIC HYPERPLASIA
1106
counts, and one man had an increase in serum prostate. specific-antigen concentrations. In the placebo group, one man became positive for the human immunodeficiency virus and three men had h e m a t u r i a .
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Month Figure 3. Mean (+-SE) Maximal Urinary-Flow Rates in Men with Benign Prostatic Hyperplasia during Treatment with Placebo (Circles), 1 mg of Finasteride (Triangles), or 5 mg of Finasteride (Squares). The stippled area indicates the range in which urinary flow was considered to be obstructed. Month 0 represents the base line. Values before month 0 were obtained during the two-week placebo run-in period. The asterisks (P <0.05), pound symbols (P <0.01), and daggers (P <0.001) indicate significant differences between the finasteride-treated groups and the placebo group.
given 5 mg of finasteride after 6 months of t r e a t m e n t and in 49 percent after 12 months. In the group given 1 mg of finasteride, 48 percent and 47 percent of the men had a reduction of at least 20 percent after 6 and 12 months, respectively. In the placebo group, this degree of reduction occurred in 18 percent and 20 percent of the men at 6 and 12 months, respectively. At all times the difference in the percentage of men with a reduction in prostatic size of a t least 20 percent was significantly greater in the finasteride-treated groups t h a n in the placebo group (P <0.001). S i d e E f f e c t s and U n r e l a t e d C o m p l i c a t i o n s
The symptoms considered by the investigators to be possibly, probably, or definitely drug-related in at least 0.5 percent of the men ace listed in Table 4. The overall frequency of these symptoms was similar in the three groups. The proportion of men reporting decreased libido and decreased ejaculate volume was significantly higher (P <0.05) in both finasteride-treated groups t h a n in the placebo group, and the proportion of men who reported impotence was significantly higher (P <0.05) in the group given 1 mg of finasteride than in the placebo group. Only eight men withdrew from the study because of sexual dysfunction (one in the placebo group, three in the groulr~iven 1 mg of finasteride, and four in th e group given 5 mg of finasteride). Two men, each taking 1 mg of finasteride daily, died during the study: one died of cardiac arrest, and one committed suicide. Prostatic cancer was diagnosed in four men (one in the placebo group, two in the group given 1 mg of finasteride, and one in the group given 5 mg offinasteride). Three of these four men h a d serum prostate-specific-antigen concentrations of more t h a n 10 pg per liter at base line. The three men taking finasteride who were found to have prostatic cancer had reductions in serum prostate-specific-antigen levels during treatment, whereas the man in the placebo group had an increase. Eleven men h a d prostatic surgery during the study. One m a n had a radical prostatectomy for prostatic cancer, and 10 men had t r a n s u r e t h r a l resections (3 in the group given 5 mg of finasteride, 4 in the group given 1 mg of finasteride, and 3 in the placebo group). There was no significant effect of t r e a t m e n t on the pulse rate, blood pressure, or visual acuity. Only eight men had serious abnormalities in laboratory values during the study. One man in the group given 5 mg of finasteride had an increase in serum creatinine, calcium, potassium, and urea nitrogen concentrations. One man in the group given 1 mg of finasteride had a decrease in red-cell and white-cell
This study was u n d e r t a k e n to evaluate the safety and efficacy of finasteride in a large number of men with beniga prostatic hyperplasia. Serum dihydrotestosterone concentrations decreased to levels present after castration soon after the initiation of finasteride therapy; the greatest degree of suppression occurred in the men who received 5 mg of finasteride daily. Serum testosterone and luteinizing hormone concentrations increased only slightly and remained well within the normal range throughout the study. Prostatic volume decreased significantly within three months in both finasteride-treated groups. The median reductions in prostatic volume after 12 months were 19 percent in the group given 5 mg offinasteride daily, 18 percent in the group given 1 mg of finasteride daily, and 3 percent in the group given placebo. Approximately 50 percent of the men who received finasteride had a decrease of 20 percent or more in the size of the prostate, a response similar to t h a t reported in men treated with an analogue of gonadotropin-releasing hormone (24 percent reduction in size) 6 or surgical castration (31 percent reduction in size).5 The reduction in prostatic volume iv in the finasteride-treated men was consistent with the significant decreases in serum prostate-specific-antigen concentrations in these men, and thus were indicative of a decrease in prostatic epithelial-cell function. The three men receiving finasteride who were found to have prostatic cancer during the study also had decreases in serum prostatespecific-antigen concentrations. Therefore, a decrease in the concentration of serum prostate-specific antigen during finasteride therapy does not mean that a m a n does not have prostatic cancer, nor should it be interpreted to mean t h a t he has been adequately t r e a t e d for prostatic cancer. The maximal urinary-flow rate increased during finasteride treatment. The proportion of men who had an increase of at least 3 ml per second after 12 months was significantly higher in both finasteride-treated groups than in the placebo group. Although the increases in the maximal urinary-flow rate were small as compared with those that occur after transurethral resection of the prostate (8 to 9 ml per second TM,19), studies of the natural history of benign prostatic hyperplasia2° indicate that the mean decrease in maximal flow is about 0.2 ml per second per year. Thus, an improvement in maximal urinary flow of 3 ml per second represents a shift of about 15 years in the natural course of the disease. Despite the improvement in
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Figure 4. Median Change (+-95 Percent Confidence Interval) in Prostatic Volume in Men with Benign Prostatic Hyperplasia during Treatment with Placebo (Circles), 1 mg of Finasteride (Triangles), or 5 mg of Finasteride (Squares). Month 0 represents the base line.
