Finasteride and bicalutamide as primary hormonal therapy in patients with advanced adenocarcinoma of the prostate

Annals of Oncology 15: 974–978, 2004 DOI: 10.1093/annonc/mdh221

Original article

Finasteride and bicalutamide as primary hormonal therapy in patients with advanced adenocarcinoma of the prostate M.-H. Tay1, D. S. Kaufman2, M. M. Regan3, S. B. Leibowitz1, D. J. George1, P. G. Febbo1, J. Manola3, M. R. Smith2, I. D. Kaplan4, P. W. Kantoff1 & W. K. Oh1* 1

Lank Center for Genitourinary Oncology, Division of Solid Tumor Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Department of Medical Oncology, Massachusetts General Hospital, Boston, MA; 3Department of Biostatistical Science, Dana-Farber Cancer Institute, Boston, MA; 4 Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA 2

Received 1 October 2003; revised 30 January 2004; accepted 3 February 2004

Background: Medical or surgical castration is effective in advanced prostate cancer but with profound sideeffects, particularly on sexual function. Effective, less toxic therapies are needed. This study examined whether the addition of finasteride to high-dose bicalutamide enhanced disease control, as measured by additional decreases in serum prostate-specific antigen (PSA). Patients and methods: Forty-one patients with advanced prostate cancer received bicalutamide (150 mg/ day). Finasteride (5 mg/day) was added at first PSA nadir. Serum PSA was measured every 2 weeks until disease progression. Questionnaires were administered to assess sexual function. Results: Median follow-up is 3.9 years. At the first PSA nadir, median decrease in PSA from baseline was 96.5%. Thirty of 41 patients (73%) achieved a second PSA nadir and median decrease of 98.5% from baseline. Median time to each nadir was 3.7 and 5.8 weeks, respectively. Median time to treatment failure was 21.3 months. Toxicities were minor, including gynecomastia. Seventeen of 29 (59%) and 12 of 24 (50%) men had normal sex drive at baseline and at second PSA nadir, respectively. One-third of men had spontaneous erection at both time points. Conclusion: Finasteride provides additional intracellular androgen blockade when added to bicalutamide. Duration of control is comparable to castration, with preserved sexual function in some patients. Key words: bicalutamide, finasteride, prostate, potency

Introduction Most men diagnosed with advanced hormone-sensitive prostate cancer remain physically and sexually active. However, the standard of care for these men is either surgical or medical castration, which causes diminished libido, erectile dysfunction, hot flushes and osteoporosis [1]. Thus, alternative hormonal treatments with less toxicity are needed. Bicalutamide monotherapy is one such example. Combined data from two large randomized studies comparing bicalutamide monotherapy with castration at a median follow-up of 6.3 years revealed no survival difference in patients with non-metastatic disease and a modest (6 weeks) but statistically significant difference in overall survival favoring castration in patients with metastatic disease. There was preservation of sexual interest, physical capacity and decreased osteoporosis in the antiandrogen arm [2, 3]. Cross-sectional studies also suggested that bicalutamide monotherapy may maintain bone mineral density and potentially reduce the risk of fracture [4].

*Correspondence to: Dr W. K. Oh, 1230 Dana Building, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA. Tel: +617-632-3466; Fax: +617-632-2165. © 2004 European Society for Medical Oncology

Intraprostatic dihydrotestosterone (DHT) levels remain high despite androgen deprivation therapy (ADT) and is presumably derived from adrenal steroids [5, 6]. Adding finasteride, a 5-α reductase inhibitor, to antiandrogen monotherapy, may enhance intracellular androgen blockade and thus augment disease control. We undertook a study to evaluate if the addition of finasteride to bicalutamide increased intracellular androgen blockade as measured by serum prostate-specific antigen (PSA) levels. We also assessed toxicity, including effects on sexual function.

