Is There a Role for Antiandrogen Monotherapy in Patients with Metastatic Prostate Cancer?

Home , Antiandrogen, Bicalutamide, Flutamide, Nilutamide, Prostate cancer, Steroidal antiandrogen

Prostate Cancer and Prostatic Diseases (2001) 4, 196–203 ß 2001 Nature Publishing Group All rights reserved 1365–7852/01 $15.00 www.nature.com/pcan Review Is there a role for antiandrogen monotherapy in patients with metastatic prostate cancer?

AV Kaisary1*, P Iversen2, CJ Tyrrell3, K Carroll4 & T Morris4 1Royal Free Hospital, London, UK; 2Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; 3Derriford Hospital, Plymouth, UK; and 4AstraZeneca, Macclesﬁeld, UK

Castration is the most widely used form of androgen ablation employed in the treatment of metastatic (M1) prostate cancer. Non-steroidal antiandrogen monotherapy is a potential alternative treatment option for men for whom castration is unacceptable or not indicated. Of the three non-steroidal antiandrogens, bicalutamide (‘Casodex’), flutamide and nilutamide, only bicalutamide has been compared with castration in large, controlled, randomised, Phase III trials in M1 patients. A post-hoc analysis of these studies indicated that bicalutamide 150 mg/day monotherapy may be of benefit to M1 patients with a prostate specific antigen (PSA) level 400 ng/ml. Significant advantages for M1 patients treated with bicalutamide were observed in subjective response rate, maintenance of sexual interest and physical capacity. Patients with a higher disease burden (PSA > 400 ng/ml) may decide that quality of life and symptomatic benefits outweigh the slight survival disadvantage seen in clinical trials and opt for bicalutamide monotherapy as an alternative to castration. Prostate Cancer and Prostatic Diseases (2001) 4, 196–203.

Keywords: non-steroidal antiandrogens; castration; prostate speciﬁc antigen

Introduction therefore, a need for alternative treatment options for these men. Since androgen sensitivity of prostate cancer was demon- Compounds that interfere with the production and/or strated in 1941,1 the mainstay of treatment for metastatic function of androgens have been introduced for the (M1) prostate cancer has been androgen deprivation, management of advanced prostate cancer. The action of generally achieved by castration, either bilateral orchiect- such antiandrogens results from the competitive inhibi- omy or maintenance luteinising hormone-releasing hor- tion of the binding of the metabolite of testosterone, mone (LHRH) agonist therapy. A major disadvantage dihydrotestosterone (DHT), to nuclear receptors in pros- associated with both methods of castration is the reduc- tate cancer cells.4 Steroidal antiandrogens have progesta- tion in the levels of circulating testosterone originating genic properties and suppress gonadotrophins to lower from the testes. This can adversely affect patient quality of plasma testosterone levels, and this also results in life, an important consideration in this palliative setting. decreased libido and sexual potency. In contrast, non- In particular, libido and sexual potency are generally steroidal antiandrogens have no antigonadotrophic diminished2,3 and this may be unacceptable to some effects. As well as binding competitively to the prostatic men. Additionally, some patients may have personal intracellular androgen receptors, they also block andro- reasons for avoiding castration, may prefer oral therapy, gen receptors in the brain, leading to successive increases or may not tolerate LHRH agonist therapy. There is, in LHRH, luteinising hormone (LH) and testosterone secretion. By maintaining levels of circulating testosterone, non-steroidal antiandrogens have less of an impact *Correspondence: AV Kaisary, Royal Free Hospital, Pond Street, on patients’ libido and sexual potency.5 London, NW3 2QG, UK. E-mail: [email protected] As a result of increasing awareness of prostate cancer Received 11 December 2000; revised 2 May 2001; accepted and advances in early detection, patients are being treated 30 May 2001 at an earlier stage of their disease. In the future, patients Antiandrogen monotherapy in M1 prostate cancer AV Kaisary et al 197 with metastatic prostate cancer will probably have less respect to survival (hazard ratio (HR) 1.30; 95% confi- tumour burden and better performance status, and there- dence interval (CI) 1.04, 1.64; P ¼ 0.02).7 However, the fore will require treatment which has minimal impact on difference in estimated median survival times between their quality of life. the bicalutamide and castration groups was small (6 This review discusses the possible role of the three non- weeks (42 days)), see Figure 1. steroidal antiandrogens — bicalutamide (‘Casodex’,a trade mark of the AstraZeneca group of companies), flutamide and nilutamide — as alternatives to castration Flutamide in patients with M1 prostate cancer. As well as examining Flutamide is also a potent non-steroidal antiandrogen, but the survival data, the benefits of non-steroidal antiandro- with lower affinity for the androgen receptor than bicalu- gen monotherapy with respect to subjective response and tamide.9 It is rapidly and extensively metabolised, and the quality of life are assessed. The tolerability profiles of the plasma half-life of its major metabolite (thought to be the three compounds are also compared. active form of flutamide) is 5 – 6h.10 Therefore, the parent drug must be administered three times daily. Studies of flutamide monotherapy against active com- parators in patients with M1 prostate cancer are sum- Survival data from non-steroidal marised in Table 1. Of these seven studies,10 – 16 only one compared flutamide monotherapy and castration.14 antiandrogen studies in M1 patients Although no definite conclusions can be drawn from this Bicalutamide small study (104 patients), overall survival at 69 months was identical in the two treatment groups. The other six Bicalutamide is a potent, non-steroidal antiandrogen and studies compared flutamide monotherapy with other meth- has a half-life of approximately 1 week, which allows ods of androgen deprivation (Table 1): maximal androgen once daily dosing.6 Two large, multicentre, randomised, blockade (MAB),16 diethylstilboestrol (DES),10 – 13 andestra- Phase III studies of identical design compared bicaluta- mustine.15 Five of the studies reported no statistically sig- mide 150 mg/day monotherapy with castration in men nificant between-group differences in survival.10 – 12,14,16 In with locally advanced or advanced prostate cancer.7,8 A contrast, in the trial of 92 patients reported by Chang et al,13 total of 480 patients with non-metastatic disease (M0) and the DES treatment group had a significantly longer overall 808 patients with confirmed metastatic disease (M1) were survival than flutamide-treated patients (43.2 vs 28.5 recruited. months; P ¼ 0.04), although median survival in the DES A pooled analysis of the M1 patients was conducted at group was longer than normally expected in this setting. a median follow-up of 100 weeks. Survival data for M1 However, interpretation of the results of all these studies is patients were considered mature at this point as 43% of difficult. The results of the largest study are only available in M1 patients had died. The data showed that bicalutamide abstract form,16 while all other studies lacked adequate 150 mg/day was less effective than castration with statistical power.