FINASTERIDE FOR BENIGN PROSTATIC ttYPERPLASIA Table 4. Side Effects in Men With Benign Prostatic Hyperplasia Treated with Finasteride or Placebo for 12 months* SIDEEFFECT
1 MG 5 5IO FINASTERIDE FINASTER1DE PLACEBO (N = 298) (N = 297) (N = 300)
Digestive system Abdominalpain 0 1.0 0.3 Diarrhea 0.7 0 0 Flatulence 0 1.0 0.7 Nausea 0 0.7 1.0 Nervous system Dizziness 0.7 0 0.7 Headache 0.3 0.7 0.7 Decreased libido 6.0t 4.7t 1.3 Urogenital system Breast pain 0.7 0.3 0 Dysuria 0.3 0.7 0 Ejaculatory disorder 4.4t 4.4t 1.7 Impotence 5.0"~ 3.4 1.7 Orgasm dysfunction 0.3 0.7 0.3 Testicular pain 0.7 1.0 0.7 Eye Lens change 0.3 0.7 0 Lens opacities 1.3 0 0.7 Miscellaneous Rash 0.3 0.7 0.3 Asthenia 0.7 1.0 1.0 Pelvic pain 0.3 0.3 0.7 * The last results for the men who did not complete the study were brought forward through month 12. J"P <0.05 for the comparisonwith the placebogroup. the maximal u r i n a r y flow, the residual volume did not decrease in these patients, possibly as a result of bladder decompensation due to chronic obstruction. The m e n who received 5 m g of finasteride daily had a significantly greater decrease i n total symptom scores t h a n the m e n given placebo. The decrease i n the scores of the m e n who received 1 mg of finasteride daily was i n t e r m e d i a t e . After 12 m o n t h s , the changes i n the total symptom scores i n all groups were 30 to 70 percent of the changes t h a t occur i n m e n t r e a t e d with t r a n s u r e t h r a l resection of the prostate. Finasteride was well tolerated. The overall frequency of side effects was similar in the three groups, but the m e n who received fmasteride were more likely to have symptoms of sexual dysfunction. The long-term risks, if any, are not known. I n s u m m a r y , finasteride t h e r a p y i n m e n with b e n i g n prostatic h y p e r p l a s i a led to s u s t a i n e d decreases i n s e r u m dihydrotestosterone concentrations, followed by decreases i n ser u m prostate-specific-antigen concentrations a n d prostatic volume. These changes were accompanied by decreases i n the n u m b e r or severity of syrup.toms of u r i n a r y tract obstruction a n d increases i n the urin~Ci'y-flow rate. The effect of a daily dose of 5 m g of finasteride was greater t h a n t h a t of a 1-mg dose. We conclude t h a t t r e a t m e n t with a 5-rag dose of finasteride is beneficial in m e n with b e n i g n prostatic hyperplasia. APPENDIX The members of the Finasteride Study Group are as follows: G.L. Andriole, Washington University, St. Louis; R. Boake, University of Alberta, Edmonton; B.R. Bracken, University of Cincinnati Medical Center, Cincinnati; W. Brannan, Ochsner Clinic, New Orleans; R.C. Bruskewitz, University of Wisconsin, Madison; C.E. Cox II, University of Tennessee, Memphis; G.R. Cunningham, Veterans Affairs Medical Center and Baylor College of Medicine, Houston; P.C. Devine and P.F. Schellhammer, Eastern Virginia Medical School, Nor, folk; M. Elhilai, Royal Victoria Hospital, Montreal; J. Geller, Mercy Hospital and Medical Center, San Diego, Calif; J.T. Grayhack, Northwestern University Medical School, Chicago; L.H. Harrison, Bowman Gray School of Medicine, Winston-Salem, N.C.; P.B. Hudson, Veteran Affairs Medical Center, Bay Pines, Fla.; J. Imperato and E.D. Vaughan, Jr., New York Hospital, New York; M.M. Lieber, Mayo Clinic, Rochester, Minn.; M.C. Lippert, University of Texas, Dallas; P. Narayan, University of California, San Francisco; J.P. Perreault, Hospital St. Luc, Montreal; M.I. Resnick, Case Western
1107
Reserve University School of Medicine, Cleveland; R. Norman and R. Rittmaster, Dalhousie University, Halifax, N.S.; N.A. Romas and W. Rosner, St. Luke's Roosevelt Hospital Center, New York; S. Rosenblatt, University of California, Newport Beach; J.B. Roy, University of Oklahoma Health Sciences Center, Oklahoma City; E.J. Seidmon, Temple University Hospital, Philadelphia; J.S. Tenover, Harborview Medical Center, Seattle; J. Trachtenberg, Toronto General Hospital Toronto; P.C. Walsh, Johns Hopkins Hospital, Baltimore; R.D. Williams, University of Iowa Hospital and Clinic, Iowa City; and G.J. Gormley, E. Stoner, F. Pappas, A.M. Taylor, B. Binkowitz, and J. Ng, Merck Research Laboratories, Rahway, N.J. REFERENCES
1. BirkhoffJR. Natural history of benign prostatic hypertrophy. In: Hinman F, ed. Benign prostatic hypertrophy. New York: Springer-Verlag, 1983;5-9 2. Rotkin IO. Origins, distribution, and risk of benign prostatic hypertrophy. In: Hinman F, ed. Benign prostatic hypertrophy. New York: Springer-Verlag, 1983:10-21. 3. Glynn RJ, Campion EW, Bouchard GR, Silbert JB. The development of benign prostatic hyperplasia among volunteers in the Normative Aging Study. Am J Epidemiol 1985;121:78-90. 4. Roos NP, Wennberg JR, Malenka DJ, et al. Mortality and reoperation after open and transurethral resection of the prostate for benign prostatic hyperplasia. N Engl J Med 1989;320: 1120-4. 5. Bosch RJ, Griffiths DJ, Blom JM, Schreeder FH. Treatment of benign prostatic hyperplasia by androgen deprivation: effects on prostate size and urodynamic parameters. J Uro1198;141:68-72. 6. Peters CA, Walsh PC. The effect of nafareline acetate, a luteinizing-hormone-releasing hormone agonist, on benign prostatic hyperplasia. N Engl J Med 1987;317:599-604. 7. Imperato-McGinleyJ, Guerrero L, Gautier T, Peterson RE. Steroid 5a-reductase deficiency in man: an inherited form of male pseudohermaphroditism. Science 1974;186:1213-5. 8. Walsh PC, Madden JD, Harrod MJ, Goldstein JL. MacDonald PC, Wilson JD. Familial incomplete male pseudohermaphroditism, type 2: decreased dihydrotestosterone formation in pseudovaginal perineosrotal hypospadias. N Engl J Med 1974;29h944-9. 9. Ramusson GH. Biochemistry and pharmacology of 5a-reductase inhibitors. In: Furr BJA, Wakeling AE, eds. Pharmacology and clinical uses of inhibitors of hormone secretion and action. London: Baili~re Tindall, 1987;308-25. 10. Gormley GJ, Stoner E. The role of5a-reductase inhibitors in the treatment of benign prostatic hyperplasia. In: Lepor H, Paulson DF, eds. Problems in urology, Vol. 5, Philadelphia: J.B. Lippincott, 1991;436-40. 11. Rittmaster RS, Stoner E, Thompson DL, Nance D, Lasseter KC. Effect of MK-906, a specific 5a-reductase inhibitor, on serum androgens and androgen conjugates in normal men. J Androl 1989;10:259-62. 12. Gormley GJ, Stoner E, Rittmaster RS, et al. Effects offinasteride (MK-906), a 5a-rednctase inhibitor, on circulating androgens in male volunteers. J Clin Endocrinol Metab 1990;70:1136-41. 13. Stoner E, Finasteride Study Group. The clinical effects of a 5a-reductase inhibitor, finasteride, on benign prostatic hyperplasia. J Urol 1992;147:1298-302. 14. Stoner E. The clinical development of a 5a-reductase inhibitor, finasteride. J Steroid Biochem Mol Biol 1990;37:375-8. 15. Boyarsky S, Jones G, Paulson DF, Prout GR Jr. A new look at bladder neck obstruction by the Food and Drug Administration regulators: guide lines for investigation of benign prostatic hypertrophy. Trans Am Assoc Genitourin Surg 1976;68:29-32. 16. Susset JG. Development of nomograms for application of uroflowmetry. In: Hinman F, et Benign prostatic hypertrophy. New York: Springer-Verlag, 1983:528-38. 17. Levin AC, Kirschenbaum A, Kaplan P, Droller MA, Babrilove JL. Serum prostate-antigen levels in patients with benign prostatic hypertrophy treated with leuprolide. Urology 1989;34:10-3. 18. Bruskewitz RC, Christensen MM. Critical evaluation of transurethral resection and incision of the prostate. Prostate Suppl 1990;3:27-38. 19. Lepor H, Rigaud G. The efficacy oftransurethral resection of the prostate in men with moderate symptoms ofprostatism. J Urol 1990;143:533-7. 20. Drach GW, Layton TN, Binard WJ. Male peak urinary flow rate: relationship to volume voided and age. J Uro11979;122:210-4.