Patients and methods Eligibility criteria Patients with advanced prostate adenocarcinoma were eligible for the study. Advanced disease was defined by any of the following: positive bone scan; computed tomographic (CT) scan of bidimensionally measurable lesions; PSA ≥100 ng/ml or lymph nodes histologically positive for prostatic adenocarcinoma. In addition, patients may have failed treatment with radiotherapy (RT) or radical prostatectomy (RP). RT failures were defined as having a PSA ≥4 ng/ml 1 year after RT and a PSA increase ≥25% over nadir value, a positive prostate biopsy performed ≥2 years after RT, or a rising trend in the PSA as indicated by three values, with the second ≥25% higher than the nadir and the third ≥25% higher than the second at any time following the initiation of RT.

975 Failures following RP were defined as having a PSA ≥1 ng/ml. All patients had a life expectancy ≥3 months and a Cancer and Leukemia Group B (CALGB) performance status ≤2 at study entry. Patients with prior ADT for metastatic disease, active liver disease or impending spinal cord compression were not eligible. Written consents were obtained before treatment.

Treatment plan At study entry, baseline complete blood count, liver function tests, PSA, bone and CT scans were obtained. All except two patients were known to have undergone prophylactic breast irradiation prior to initiation of drug treatment. Pretreatment evaluation of sexual function was performed via a self-administered questionnaire, consisting of five questions derived from two previous quality-of-life studies and validated in a similar setting [7–9]. These questions addressed the quality and quantity of sexual functioning outcomes including erections, orgasms and libido over the last 4 weeks. Bicalutamide (Casodex®, Astra-Zeneca) was administered at a dose of 150 mg orally once per day and serum PSA measured every 2 weeks. At the first PSA nadir (defined as two consecutive values with each value ≥90% of the other), finasteride (Proscar®, Merck) was added at a dose of 5 mg orally daily. At the second PSA nadir, the sexual function questionnaire was readministered. Bone and CT scans were repeated if baseline scans were positive. Patients had monthly visits with physical examination and blood tests for the first 3 months of study and then every 3 months until treatment failure. At treatment failure, all blood tests and appropriate scans were repeated.

patients reached a second PSA nadir with the addition of finasteride. At the last follow-up, 11 patients who achieved second PSA nadir remained free of treatment failure and 19 had progressed. At the first PSA nadir, 34 (83%; 95% CI 68–93%), 32 (78%; 95% CI 62–89%) and 29 (71%; 95% CI 54–84%) patients achieved ≥50%, ≥75% and ≥90% decline in PSA from baseline, respectively. Corresponding PSA declines at the second nadir

Table 1. Baseline characteristics of the 41 patients in the study Characteristic

No. of patients (%) or median (IQR)a

Age, years (range)

69 (65–72)

Race Black

1 (2)

White

40 (98)

Stage at diagnosis A1 or A2

4 (10)

B0

3 (7)

B1

4 (10)

B2

13 (32)

C

4 (10)

Treatment failure and therapy at the time of failure

D1

4 (10)

Treatment failure was defined as a PSA value ≥150% of the nadir value on two separate determinations spaced ≥2 weeks apart or progressive or new lesions on bone or CT scans. The first maneuver following failure was discontinuation of both drugs at a time left to the discretion of the treating physicians. Patients were taken off study and offered standard ADT: leuteinizing hormonereleasing hormone (LH-RH) agonist or orchiectomy.

Unknown

9 (22)

Gleason grade at diagnosis 5

Statistical considerations Data are summarized as median and interquartile range (25th to 75th percentiles), or as number and per cent of patients; 95% exact binomial confidence intervals are reported for PSA response proportions and all patients who began study treatment were included in the denominators. Time-to-event variables were calculated from the date of treatment initiation and analyzed using the Kaplan–Meier method to account for censoring; Greenwood estimates of the standard errors were used to construct 95% confidence intervals (CI).