Figure 1 Kaplan-Meier analysis of overall survival in M1 patients treated with bicalutamide 150 mg monotherapy or castration (n ¼ 805). Reproduced with kind permission.7

Prostate Cancer and Prostatic Diseases Antiandrogen monotherapy in M1 prostate cancer AV Kaisary et al 198 Table 1 Summary of comparative, randomised studies of ﬂutamide (250 mg three times daily) monotherapy in M1 patients

No. Reference Comparator patients Efﬁcacy outcome

Jacobo et al., 197611 DES 1 mg 15 No significant difference between groups in objective progression Lund & Rasmussen 198812 DES 3 mg 40 No statistically significant difference in subjective response between groups. Preservation of sexual potency in patients receiving flutamide monotherapy Chang et al., 199613 DES 3 mg 92 Patients receiving DES had a statistically significant longer time to treatment failure and longer overall survival Neri & Kassem 199610 DES 1 mg 125 No statistically significant difference in objective response, time to progression or overall survival between groups Boccon-Gibod et al., 199714 Orchiectomy 104 No difference in overall survival between the two groups Johansson et al., 198815 Estramustine 560 mg 30 A statistically significant difference in progression-free survival in favour of estramustine Pavone-Macaluso 199416 MAB (flutamide plus castration) 319 No difference in objective response or survival between groups

MAB, maximal androgen blockade; DES, diethylstilboestrol.