Vol. 167, 1102-1107,February 20( Printed in U.S,
THE EFFECT OF FINASTERIDE IN MEN WITH BENIGN PROSTATIC HYPERPLASIA GLEEN J. GORMLEY, M.D., PH.D., ELIZABETH STONER, M.D., REGINALD C. BRUSKEWITZ, M.D., JULIANNE IMPERATO-MCGINLEY,M.D., PATRICK C. WALSH, M.D., JOHN D. MCCONNELL, M.D., GERALD L. ANDRIOLE, M.D., JACK GELLER, M.D., BRUCE R. BRACKEN, M.D., JOYCE S. TENOVER, M.D., PH.D.,
E. DARRACOTTVAUGHAN, M.D., FRANCES PAPPAS, M.S., ALICE TAYLOR, M.S., BRUCE BINKOWITZ, M.S., AND JENNIFER NG, S.D., FOR THE FINASTERIDE STUDY GROUP (Reprinted with permission from N Engl J Med, 327: 1185-1191, 1992)
ABSTRACT
Background. Benign prostatic hyperplasia is a progressive, androgen-dependent disease resulting in enlargement of the prostate gland and urinary obstruction. Preventing the conversion of testosterone to its tissue-active form, dihydrotestosterone, by inhibiting the enzyme 5areductase could decrease the action of androgens in their target tissues; in the prostate the result might be a decrease in prostatic hyperplasia and therefore in symptoms of urinary obstruction. Methods. In a double-blind study, we evaluated the effect of two doses offinasteride (1 mg and 5 mg) and placebo, each given once daily for 12 months, in 895 m e n with prostatic hyperplasia. Urinary symptoms, u r i n a r y flow, prostatic volume, and serum concentrations of dihydrotestosterone and prostate-specific antigen were determined periodically during the t r e a t m e n t period. Results. As compared with the men in the placebo group, the men treated with 5 mg of finasteride per day had a significant decrease in total urinary-symptom scores (P <0.001), an increase of 1.6 ml per second (22 percent, P <0.001) in the maximal urinary-flow rate, and a 19 percent decrease in prostatic volume (P <0.001). The men treated with 1 mg of finasteride per day did not have a significant decrease in total urinary-symptom scores, but had an increase of 1.4 ml per second (23 percent) in the maximal urinary-flow rate, and an 18 percent decrease in prostatic volume. The men given placebo had no changes in total urinary-symptom scores, an increase of 0.2 ml per second (8 percent) in the maximal urinary-flow rate, and a 3 percent decrease in prostatic volume. The frequency of adverse effects in the three groups was similar, except for a higher incidence of decreased libido, impotence, and ejaculatory disorders in the finasteride-treated groups. Conclusions. The t r e a t m e n t of benign prostatic hyperplasia with 5 mg of finasteride per day results in a significant decrease in symptoms of obstruction, an increase in urinary flow, and a decrease in prostatic volume, but at a slightly increased risk of sexual dysfunction. Benign prostatic hyperplasia is common in aging men. The resulting enlargement of the prostate gland can lead to urethral obstruction and even complete urinary retention. 1-a The standard treatmefit is surgical resection of the prostate,4 and there has been no effective medical therapy. Androgens are required to maintain the size and function of the prostate in men. The prostate does not become enlarged in boys castrated before puberty, and androgen deprivation leads to a reduction in the size of the prostate.S, GThe androgen primarily responsible for prostatic growth and enlargement is dihydrotestosterone. Men who have 5areductase deficiency7,s and who therefore cannot convert testosterone to dihydrotestosterone have poor prostatic growth, although some other tissues are responsive to testosterone alone. A compound that selectively inhibited 5a-reductase
could therefore provide an effective treatment for benign prostatic hyperplasia while causing less severe androgen de ficiency in other tissues than do less selective approaches. 9,1 Finasteride is a competitive inhibitor of 5a-reductase. 9 Ad ministration of this drug for short periods results in de creased serum dihydrotestosterone concentrations, a reduc tion in the size of the prostate, and improvement in urinary flow rate. 1°-14 The purpose of this study was to evaluate th~ safety and efficacy of the administration of finasteride for 1', months in a large number of men with benign prostati hyperplasia. METHODS
Subjects This was a multicenter, double-blind, placebo-controllec E.S., F.P., A.T., B.B., J.N.); University of Wisconsin, Madison (R.C.B.); New YorkHospital, New York (J.I.-M., E.D.V.); Johns Hop- study conducted at 25 centers in the United States and kins Hospital, Baltimore (P.C.W.); University of Texas, Dallas centers in Canada. The study was approved by the institu (J.D.M.); WashingtonUniversity, St. Louis (G.L.A.);MercyHospital and Medical Center, San Diego, Calif. (J.G.); University of Cincin- tional review board at each center, and all the men gaw nati Medical Center, Cincinnati (B.R.B.); and Harborview Medical written informed consent. A total of 895 men ranging in ag~ Center, Seattle (J.S.T.). Address reprint requests to Dr. Gormleyat from 40 to 83 years who had benign prostatic hyperplasi~ Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065. * The members of the Finasteride Study Group are listed in the were enrolled in the study. All the men had some symptom~ Appendix. of urinary obstruction, an enlarged prostate gland on digita 1102 From the Merck Research Laboratories, Rahway, N.J. (G.J.G.,
1103
FINASTERIDE FOR BENIGN PROSTATIC HYPERPLASIA rectal e x a m i n a t i o n , and m a x i m a l urinary-flow r a t e s o f less t h a n 15 ml p e r second (with a voided volume of 150 m l or more). Men w i t h v e r y low urinary-flow r a t e s were n o t excluded, u n l e s s t h e y were considered to be a t r i s k for total u r i n a r y obstruction. A n y m a n whose rectal e x a m i n a t i o n suggested the p r e s e n c e of prostatic cancer was r e q u i r e d to h a v e a biopsy w i t h negative r e s u l t s for e n t r y into t h e study. Men with a r e s i d u a l u r i n a r y volume of more t h a n 350 ml, a s e r u m prostate-specific-antigen concentration of >-40 p g p e r liter, or evidence of p r o s t a t i c cancer, u r i n a r y t r a c t infection, chronic prostatitis, or neurogenic b l a d d e r were excluded.
Table 1. Reasons for Withdrawal from the Finasteride Study.* R F~S ON FOR
5 MG FINASTERIDE 1 MG FINASTERIDE PLACEBO
~VITIIDIL~WAL
(N = 297)
(N = 298)
(N = 300)
number (percent)
Adverse effects 16 (5) 14 (5) 18 (6) Lack of efficacy 12 (4) 4 (1) 9 (3) Unknownt 3 (1) 2 (1) 4 (1) Other 9 (3) 8 (3) 6 (2) Total 40 (13) 28 (9) 37 (12) * Because ofrounding, the percentages may not add up to the totals. t The patients were lost to follow-up.