6

3 (7)

7

12 (29)

8

6 (15)

9

6 (15)

10 Unknown Received primary local treatment

This protocol was approved by the Dana-Farber/Partners Cancer Care Institutional Review Board. From January 1997 to August 2000, 43 patients were enrolled. Two patients decided against participation after registration. Characteristics of the remaining 41 patients are shown in Table 1. Fourteen and 21 patients had prior primary RP or RT, respectively, while six had no prior primary treatment. The median duration of follow-up was 3.9 years (range 0.5 to 5.4 years). Five out of 41 patients had no documentation of treatment response. Two patients withdrew because of newly diagnosed polymyalgia rheumatica and chronic lymphocytic leukemia; each not considered treatment-related. Three patients were not evaluable because of inadequate follow-up. Thirty-four of 36 remaining patients reached a first PSA nadir with bicalutamide. Thirty

1 (2) 10 (24) 35 (85)

RP

14 (34)

RT

21 (51)

None Breast RT performed

Results

3 (7)

6 (15) 39 (95)

Status at enrolment By bone or CT scan

5 (12)

PSA ≥100 only

1 (2)

Rising PSA post-RT

20 (49)

Rising PSA post-RP

12 (29)

Positive lymph nodes

3 (7)

ECOG performance status

a

0

36 (88)

1

4 (10)

2

1 (2)

IQR, interquartile range (25th–75th percentiles). CT, computed tomography; ECOG, Eastern Cooperative Oncology Group; PSA, prostate-specific antigen; RP, radical prostatectomy; RT, radiotherapy.

976 were seen in 30 (73%; 95% CI 57–86%), 29 (71%; 95% CI 54– 84%) and 26 (63%; 95% CI 47–78%) patients, respectively. The median PSA level at baseline was 19.1 ng/ml. Among 34 patients who achieved a first PSA nadir on bicalutamide alone, the median PSA nadir was 0.75 ng/ml (median 96.5% decrease from baseline) and median time to first nadir was 3.7 weeks. The median PSA nadir for the 30 patients at second PSA nadir was 0.35 ng/ml (median 98.5% decrease from baseline) and median time taken was 5.8 weeks following initiation of bicalutamide. The median treatment failure-free survival (TFFS) was 21.3 months (95% CI 12.6–32.9 months) and estimated 2 and 4 years TFFS were 43.6% (95% CI 30.1–63%) and 29.9% (95% CI 17.6–50.9%), respectively. Information on additional hormonal therapy was available for 17 of the 19 patients who failed treatment following the second PSA nadir. Fifteen patients received ADT, which included leuprolide acetate, one continued treatment with bicalutamide alone, and another patient remained on bicalutamide plus finasteride off protocol. Further information was available for 14 of the 15 patients treated with ADT. Twelve patients achieved third PSA nadir while two patients experienced PSA progression before reaching further nadir. The median time to PSA progression from initiation of leuprolide acetate was 9.8 months (range 3–22 months) with two patients censored at 5 and 10 months. Common toxicities are outlined in Table 2. The most common side-effects were mild gynecomastia and breast tenderness, mild anemia and fatigue. Despite prior breast irradiation, 18 of 39 patients developed gynecomastia. Mild abdominal discomfort and diarrhea were seen, which resolved with supportive care. Transient mild transaminitis seen in four patients resolved spontaneously despite continuation of treatment. A patient developed grade 3 prolonged prothromin time while on warfarin. Secondary malignancies were reported in two patients (lymphoma; synchronous lymphoma and colon carcinoma) but were not thought to be treatment-related. Twenty-nine of the 41 patients completed the baseline sexual function questionnaire while 24 completed the questionnaire at second PSA nadir value; 18 patients completed the questionnaire Table 2. Common toxicities among the 41 patients treated with bicalutamide and finasteride Toxicity

Grade 1 or 2

Gynecomastia/breast tenderness

25 (61%)

Grade 3 or 4

Gastrointestinal Cramps/abdominal/epigastric pain

5 (12%)

Diarrhea

2 (5%)

LFT abnormalities

4 (10%)

Constitutional Weight loss

4 (10%)

Fatigue

7 (17%)

Hemoglobin

11 (27%)

Erectile impotence LFT, liver function test.