Nilutamide gested by the findings of the two large bicalutamide monotherapy studies.7 In contrast to the M1 setting, M0 Nilutamide is structurally similar to flutamide but has a patients (after a median follow-up of 6.3 y with a death 17 longer half-life (approximately 2 days). rate of 56%) demonstrated no statistically significant There are no comparative studies of nilutamide mono- difference in overall survival between the bicalutamide therapy vs castration in M1 patients. Published clinical 150 mg/day and castration groups (HR 1.05; 95% CI 0.81, experience with nilutamide monotherapy is limited to a 1.36; P ¼ 0.70).8 In addition, in a small study of flutamide single uncontrolled study of 26 previously untreated monotherapy, a post-hoc analysis of 28 evaluable M1 18 patients with metastatic prostate cancer. The objective patients suggested flutamide monotherapy might offer a response rate to nilutamide 100 mg three times daily was reasonable alternative to castration in patients with low- approximately 40%, with a median progression-free sur- volume disease.14 However, the authors recommended vival and median overall survival of 9 and 23 months, that these results should be interpreted with extreme respectively. However, because of the small sample size caution. In this study tumour burden was stratified on and lack of control group, it is impossible to draw any the basis of prostate specific antigen (PSA), since PSA meaningful conclusions regarding the efficacy of niluta- concentrations in the serum correlate approximately with mide monotherapy. disease bulk.19,20 Prostatic disease burden has been reported to affect antiandrogen efficacy in MAB regimens. Two studies have reported benefits for MAB over castration in patients Does disease volume affect the efficacy with minimal metastases but not those with extensive of antiandrogen therapy? disease.21,22 However, a recent meta-analysis suggests the trend for efficacy in minimal disease is in favour of Theoretical basis castration23 and therefore this question has yet to be resolved. There is a theoretical basis for antiandrogen efficacy being Pre-treatment PSA values have also been found to be affected by tumour volume. Castration removes the major related to survival outcome in a study of 67 patients with source of androgens from the body, irrespective of disease metastatic prostate cancer treated with orchiectomy or burden. In contrast, antiandrogens reduce exposure of flutamide plus goserelin (‘Zoladex’, a trade mark of the prostate cancer cells to androgen by competing for the AstraZeneca group of companies).24 A PSA level of androgen receptor binding sites in the tumour cells. 300 ng/ml could be used to discriminate between poor Therefore, the effectiveness of antiandrogens is partly ( > 300 ng/ml) and better ( < 300 ng/ml) risk groups dependent on the number of androgen receptor binding (P ¼ 0.003). sites and, indirectly, on tumour burden. In addition, tumour volume will affect antiandrogen penetration. It follows that a dose of antiandrogen is likely to block androgen receptors more effectively in a patient with a Evidence from studies of antiandrogen monotherapy low tumour burden than in a patient with a high tumour Based on PSA values, a post-hoc analysis of the two large burden. Other factors, such as mutations in the androgen bicalutamide monotherapy studies7,8 was conducted to receptor gene, which occur more frequently in metastatic establish whether there was a trend which related efficacy lesions than primary tumours, may also affect the binding to the burden of the disease within the M1 patient and therefore the efficacy of antiandrogens in patients, population. particularly in patients with high-volume disease. In this analysis, the M1 patients were divided into three groups of approximately equal size according to baseline ¼ Circumstantial evidence from clinical studies levels of PSA: < 100 ng/ml (n 271), 100 – 400 ng/ml (n ¼ 246) and > 400 ng/ml (n ¼ 260). As shown in Figure The possibility that the efficacy of antiandrogen mono- 2, bicalutamide 150 mg/day and castration had similar therapy may be dependent on disease volume is sug- efficacy in M1 patients with PSA 400 ng/ml

Prostate Cancer and Prostatic Diseases Antiandrogen monotherapy in M1 prostate cancer AV Kaisary et al 199 (PSA < 100 ng/ml, HR 1.1; PSA 100 – 400 ng/ml, HR 1.1). In revealed that the subjective response rate was significantly contrast, the survival data favoured castration in M1 higher in the bicalutamide 150 mg/day group than in the patients with baseline PSA > 400 ng/ml (HR 1.4). castration group (70.0 vs 58.2%; P ¼ 0.046), see Figure 3.7 Similar data relating survival to disease burden are not The odds ratio for this difference was 1.68, an odds ratio of available from the comparative flutamide monotherapy > 1 indicating a greater chance of a subjective response studies. being observed in M1 patients receiving bicalutamide. Data on the subjective response to flutamide monotherapy is limited, but in their study comparing flutamide Effect of non-steroidal antiandrogens on monotherapy and flutamide-based MAB, Pavone-Maca- luso16 reported that 66.2% of patients had a subjective subjective response and quality of life in response to flutamide monotherapy, a figure similar M1 patients to that reported for bicalutamide 150 mg/day in the two large monotherapy studies but inferior to that for Subjective response flutamide-based MAB (79.8%). In the two large bicalutamide monotherapy trials, a total of 288 M1 patients were symptomatic at study entry and therefore potentially able to exhibit a subjective response Quality of life during the study.7 Criteria for a subjective response were based on scores for performance status, cancer-related pain With increasing awareness of prostate cancer and and requirements for cancer-related analgesia. Analysis advances in early detection, quality of life has become

Figure 2 Kaplan-Meier analysis of overall survival in M1 patients treated with (a) bicalutamide 150 mg monotherapy or (b) castration according to baseline PSA (n ¼ 777).