Study P r o t o c o l After a two-week period d u r i n g which the m e n received a placebo in single-blind fashion, t h e y were r a n d o m l y a s s i g n e d in a double-blind fashion to one of t h r e e t r e a t m e n t groups: 297 were a s s i g n e d to receive a 5-rag t a b l e t of f i n a s t e r i d e daily, 298 to receive a 1-mg t a b l e t of f i n a s t e r i d e daily, and 300 to receive a placebo t a b l e t each day. The t a b l e t s were t a k e n once each d a y for 12 months. E a c h m a n w a s e v a l u a t e d m o n t h l y by t h e s a m e investigator, a t which t i m e u r i n a r y symptoms, side effects, a n d the degree of compliance w i t h t h e t r e a t m e n t r e g i m e n were a s s e s s e d a n d the urinary-flow r a t e and r e s i d u a l u r i n a r y volume w e r e m e a s u r e d . P r o s t a t i c volu m e was m e a s u r e d at b a s e line a n d a f t e r 6 a n d 12 m o n t h s of t r e a t m e n t . I n addition, each m a n h a d a complete o p h t h a l m o logic e x a m i n a t i o n a t base line a n d after 12 m o n t h s . E v e r y t h r e e m o n t h s , s e r u m a m i n o - t r a n s f e r a s e s , u r e a nitrogen, creatinine, sodium, potassium, calcium, a n d glucose w e r e m e a s u r e d a n d a complete blood count was performed. A f t e r m o n t h 12, t h e m e n could e n t e r a n open s t u d y in which t h e y received 5 m g of f i n a s t e r i d e daily. Compliance w i t h t r e a t m e n t was excellent as d e t e r m i n e d b y counting t h e n u m b e r of t a b l e t s r e m a i n i n g a t each visit a n d by periodic m e a s u r e m e n t s of s e r u m d i h y d r o t e s t o s t e r e n e concentrations. D u r i n g t h e study, 40 (13 percent) of t h e m e n in t h e group receiving 5 m g o f f i n a s t e r i d e , 28 (9 percent) of those receiving 1 m g of f i n a s t e r i d e , and 37 (12 percent) of those receiving placebo w i t h d r e w from t h e s t u d y for t h e reasons shown in Table 1. Evaluation Procedures T h e p a t i e n t s ' s y m p t o m s were a s s e s s e d on t h e basis of t h e i r responses to a q u e s t i o n n a i r e m o d i f e d from t h a t of B o y a r s k y et al. is T h e total s y m p t o m score was calculated from t h e responses to n i n e questions a b o u t u r i n a r y h e s i t a n c y , t e r m i n a l dribbling, i m p a i r m e n t of~the size a n d force of t h e u r i n a r y s t r e a m , i n t e r r u p t i o n of u r i n a t i o n , incomplete e m p t y i n g , urgency, d y s u r i a , clothes wetting, a n d s t r a i n i n g or p u s h i n g to s t a r t u r i n a r y flow. Each s y m p t o m was scored according to a five-point scale, w i t h a score of 0 i n d i c a t i n g t h e a b s e n c e of a s y m p t o m a n d a score of 4 t h e presence of a severe s y m p t o m , so t h a t the w o r s t possible score was 36. The total score was divided into two subgroups: one covering changes due to obstructive u r o p a t h y and t h e o t h e r covering changes involving n o n o b s t r u c t i v e u r o p a t h y . The o b s t r u c t i v e - u r o p a t h y score w a s c a l c u l a t e d from the r e s p o n s e to t h e first five questions, a n d t h e n o n o b s t r u c t i v e - u r o p a t h y score was c a l c u l a t e d from t h e r e s p o n s e to t h e l a s t four questions. T h e s y m p t o m score was v a l i d a t e d in studies of n o r m a l m e n a n d m e n w i t h benign p r o s t a t i c h y p e r p l a s i a before a n d after t r a n s u r e t h r a l resection of t h e prostate. The m e a n ( ± S D ) score in t h e 20 n o r m a l m e n was 0.9 --- 1.8 ( u n p u b l i s h e d data). The m e a n score among 20 m e n s t u d i e d in t h e office of a urologist before a n d 1 to 3 m o n t h s a f t e r s u r g e r y d e c r e a s e d from 10.9 - 5.9 to 3.7 - 3.8, a n d it decreased from a preoperative m e a n of 8.1 -+ 3.5 to 4.4 ± 3.6 among 7 m e n who responded to a questionnaire mailed 12 months after surgery. U r i n a r y - o u t f l o w obstruction w a s m e a s u r e d w i t h a u r i n a r y
flow-meter (Urodyn 1000, Dantec, Mahwah, N.J.). I n n o r m a l men, the m a x i m a l u r i n a r y flow exceeded 15 ml p e r second and t h e i r m e a n u r i n a r y flow was more t h a n 6.9 ml p e r second. 16 M e a s u r e m e n t s of m a x i m a l a n d m e a n urinary-flow r a t e s were used in t h e a n a l y s e s only if a t l e a s t 150 ml of u r i n e was excreted. A p p r o x i m a t e l y 9 percent of t h e urinary-flow m e a s u r e m e n t s w e r e excluded on this basis. R e s i d u a l u r i n a r y volume was m e a s u r e d b y t r a n s a b d o m i n a l u l t r a s o n o g r a p h y . P r o s t a t i c volume was m e a s u r e d by m a g n e t i c r e s o n a n c e i m a g i n g a t base line a n d after 3, 6, a n d 12 m o n t h s of t r e a t ment. M e a s u r e m e n t s were m a d e in t h e axial, sagittal, a n d coronal planes, a n d t h e volume of the p r o s t a t e was c a l c u l a t e d according to the following formula: volume (in milliliters) = ( 4 / 3 ) ~ a x i a l value/2)(coronal value/2)(sagittal value/2). W i t h the use of this a p p r o a c h t h e m e a n (-+SD) p r o s t a t i c volume in 23 m e n r a n g i n g in age from 31 to 50 y e a r s (mean, 41) with no u r i n a r y s y m p t o m s w a s 25 ± 19 ml. Laboratory Tests S e r u m t e s t o s t e r o n e a n d d i h y d r o t e s t o s t e r o n e were m e a s u r e d by r a d i o i m m u n o a s s a y a f t e r c h r o m a t o g r a p h i c s e p a r a tion a t Endocrine Sciences (Tarzana, Calif.). 12 The s e n s i t i v i t y of t h e a s s a y was 5 ng p e r deciliter (0.17 nmol p e r liter) for t e s t o s t e r o n e and 2 ng p e r deciliter (0.07 nmol p e r liter) for dihydrotestosterone, a n d t h e i n t e r - a s s a y v a r i a t i o n s were 9.6 p e r c e n t a n d 11.7 percent, respectively. The r a n g e of s e r u m t e s t o s t e r o n e in n o r m a l m e n w a s 344 to 1029 n g p e r deciliter (12 to 36 nmol p e r liter), a n d of s e r u m dihydrotestosterone, 30 to 88 ng per deciliter (1.0 to 2.9 nmol p e r liter). S e r u m luteinizing h o r m o n e w a s m e a s u r e d by r a d i o i m m u n o a s s a y with h u m a n p i t u i t a r y s t a n d a r d s obtained from t h e World H e a l t h Organization. S e r u m prostate-specific a n t i g e n w a s m e a s u r e d by MRL L a b o r a t o r i e s (Cincinnati) w i t h a solidphase, two-site i m m u n o r a d i o m e t r i c a s s a y (Hybritech, L a Jolla, Calif.). The normal concentration was less t h a n 4 p g p e r liter, the sensitivity of the a s s a y was 0.2 p g p e r liter, and the i n t e r a s s a y variation was 3.8 percent. The m e a s u r e m e n t s were m a d e as the samples were collected, and the results were not released from the central laboratory until the end of the study. Statistical Analysis A n i n t e n t i o n - t o - t r e a t a n a l y s i s was used in e v a l u a t i n g t h e results. T h e l a s t r e s u l t s in m e n who did not complete t h e s t u d y were carried f o r w a r d t h r o u g h month 12. An a n a l y s i s of the d a t a b a s e d only on r e s u l t s in m e n for w h o m d a t a w e r e available a t each t i m e p o i n t (per protocol analysis) produced r e s u l t s t h a t were s i m i l a r to those of t h e i n t e n t i o n - t o - t r e a t analysis. A n a n a l y s i s of v a r i a n c e was used to compare t h e effects of t r e a t m e n t on t h e total, obstructive-uropathy, a n d n o n o b s t r u c t i v e - u r o p a t h y s y m p t o m scores; p r o s t a t i c volume; m a x i m a l urinary-flow rate; a n d s e r u m h o r m o n e a n d p r o s t a t e - s p e c i f c - a n t i g e n v a l u e s a t each time point. The a n a l ysis of v a r i a n c e model a n a l y z e d the effects of i n t e r a c t i o n s b e t w e e n t r e a t m e n t groups, b e t w e e n s t u d y centers, and bet w e e n t r e a t m e n t groups a n d s t u d y centers. No significant q u a l i t a t i v e i n t e r a c t i o n w a s found. All a n a l y s e s of v a r i a n c e
1104
FINASTERIDE FOR BENIGN PROSTATIC HYPERPLASIA
Table 2. Base-Line Characteristics of Men with Benign Prostatic Hyperplasia, According to Treatment-Group Assignment.* ~ILa.RACTERISTIC
PLACEBO
i MG FINASTERIDE
5 Me FXNASTERIDE
No. randomized
300
298
297
No. completing study 263 270 257 Age (yr) Mean 64 64 64 Range 45-82 41-83 40-80 Race White 288 282 286 Black 8 13 6 Other 4 3 5 Mean urinary flow (ml/sec) 5.6 +- 2.1 5.3 -+ 2.2 5.6 ± 2.1 Total voided volume (ml) 260 ± 114 244 ± 94t 258 ± 112 Residual volume (ml) 73 ± 91 76 -+ 94 73 ± 69 Serum prostate-specific 4.1 -+ 4.8 3.8 ± 7.2 3.6 -+ 4.2 antigen (t~g/liter) Serum dihydrotestosterone 42 ± 18 41 ± 17 42 ± 18 (ng/dl)~ Serum testosterone (ng/dl)§ 436 ± 145 452 ± 148 446 ± 161 Serum luteinizing hormone 6.8 ± 2.8 6.8 ± 2.7 6.6 ± 2.6 (U]liter) * Base-line measurements were made just before treatment was begun (mouth 0). Plus--minus values are means ± SD. t P <0.05 for the comparison with the placebo group. To convert values for dihydrotestosterone to nanomoles per liter, multiply by 0.033. § To convert values for testosterone to nanomoles per liter, multiply by 0.035.