2 (5%)

1(2%)

at both times. Effects on sexual function are summarized in Table 3. At any time during the study, most men (≥79%) were concerned with an active sex life. The proportion of men with significant lack of sexual interest, spontaneous erection or difficulty maintaining erection for sexual intercourse did not differ much at either time point. There were proportionally more men (71% versus 58–66%) who were not sexually active at the second PSA nadir. Among 18 men who completed the questionnaire at both time points, nine (50%) had no or mild loss of libido (defined as being troubled by lack of sexual interest) at baseline. At the second PSA nadir, libido was lowered in two while maintained in five men, and not known in two men. Two of the six men who had significant loss (defined as somewhat or very much a problem) of libido at baseline had improvement at second PSA nadir. Among the six men who did not have erectile dysfunction at baseline, four maintained their erectile function (defined as any erections at all) while the other two men had worsening erectile dysfunction at second PSA nadir. Lastly, one of the 12 men with erectile dysfunction at baseline had an improved erectile function at the second PSA nadir.

Discussion Despite castrate testosterone levels following ADT, intraprostatic DHT remains 15–40% of baseline [5]. Therefore, ADT incompletely deprives cancer cells of androgenic stimulation. Furthermore, it causes loss of libido, erection dysfunction and accelerated osteoporosis. Theoretically, androgenic stimulation of the prostate could be blocked at two points without lowering serum testosterone levels: conversion of testosterone to DHT within the prostate by inhibitors of 5-α reductase and testosterone, and DHT binding to androgen receptors by antiandrogens. In this manner, serum testosterone is unaffected and thus potentially preserves libido and erectile function. Serum PSA was used as a surrogate marker of response as the androgen response element in PSA gene is regulated and promoted by DHT [10, 11]. The choice of bicalutamide as the antiandrogen in this treatment protocol was based on its extensive data as monotherapy, as well as a decreased incidence of diarrhea and greater once-daily dosing convenience compared to flutamide [12]. Finasteride reduces intracellular levels of DHT and delays the time to local and distant recurrences in men with detectable PSA post-RP [13, 14]. It also decreased the prevalence of prostate cancer by 25% in a recent phase III trial with no prior history of prostate cancer [15]. In this study, additional PSA suppression was seen following the addition of finasteride to bicalutamide. With bicalutamide alone, PSA fell to a nadir value that was 3.5% of the baseline value. After finasteride was added, the PSA nadir was 1.5% of the baseline value. This result provides indirect evidence of additive intracellular androgen suppression with the addition of finasteride to bicalutamide. It is possible that the additional PSA suppression may have come from the activity of finasteride on normal prostatic epithelium following recovery from RT. However, given that the response was also seen in 10 post-RP patients, we believe this was unlikely. In fact, a similar effect on PSA by finasteride was also seen after flutamide in another study [7]. One additional

977 Table 3. Response to sexual function questionnaire at baseline and at second prostate-specific antigen (PSA) nadir. With the exception of the last question, each question referred to the last 4 weeks Baseline PSA, n (%)

Second nadir, n (%)

29

24

No

19 (70)

16 (67)

Yes

8 (30)

8 (33)

Missing

2

Questionnaires completed Any erections at all

–

Trouble achieving erection before intercourse No

6 (21)

Yes No intercourse in the past 4 weeks

2 (8)

6 (21)

5 (21)

17 (58)

17 (71)

Trouble keeping erection during intercourse No

7 (24)

4 (17)

Yes

3 (10)

3 (12)

19 (66)

17 (71)

No intercourse in past 4 weeks

How much the following has caused difficulty for you (a) Lack of sexual interest NA or missing Little or no problem

4 (14)

5 (21)

17 (59)

12 (50)