Prostate Cancer and Prostatic Diseases Antiandrogen monotherapy in M1 prostate cancer AV Kaisary et al 200

Figure 3 Subjective response to bicalutamide 150 mg and castration in M1 patients. Reproduced with kind permission.7 *P ¼ 0.046.

an important consideration in patients with advanced functioning, vitality, emotional wellbeing, and physical malignancy receiving palliative treatment. A comparative capacity. trial of 656 men with and without prostate cancer showed There are no data on the comparative effects of fluta- that a decline in sexual function was the most common mide monotherapy vs castration on sexual parameters, as cause of disease-specific stress,25 and hence reduced the majority of the patients studied by Boccon-Gibod and quality of life. The impact of such factors can be consider- colleagues14 were impotent before study entry. Compara- able, with survey data showing that many men are will- tive data on other aspects of quality of life were not ing to accept a treatment with higher mortality rates to reported in any of the flutamide monotherapy studies. avoid a 100% chance of impotence.26,27 In the two large trials of bicalutamide 150 mg/day monotherapy compared with castration, quality of life was assessed at 12 months by a questionnaire covering 10 Tolerability of non-steroidal quality of life dimensions (overall health, pain, emotional antiandrogens wellbeing, vitality, social function, physical capacity, sexual interest, sexual functioning, activity limitation and bed Antiandrogen monotherapy is generally well tolerated in disability).7 Very few patients with M1 disease answered men with metastatic prostate cancer, although differences the question on sexual function. When the results for M1 in side effect profiles are apparent, which may influence and M0 patients were combined, a non-significant trend the choice of antiandrogen. towards less reduction of sexual function was seen in In the two large-scale bicalutamide monotherapy stu- patients treated with bicalutamide compared with castra- dies, the events reported most frequently by the patients tion (20 vs 36%). In patients with M1 disease, statistically with M1 disease treated with bicalutamide 150 mg/day significant advantages were demonstrated in patients ran- were breast pain and gynaecomastia.7,8 This was as domised to bicalutamide for physical capacity and sexual expected because antiandrogens block receptors in a interest (P ¼ 0.032 and 0.041, respectively), see Figure 4.7 variety of testosterone-sensitive tissues, leaving unop- Only the quality of life domain ‘overall health’ favoured posed oestrogen action in the breast. The incidence of castration and this was not statistically significant. hot flushes was lower in the bicalutamide group (9.5%) Similarly, antiandrogen monotherapy (bicalutamide than in the castration group (38.6%). Otherwise the 150 mg/day) has been shown to confer quality of life adverse event profiles for the two treatment groups advantages over MAB (goserelin plus flutamide) in a were similar. The incidence of diarrhoea was low in study involving a total of 220 patients (49.5% stage M0 both treatment arms (3.9 and 5.8% in the bicalutamide- and 50.5% stage M1 prostate cancer).28 After a median treated patients from the two studies, respectively). Few follow-up of 38 months, significantly fewer patients M1 patients in the bicalutamide monotherapy group receiving antiandrogen monotherapy complained of loss discontinued treatment due to drug-related adverse of sexual interest (P ¼ 0.01) and erectile dysfunction events (2.2%) (AstraZeneca, data on file). Bicalutamide (P ¼ 0.002) than in the MAB group. There were also was not associated with clinical hepatotoxicity in this significant trends favouring antiandrogen monotherapy study, although isolated cases of elevated liver enzymes with respect to other quality of life parameters, ie social were observed.29 Cases of hepatic failure in bicalutamide-

Prostate Cancer and Prostatic Diseases Antiandrogen monotherapy in M1 prostate cancer AV Kaisary et al 201