were performed with both parametric methods (with use of the actual c h a n g e from b a s e line) a n d n o n p a r a m e t r i c m e t h ods (a r a n k t r a n s f o r m a t i o n o f t h e s e v a l u e s a c r o s s t r e a t m e n t g r o u p s a n d c e n t e r s ) to e n s u r e t h e c o n s i s t e n c y o f i n f e r e n c e s . B e c a u s e of a g e n e r a l lack of s y m m e t r y in the d i s t r i b u t i o n s , t h e m e d i a n v a l u e s a r e g i v e n for p r o s t a t i c v o l u m e a n d s e r u m p r o s t a t e - s p e c i f i c a n t i g e n , e x c e p t i n t a b l e s 2 a n d 3. T h e v a l u e s for all o t h e r v a r i a b l e s a r e g i v e n a s m e a n c h a n g e s . W i t h i n group tests were done with a paired t-test or with Puri's e x t e n s i o n of t h e s i g n e d - r a n k test, w i t h d a t a s t r a t i f i e d accordi n g to c e n t e r . T h e C o c h r a n - M a n t e l - H a e n s z e l t e s t w a s u s e d to analyze categorical variables, with data stratified according to c e n t e r . All t e s t s o f s i g n i f i c a n c e w e r e t w o - t a i l e d , a n d all P v a l u e s o f 0.05 o r l e s s w e r e c o n s i d e r e d to i n d i c a t e s i g n i f i c a n c e . N o a d j u s t m e n t w a s m a d e for t h e p e r f o r m a n c e o f m u l t i p l e tests. RESULTS
The base-line char~teristics of the men enrolled in the study are shown in Tables 2 and 3. The three treatment groups were similar except that the total voided volume was significantly lower (P <0.05) and the obstructive-symptom scores significantly higher (P <0.05) in the men who received 1 mg of finasteride than in those who received placebo. Changes In Hormone Secretion Speclfic-Antlgen Levels
and Prostate-
The mean base-line concentrations of serum dihydrotestosterone, testosterone, luteinizing hormone, and prostatespecific a n t i g e n w e r e s i m i l a r in t h e t h r e e groups. The m e a n s e r u m d i h y d r o t e s t o s t e r o n e c o n c e n t r a t i o n s d e c r e a s e d significantly in t h e two f i n a s t e r i d e - t r e a t e d groups (P <0.001) during the first two weeks of treatment and did not change t h e r e a f t e r (fig. 1A). T h e d e c r e a s e i n s e r m n d i h y d r o t e s t o s t e r ° one concentrations among the men who received 5 mg of finasteride daily was significantly greater than that among t h e m e n w h o r e c e i v e d 1 m g o f f i n a s t e r i d e d a i l y ( P -<0.01) a t all t i m e s f r o m 2 w e e k s to 12 m o n t h s . I n b o t h f i n a s t e r i d e - t r e a t e d g r o u p s , s e r u m t e s t o s t e r o n e conc e n t r a t i o n s i n c r e a s e d a p p r o x i m a t e l y 8 to 10 p e r c e n t a f t e r t w o weeks of treatment, and they remained increased thereafter.
The mean (_+SD) values in the men who received 5 mg el finasteride were 484 - 173 ng per deciliter (17 - 6 nmol Pez liter) after 2 weeks and 488 -+ 173 ng per deciliter (17 _+£ nmol per liter) after 12 months, as compared with 492 __. 161 ng per deciliter (17 - 6 nmol per liter) and 489 _+ 161 ng pel deciliter (17 _+6 nmo] per liter), respectively, in the men who received i mg of finasteride. Despite the increases, all value~ were within the normal range at all times. The values in th~ two finasteride-treated groups were significantly higher (} <0.001) than those in the placebo group at all times, bul there was no significant difference between the two finasteride-treated groups. Serum luteinizing hormone concentrations increased in all three groups during the first two months. However, the in creases in both finasteride-treated groups were significantb higher than those in the placebogroup (P <0.05). Amongthe men who received 5 mg of finasteride, the mean (-+SD)serurr ]uteinizing hormone concentration increased from 6.6 _+ 2.( U per liter to 7.4 _ 2.7 U per-literafter 2 months and to 7.6 _+ 2.9 U per liter after 12 months. Amongthe men who received 1 mg of finasteride, the serum luteinizing hormone coneen. tration increased from 6.8 _ 2.7 U per liter to 7.7 +- 3.3 U pc, liter after 2 months and to 7.8 -+ 3.4 U per liter after 12 months, and in the men who receivedplacebo, the concentra. tion increased from 6.8 _ 2.8 U per liter to 7.2 _ 3.1 U pel liter and 7.3 --- 3.4 U per liter, respectively. The median serum prostate-specifc-antigen concentra. tions in the placebo group did not change during the 12. month treatment period (Fig. 1B). In contrast the men in b o t h f i n a s t e r i d e - t r e a t e d g r o u p s h a d s i g n i f i c a n t r e d u c t i o n s i~ s e r u m p r o s t a t e - s p e c i f i c a n t i g e n ( P < 0 . 0 0 1 for t h e c o m p a r i s o ~ w i t h t h e p l a c e b o g r o u p ) a t all t i m e s f r o m m o n t h 3 througl7 m o n t h 12 o f t r e a t m e n t (Fig. 1B). T h e m e d i a n d e c r e a s e w a s 5£ p e r c e n t a m o n g t h e m e n w h o r e c e i v e d 5 m g o f f i n a s t e r i d e and 48 p e r c e n t a m o n g t h o s e w h o r e c e i v e d 1 m g o f f i n a s t e r i d e .