8 (28)

7 (29)

9 (31)

9 (38)

17 (59)

9 (38)

3 (10)

6 (24)

4 (15)

6 (25)

Somewhat or very much a problem (b) Unable to relax and enjoy sex NA Little or no problem Somewhat or very much a problem (c) Difficulty becoming sexually aroused NA or missing Little or no problem

16 (59)

11 (46)

Somewhat or very much a problem

7 (26)

7 (29)

Missing

2

–

(d) Difficulty having an orgasm NA

7 (24)

7 (29)

Little or no problem

10 (34)

6 (25)

Somewhat or very much a problem

12 (42)

11 (46)

(e) Difficulty getting or keeping an erection NA

7 (25)

7 (29)

Little or no problem

8 (30)

4 (17)

12 (45)

13 (54)

Somewhat or very much a problem Missing

2

–

caveat is that the first PSA plateau achieved at the first nadir and confirmed with a second PSA reading is presumed to be the maximal response attainable with bicalutamide alone and the subsequent drop in PSA is due to finasteride. Despite initial response rates of 80–90% from LH-RH agonists, nearly all men develop progressive disease after an average of 18–24 months. In this study, median duration of response (21.3 months) was comparable to LH-RH agonists although this requires confirmation in a prospective randomized trial. Furthermore, 12 of 14 (86%) patients in this study remained responsive to subsequent LH-RH agonists, although the duration of their efficacy appeared shorter had LH-RH agonists been used upfront. Nevertheless, this observation indicates that the combination of finasteride and bicalutamide as primary hormonal therapy for advanced prostate cancer probably may not compromise the overall duration of the androgen-responsive disease. Being a phase II study, no comparison can be made with other modalities such as LH-RH analog or bicalutamide monotherapy. However, in several studies, post-treatment PSA nadir is predictive of freedom from treatment failure and survival [16, 17]. Therefore, whether the lower PSA nadir achieved with bicalutamide and finasteride prolongs disease-free and overall survival can only be answered in a phase III study. Many men with prostate cancer are concerned with loss of libido and erectile dysfunction with ADT. In a previous study on the quality of life outcome in men with advanced prostate cancer after primary ADT, only 5.6% of men retained sexual interest during ADT. Spontaneous erection was absent in 83% of men while only 8% had erection firm enough for sexual intercourse [18]. In this study, higher proportions of men had better sexual function: 50% with adequate sexual interest, 33% with spontaneous erection. In addition, 79% of men who completed the questionnaires at either time point indicated that an active sex life was at least of some concern. In fact, 50% and 46% of men who answered the sexual function questionnaire at the second PSA nadir did not complain of loss of sex drive or having difficulty in becoming sexually aroused, respectively; this was comparable to baseline (59% for both questions). Although most men were not sexually active during the study, spontaneous erections were reported in one-third of men who completed the questionnaires at both time points, an encouraging finding compared with ADT. Finally, among the 18 men who answered both questionnaires at baseline and at second PSA nadir, two men had lowered sex drive as a result of treatment, but there were also two men with an increased sex drive. Although serum testosterone was not measured at either time, one possible reason for this phenomenon could be due to elevated serum testosterone as a result of the bicalutamide therapy.

How much do you care about having an active sex life? A lot

10 (36)

7 (29)

Some

12 (43)

12 (50)

A little

1 (4)

1 (4)

Not at all

5 (18)

4 (17)

Missing

1

–

Conclusion This pilot study demonstrates that bicalutamide and finasteride may be given as primary hormonal therapy for advanced prostate cancer with few side-effects. In addition, this study shows an additive effect of finasteride to the androgen-suppressive effect of bicalutamide. Overall duration of hormone responsiveness in this

978 study appears comparable to standard ADT but this should be confirmed in a prospective randomized trial. Thus, this therapy may represent a promising approach for men with advanced prostate cancer and minimal disease burden and who desire potency sparing therapy.

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