Figure 4 Quality of life analysis of the effect of treatment with bicalutamide 150 mg or castration at 12 months in M1 patients. Reproduced with kind permission.7

treated patients are rare.30 Interstitial pneumonitis, an patients (11%) in the group receiving flutamide, but there inflammatory condition of the lung, has also only been were no reports of fatal hepatotoxicity in either group. reported with bicalutamide therapy in isolated cases.31 Gynaecomastia and breast pain are also the most common adverse events observed during flutamide monotherapy for advanced prostate cancer.32 Gastroin- testinal side effects, in particular diarrhoea, are also com- Conclusion monly associated with flutamide treatment,33 – 35 which can lead to treatment withdrawal.32 Additionally, cases Of the three non-steroidal antiandrogens, only bicaluta- of clinical hepatotoxicity have been documented during mide has been compared with castration in controlled, flutamide therapy,32,36 some of which have been fatal.36 randomised, Phase III trials in M1 patients. Indeed, the Nilutamide is associated with delayed adaptation to majority of data on non-steroidal antiandrogen mono- darkness after exposure to bright light,37 – 42 nausea and therapy in M1 prostate cancer originates from the com- vomiting,18,38 – 40 and alcohol intolerance.18,39,40,43 These bined results of two large-scale studies comparing problems have not been associated with either bicaluta- bicalutamide 150 mg/day with castration.7,8 While flutamide or flutamide. In the small uncontrolled study mide has been compared with castration and other forms reported by Decensi et al18 decreased adaptation to dark- of androgen deprivation in Phase II and III studies, most ness, nausea and alcohol intolerance were reported by studies had insufficient power to detect significant differ- 30.8, 26.9, and 19.2% of M1 patients, respectively. Inter- ences in survival outcome. There are no comparative data stitial pneumonitis has also been reported with on nilutamide monotherapy. nilutamide.32,39,42,44,45 A post-hoc analysis of M1 patients in the bicalutamide There are no direct comparisons between the non- monotherapy studies, categorised by baseline PSA values, steroidal antiandrogens in the monotherapy setting. indicated that bicalutamide 150 mg/day monotherapy However, in the MAB setting, diarrhoea was found to may be of particular benefit to M1 patients with a lower be less frequent with bicalutamide therapy than with disease burden (PSA 400 ng/ml) for whom castration is flutamide (12 vs 26%; P < 0.001).46 Overall, withdrawal not indicated or acceptable. Compared with castration, from therapy due to adverse events occurred for 10 and bicalutamide 150 mg/day monotherapy is associated with 16% of patients receiving bicalutamide and flutamide, a small survival disadvantage in M1 patients with a respectively. Furthermore, there were fewer withdrawals higher disease burden (PSA > 400 ng/ml). However, due to diarrhoea in the bicalutamide group than in because of quality of life advantages, these patients may flutamide-treated patients (0.5 vs 6%). Treatment-related still decide on antiandrogen monotherapy. The efficacy of abnormal liver function test results were reported for 27 second-line castration therapy following initial antiandro- patients (7%) in the group receiving bicalutamide and 43 gen therapy has not been formally assessed. However, it is

Prostate Cancer and Prostatic Diseases Antiandrogen monotherapy in M1 prostate cancer AV Kaisary et al 202 interesting to note that following progression in the M0 14 Boccon-Gibod L et al. Flutamide versus orchidectomy in the patients, some form of castration therapy was the com- treatment of metastatic prostate carcinoma. Eur Urol 1997; 32: monest form of second-line therapy. Patients treated with 391 – 396. 15 Johansson JE, Andersson SO, Beckman KW, Zador G. Clinical bicalutamide tended to progress earlier than patients evaluation with long-term follow-up of flutamide and estramus- treated with castration; however, there was little differ- tine as initial treatment of metastatic carcinoma of the prostate. ence between the treatment groups in terms of survival. Am J Clin Oncol 1988; 11(Suppl 2): S183 – S186. This suggests that the development of a hormone-resistant 16 Pavone-Macaluso M. Flutamide monotherapy versus combined state with initial antiandrogen therapy is unlikely to be a androgen blockade in advanced prostate cancer. Interim report of common problem, as patients still appear to respond to an Italian multicenter, randomised study. SIU 23rd Congress 1994: Abs. 354. second-line castration therapy. Thus, initial bicalutamide 17 Harris MG, Coleman SG, Faulds D, Chrisp P.Nilutamide. A review monotherapy may be followed by castration on progres- of its pharmacodynamic and pharmacokinetic properties, and sion, with little risk of decreased efficacy being apparent. therapeutic efficacy in prostate cancer. Drugs Aging 1993; 3:9– 25. Castration is the most widely used form of androgen 18 Decensi AU et al. Monotherapy with nilutamide, a pure nonster- ablation employed in the treatment of metastatic prostate oidal antiandrogen, in untreated patients with metastatic carci- cancer. Patients may have personal reasons for avoiding noma of the prostate. 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