Table 3. Symptom Scores, Maximal Urinary-Flow Rates, and Prostatic Volume in Men with Benign Prostatic Hyperplasia Treated with Finasteride or Placebo.*
GROUP
BASZLIXE
12 Mom~ts
PERCENT CHANGEAT
12 hIo.'crHst Total symptom score Placebo 1 mg finasteride 5 mg finasteride Obstructive-symptom
9.8 ± 5.3 10.6 ± 5.7 10.2 ± 5.5
8.8 ± 6.1 8.8 ± 5.9 7.5 ± 5.25
-2 -9 -21
score
Placebo 6.7 -+ 3.5 5.9 -+ 3.8 -2 1 mg finasteride 7.4 ± 3.85 6.0 ± 3.85 -12 5 mg finasteride 7.0 -+ 3.6 5.1 ± 3.6§ -23 Nonobstructive-symptom score Placebo 3.4 ± 2.1 3.1 ± 2.6 +3 1 mg finasteride 3.6 ± 2.4 3.1 -+ 2.5 0 5 mg finasteride 3.6 ± 2.3 2.6 -+ 2.09 -18 Maximal urinary flow (mYsee) Placebo 9.6 ± 3.5 9.8 ± 3.7 +8 1 mg finasteride 9.2 ± 3.4 10.6 ± 4.0§ +23 5 mg finasteride 9.6 ± 3.7 11.2 ± 4.7§ +22 Prostatic volume (ml) Placebo 61.0 ± 36.5 59.8 -+ 39.4 -3 1 mg finasteride 60.9 ± 34.3 49.1 ± 26.6§ -18 5 mg finasteride 58.6 -+ 30.5 47.5 ± 23.6§ -19 * Base-line values were obtained just before treatment was begun (month 0). Plus--minus values are means ± SD. t Values are the means of the percent changes from base line in each man and therefore cannot be derived from the base-line and 12-month results shown. * P <=0.05for the comparisou with the placebo group at the same time. § P <=0.001 for the comparison with the placebo group at the same time. P <=0.01 for the comparison with the placebo group at the same time.
FINASTERIDE FOR BENIGN PROSTATIC HYPERPLASIA Changes
in Symptom
Scores
0
The symptom scores at base line and at 12 months are shown in Table 3, and the results of t r e a t m e n t at each time point are shown in Figure 2. In the placebo group the total symptom scores decreased during the first four months, indicating t h a t these patients h a d fewer or less severe symptoms, but then increased gradually toward base-line values. In contrast, the men treated with 5 mg of finasteride had a significant decrease in total symptom scores at several points from week 2 through month 12 (P <0.02 at months 2 and 7, P <0.01 at months 10 and 11, and P <0.001 at month 12), as compared with the placebo group. The maximal decrease in the scores at 12 months was 2.7 points in the group given 5 mg of finasteride (Table 3). The men treated with 1 mg of finasteride h a d no significant changes in the symptom scores. The changes in the obstructive-symptom scores were similar to those in the total scores. The mean obstructivesymptom score at base line was approximately 7 (table 3). At 12 months, the scores were lower by 1.9 points in the group given 5 mg of finasteride, by 1.4 in the group given 1 mg of finasteride, and by 0.8 in the group given placebo. The scores decreased in all three groups during the first nine months of treatment. The scores continued to decrease in the group given 5 mg of finasteride but increased in the group given placebo, such t h a t the scores in these two groups were significantly different (P <0.001) at 12 months. The scores in the group given 1 mg of finasteride did not change after 9 months, but they were significantly different from the scores in the group given placebo at 12 months (P <0.05). The nonobstructive-symptom scores decreased in the group given 5 mg of finasteride but not in the other two groups. The
m
9O
o
60 ~:
(n
15('~
0
-0.50
_
_-
I
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I
I
I
I
I
I
l
I
1
2
3
4
5
6
7
8
9
10
11
12
A
Month 4
~-'-
"5
2~3
2 I_
o..~
0,. -0.5 0
i 3
i 6
I 9
! 12
Month
Figure 1. Effect of Treatment with Placebo (Circles), 1 mg of Finasteride (Triangles), or 5 mg of Finasteride (Squares) on Mean (±SE) Serum Dihydrotestosterone (Panel A) and Median (---95 Percent Confidence Interval) Serum Prostate-Specific-Antigen (Panel B) Concentrations in Men with Benign Prostatic Hyperplasia. The stippled area in Panel A indicates the normal range in men. To convert values for dihydrotestosterone to nanomoles per liter, multiply by 0.033. Month 0 represents the base line. Values before month 0 were obtained during the two-week placebo run-in period.
1105
I
E
O ~
~c E m
-I
~ 3u - 3 C
•
-4
•
I
I
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!
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I
1
2
3
4
5
6
7
# I
I
8
9
i
10
#
t
!
i
11 12
Month
Figure 2. Mean (-SE) Change in the Total Symptom Score in Men with Benign Prostatic Hyperplasia during Treatment with Placebo (Circles), 1 mg of Finasteride (Triangles), or 5 mg of Finasteride (Squares). The asterisks (P <0.05), the pound symbols (P <0.01), and the dagger (P <0.001)--indicate significant differences between the finasteride-treated groups and the placebo group. Month 0 represents the base line.
scores in the group given 5 mg of finasteride were significantly lower t h a n those in the placebo group at 10 months (P = 0.05) and 12 months (P <0.01) (Table 3). Changes
in Urinary
Flow Rate
The maximal urinary-flow rates increased slightly during the two-week p r e t r e a t m e n t period in all three groups. During the 12 months of treatment, the maximal urinary-flow rates increased progressively in both finasteride-treated groups, but not in the group given placebo (Table 3, Fig. 3). At 6 and 12 months the maximal flow rates in both finasteride-treated groups were significantly greater than both the" base-line values and the values in the placebo group (P <0.05 to P <0.001). After 12 months of t r e a t m e n t the maximal urinaryflow rate had increased by at least 3 ml per second in 31 percent of the men who received 5 mg of finasteride, 30 percent of those who received 1 mg of finasteride, and 17 percent of those who received placebo. The differences between the placebo group and the two finasteride-treated groups were significant (P ~0.001). The maximal urinaryflow rates at base line were not significantly different between the men who had increases in maximal urinary flow of at least 3 ml per second and the men who did not have Such increases. At each measurement from 5 to 12 months, the mean urinary-flow rates increased slightly but significantly more in the men treated with 5 mg of finasteride than in the men given placebo. The mean values at base line and after 12 months were 5.6 - 2.1 and 6.4 _ 2.7 ml per second in the group given 5 mg of finasteride, 5.3 +- 2.2 and 6.1 --- 2.4 ml per second in the group given i mg of finasteride, and 5.6 + 2.1 and 5.8 - 2.3 ml per second in the group given placebo. There were no significant differences in residual u r i n a r y volume between the groups at any time. Changes
in the Size of the Prostate
During the first six months, the median size of the prostate decreased progressively in both finasteride-treated groups (Fig. 4), after which it did not change significantly, and it was significantly smaller in both finasteride-treated groups than in the placebo group at all times (P <0.001). After 12 months of treatment, the prostate h a d shrunk by 19 percent from base line in the group given 5 mg of finasteride, by 18 percent in the group given 1 mg offinasteride, and by 3 percent in the group given placebo (Table 3). The prostatic volume had decreased by at least 20 percent in 43 percent of the men
FINASTERIDE FOR BENIGN PROSTATIC HYPERPLASIA
1106
counts, and one man had an increase in serum prostate. specific-antigen concentrations. In the placebo group, one man became positive for the human immunodeficiency virus and three men had h e m a t u r i a .
12
,o ;i!ii!iiiii? :=.i!:,i!!i~" ,~
-0.5-0.250
DISCUSSION
1
2
3
4
5
6
7
8
9
10 11 12
Month Figure 3. Mean (+-SE) Maximal Urinary-Flow Rates in Men with Benign Prostatic Hyperplasia during Treatment with Placebo (Circles), 1 mg of Finasteride (Triangles), or 5 mg of Finasteride (Squares). The stippled area indicates the range in which urinary flow was considered to be obstructed. Month 0 represents the base line. Values before month 0 were obtained during the two-week placebo run-in period. The asterisks (P <0.05), pound symbols (P <0.01), and daggers (P <0.001) indicate significant differences between the finasteride-treated groups and the placebo group.
given 5 mg of finasteride after 6 months of t r e a t m e n t and in 49 percent after 12 months. In the group given 1 mg of finasteride, 48 percent and 47 percent of the men had a reduction of at least 20 percent after 6 and 12 months, respectively. In the placebo group, this degree of reduction occurred in 18 percent and 20 percent of the men at 6 and 12 months, respectively. At all times the difference in the percentage of men with a reduction in prostatic size of a t least 20 percent was significantly greater in the finasteride-treated groups t h a n in the placebo group (P <0.001). S i d e E f f e c t s and U n r e l a t e d C o m p l i c a t i o n s
The symptoms considered by the investigators to be possibly, probably, or definitely drug-related in at least 0.5 percent of the men ace listed in Table 4. The overall frequency of these symptoms was similar in the three groups. The proportion of men reporting decreased libido and decreased ejaculate volume was significantly higher (P <0.05) in both finasteride-treated groups t h a n in the placebo group, and the proportion of men who reported impotence was significantly higher (P <0.05) in the group given 1 mg of finasteride than in the placebo group. Only eight men withdrew from the study because of sexual dysfunction (one in the placebo group, three in the groulr~iven 1 mg of finasteride, and four in th e group given 5 mg of finasteride). Two men, each taking 1 mg of finasteride daily, died during the study: one died of cardiac arrest, and one committed suicide. Prostatic cancer was diagnosed in four men (one in the placebo group, two in the group given 1 mg of finasteride, and one in the group given 5 mg offinasteride). Three of these four men h a d serum prostate-specific-antigen concentrations of more t h a n 10 pg per liter at base line. The three men taking finasteride who were found to have prostatic cancer had reductions in serum prostate-specific-antigen levels during treatment, whereas the man in the placebo group had an increase. Eleven men h a d prostatic surgery during the study. One m a n had a radical prostatectomy for prostatic cancer, and 10 men had t r a n s u r e t h r a l resections (3 in the group given 5 mg of finasteride, 4 in the group given 1 mg of finasteride, and 3 in the placebo group). There was no significant effect of t r e a t m e n t on the pulse rate, blood pressure, or visual acuity. Only eight men had serious abnormalities in laboratory values during the study. One man in the group given 5 mg of finasteride had an increase in serum creatinine, calcium, potassium, and urea nitrogen concentrations. One man in the group given 1 mg of finasteride had a decrease in red-cell and white-cell
This study was u n d e r t a k e n to evaluate the safety and efficacy of finasteride in a large number of men with beniga prostatic hyperplasia. Serum dihydrotestosterone concentrations decreased to levels present after castration soon after the initiation of finasteride therapy; the greatest degree of suppression occurred in the men who received 5 mg of finasteride daily. Serum testosterone and luteinizing hormone concentrations increased only slightly and remained well within the normal range throughout the study. Prostatic volume decreased significantly within three months in both finasteride-treated groups. The median reductions in prostatic volume after 12 months were 19 percent in the group given 5 mg offinasteride daily, 18 percent in the group given 1 mg of finasteride daily, and 3 percent in the group given placebo. Approximately 50 percent of the men who received finasteride had a decrease of 20 percent or more in the size of the prostate, a response similar to t h a t reported in men treated with an analogue of gonadotropin-releasing hormone (24 percent reduction in size) 6 or surgical castration (31 percent reduction in size).5 The reduction in prostatic volume iv in the finasteride-treated men was consistent with the significant decreases in serum prostate-specific-antigen concentrations in these men, and thus were indicative of a decrease in prostatic epithelial-cell function. The three men receiving finasteride who were found to have prostatic cancer during the study also had decreases in serum prostatespecific-antigen concentrations. Therefore, a decrease in the concentration of serum prostate-specific antigen during finasteride therapy does not mean that a m a n does not have prostatic cancer, nor should it be interpreted to mean t h a t he has been adequately t r e a t e d for prostatic cancer. The maximal urinary-flow rate increased during finasteride treatment. The proportion of men who had an increase of at least 3 ml per second after 12 months was significantly higher in both finasteride-treated groups than in the placebo group. Although the increases in the maximal urinary-flow rate were small as compared with those that occur after transurethral resection of the prostate (8 to 9 ml per second TM,19), studies of the natural history of benign prostatic hyperplasia2° indicate that the mean decrease in maximal flow is about 0.2 ml per second per year. Thus, an improvement in maximal urinary flow of 3 ml per second represents a shift of about 15 years in the natural course of the disease. Despite the improvement in
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Figure 4. Median Change (+-95 Percent Confidence Interval) in Prostatic Volume in Men with Benign Prostatic Hyperplasia during Treatment with Placebo (Circles), 1 mg of Finasteride (Triangles), or 5 mg of Finasteride (Squares). Month 0 represents the base line.
FINASTERIDE FOR BENIGN PROSTATIC ttYPERPLASIA Table 4. Side Effects in Men With Benign Prostatic Hyperplasia Treated with Finasteride or Placebo for 12 months* SIDEEFFECT
1 MG 5 5IO FINASTERIDE FINASTER1DE PLACEBO (N = 298) (N = 297) (N = 300)
Digestive system Abdominalpain 0 1.0 0.3 Diarrhea 0.7 0 0 Flatulence 0 1.0 0.7 Nausea 0 0.7 1.0 Nervous system Dizziness 0.7 0 0.7 Headache 0.3 0.7 0.7 Decreased libido 6.0t 4.7t 1.3 Urogenital system Breast pain 0.7 0.3 0 Dysuria 0.3 0.7 0 Ejaculatory disorder 4.4t 4.4t 1.7 Impotence 5.0"~ 3.4 1.7 Orgasm dysfunction 0.3 0.7 0.3 Testicular pain 0.7 1.0 0.7 Eye Lens change 0.3 0.7 0 Lens opacities 1.3 0 0.7 Miscellaneous Rash 0.3 0.7 0.3 Asthenia 0.7 1.0 1.0 Pelvic pain 0.3 0.3 0.7 * The last results for the men who did not complete the study were brought forward through month 12. J"P <0.05 for the comparisonwith the placebogroup. the maximal u r i n a r y flow, the residual volume did not decrease in these patients, possibly as a result of bladder decompensation due to chronic obstruction. The m e n who received 5 m g of finasteride daily had a significantly greater decrease i n total symptom scores t h a n the m e n given placebo. The decrease i n the scores of the m e n who received 1 mg of finasteride daily was i n t e r m e d i a t e . After 12 m o n t h s , the changes i n the total symptom scores i n all groups were 30 to 70 percent of the changes t h a t occur i n m e n t r e a t e d with t r a n s u r e t h r a l resection of the prostate. Finasteride was well tolerated. The overall frequency of side effects was similar in the three groups, but the m e n who received fmasteride were more likely to have symptoms of sexual dysfunction. The long-term risks, if any, are not known. I n s u m m a r y , finasteride t h e r a p y i n m e n with b e n i g n prostatic h y p e r p l a s i a led to s u s t a i n e d decreases i n s e r u m dihydrotestosterone concentrations, followed by decreases i n ser u m prostate-specific-antigen concentrations a n d prostatic volume. These changes were accompanied by decreases i n the n u m b e r or severity of syrup.toms of u r i n a r y tract obstruction a n d increases i n the urin~Ci'y-flow rate. The effect of a daily dose of 5 m g of finasteride was greater t h a n t h a t of a 1-mg dose. We conclude t h a t t r e a t m e n t with a 5-rag dose of finasteride is beneficial in m e n with b e n i g n prostatic hyperplasia. APPENDIX The members of the Finasteride Study Group are as follows: G.L. Andriole, Washington University, St. Louis; R. Boake, University of Alberta, Edmonton; B.R. Bracken, University of Cincinnati Medical Center, Cincinnati; W. Brannan, Ochsner Clinic, New Orleans; R.C. Bruskewitz, University of Wisconsin, Madison; C.E. Cox II, University of Tennessee, Memphis; G.R. Cunningham, Veterans Affairs Medical Center and Baylor College of Medicine, Houston; P.C. Devine and P.F. Schellhammer, Eastern Virginia Medical School, Nor, folk; M. Elhilai, Royal Victoria Hospital, Montreal; J. Geller, Mercy Hospital and Medical Center, San Diego, Calif; J.T. Grayhack, Northwestern University Medical School, Chicago; L.H. Harrison, Bowman Gray School of Medicine, Winston-Salem, N.C.; P.B. Hudson, Veteran Affairs Medical Center, Bay Pines, Fla.; J. Imperato and E.D. Vaughan, Jr., New York Hospital, New York; M.M. Lieber, Mayo Clinic, Rochester, Minn.; M.C. Lippert, University of Texas, Dallas; P. Narayan, University of California, San Francisco; J.P. Perreault, Hospital St. Luc, Montreal; M.I. Resnick, Case Western
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Reserve University School of Medicine, Cleveland; R. Norman and R. Rittmaster, Dalhousie University, Halifax, N.S.; N.A. Romas and W. Rosner, St. Luke's Roosevelt Hospital Center, New York; S. Rosenblatt, University of California, Newport Beach; J.B. Roy, University of Oklahoma Health Sciences Center, Oklahoma City; E.J. Seidmon, Temple University Hospital, Philadelphia; J.S. Tenover, Harborview Medical Center, Seattle; J. Trachtenberg, Toronto General Hospital Toronto; P.C. Walsh, Johns Hopkins Hospital, Baltimore; R.D. Williams, University of Iowa Hospital and Clinic, Iowa City; and G.J. Gormley, E. Stoner, F. Pappas, A.M. Taylor, B. Binkowitz, and J. Ng, Merck Research Laboratories, Rahway, N.J. REFERENCES
1. BirkhoffJR. Natural history of benign prostatic hypertrophy. In: Hinman F, ed. Benign prostatic hypertrophy. New York: Springer-Verlag, 1983;5-9 2. Rotkin IO. Origins, distribution, and risk of benign prostatic hypertrophy. In: Hinman F, ed. Benign prostatic hypertrophy. New York: Springer-Verlag, 1983:10-21. 3. Glynn RJ, Campion EW, Bouchard GR, Silbert JB. The development of benign prostatic hyperplasia among volunteers in the Normative Aging Study. Am J Epidemiol 1985;121:78-90. 4. Roos NP, Wennberg JR, Malenka DJ, et al. Mortality and reoperation after open and transurethral resection of the prostate for benign prostatic hyperplasia. N Engl J Med 1989;320: 1120-4. 5. Bosch RJ, Griffiths DJ, Blom JM, Schreeder FH. Treatment of benign prostatic hyperplasia by androgen deprivation: effects on prostate size and urodynamic parameters. J Uro1198;141:68-72. 6. Peters CA, Walsh PC. The effect of nafareline acetate, a luteinizing-hormone-releasing hormone agonist, on benign prostatic hyperplasia. N Engl J Med 1987;317:599-604. 7. Imperato-McGinleyJ, Guerrero L, Gautier T, Peterson RE. Steroid 5a-reductase deficiency in man: an inherited form of male pseudohermaphroditism. Science 1974;186:1213-5. 8. Walsh PC, Madden JD, Harrod MJ, Goldstein JL. MacDonald PC, Wilson JD. Familial incomplete male pseudohermaphroditism, type 2: decreased dihydrotestosterone formation in pseudovaginal perineosrotal hypospadias. N Engl J Med 1974;29h944-9. 9. Ramusson GH. Biochemistry and pharmacology of 5a-reductase inhibitors. In: Furr BJA, Wakeling AE, eds. Pharmacology and clinical uses of inhibitors of hormone secretion and action. London: Baili~re Tindall, 1987;308-25. 10. Gormley GJ, Stoner E. The role of5a-reductase inhibitors in the treatment of benign prostatic hyperplasia. In: Lepor H, Paulson DF, eds. Problems in urology, Vol. 5, Philadelphia: J.B. Lippincott, 1991;436-40. 11. Rittmaster RS, Stoner E, Thompson DL, Nance D, Lasseter KC. Effect of MK-906, a specific 5a-reductase inhibitor, on serum androgens and androgen conjugates in normal men. J Androl 1989;10:259-62. 12. Gormley GJ, Stoner E, Rittmaster RS, et al. Effects offinasteride (MK-906), a 5a-rednctase inhibitor, on circulating androgens in male volunteers. J Clin Endocrinol Metab 1990;70:1136-41. 13. Stoner E, Finasteride Study Group. The clinical effects of a 5a-reductase inhibitor, finasteride, on benign prostatic hyperplasia. J Urol 1992;147:1298-302. 14. Stoner E. The clinical development of a 5a-reductase inhibitor, finasteride. J Steroid Biochem Mol Biol 1990;37:375-8. 15. Boyarsky S, Jones G, Paulson DF, Prout GR Jr. A new look at bladder neck obstruction by the Food and Drug Administration regulators: guide lines for investigation of benign prostatic hypertrophy. Trans Am Assoc Genitourin Surg 1976;68:29-32. 16. Susset JG. Development of nomograms for application of uroflowmetry. In: Hinman F, et Benign prostatic hypertrophy. New York: Springer-Verlag, 1983:528-38. 17. Levin AC, Kirschenbaum A, Kaplan P, Droller MA, Babrilove JL. Serum prostate-antigen levels in patients with benign prostatic hypertrophy treated with leuprolide. Urology 1989;34:10-3. 18. Bruskewitz RC, Christensen MM. Critical evaluation of transurethral resection and incision of the prostate. Prostate Suppl 1990;3:27-38. 19. Lepor H, Rigaud G. The efficacy oftransurethral resection of the prostate in men with moderate symptoms ofprostatism. J Urol 1990;143:533-7. 20. Drach GW, Layton TN, Binard WJ. Male peak urinary flow rate: relationship to volume voided and age. J Uro11979;122:210-4.