(ZD4054) in Patients with Non-Metastatic Castration-Resistant Prostate Cancer

ORIGINAL ARTICLE Phase III, randomized, placebo-controlled study of once-daily oral zibotentan (ZD4054) in patients with non-metastatic castration-resistant prostate cancer

K Miller1, JW Moul2, M Gleave3, K Fizazi4, JB Nelson5, T Morris6, FE Nathan7, S McIntosh6, K Pemberton6 and CS Higano8

BACKGROUND: Standard treatment options are limited for the management of non-metastatic castration-resistant prostate cancer (CRPC). This study, part of the ENTHUSE (EndoTHelin A USE) phase III programme, evaluated the efficacy and safety of the oral specific endothelin (ET)A receptor antagonist zibotentan vs placebo in patients with non-metastatic CRPC (non-mCRPC). METHODS: This was a multicentre, randomized, double-blind, phase III study. Patients (n ¼ 1421) with non-mCRPC and biochemical progression (determined by rising serum PSA levels) were randomized to receive zibotentan 10 mg or placebo once daily. Based on the lack of efficacy signal in another ENTHUSE phase III study, an interim analysis was performed to determine whether the study was likely to achieve the co-primary objectives of improved overall survival (OS) and progression-free survival (PFS). RESULTS: Criteria for continuation of this study were not met. A total of 79 deaths and 293 progression events were recorded at final data cutoff. Zibotentan-treated patients did not significantly differ from placebo-treated patients for OS (hazard ratio (HR): 1.13; 95% confidence interval (CI): 0.73–1.76, P ¼ 0.589) or PFS (HR: 0.89; 95% CI: 0.71–1.12, P ¼ 0.330). The most commonly reported adverse events in zibotentan-treated patients were peripheral oedema (37.7%), headache (26.2%) and nasal congestion (24.9%); each occurred with 415% higher incidence than in the placebo group. CONCLUSIONS: This trial was terminated early because of failure at interim analysis of the efficacy data to meet the defined criteria for continuation. Owing to the absence of demonstrable survival benefits in the ENTHUSE clinical studies, zibotentan is no longer under investigation as a potential treatment for prostate cancer.

Prostate Cancer and Prostatic Disease (2013) 16, 187–192; doi:10.1038/pcan.2013.2; published online 5 February 2013 Keywords: zibotentan; ZD4054; non-metastatic; castration-resistant

INTRODUCTION investigating zibotentan treatment in patients with mCRPC and Prostate cancer is the second most frequently diagnosed cancer non-mCRPC. in men worldwide.1 Patients with advanced disease invariably We report the findings from the phase III ENTHUSE study develop castration-resistant prostate cancer (CRPC).2 A substantial assessing the efficacy and safety of zibotentan vs placebo in non- proportion of these patients can remain asymptomatic for several mCRPC (ENTHUSE M0; clinicaltrials.gov NCT00626548). The trial years,3,4 and current treatment depends on a number of factors; was terminated early because of failure to meet defined efficacy pivotally, the presence or absence of metastases. In fact, there is criteria for continuation at interim analysis. no standard of care approach for these patients, and there is no therapy that has been shown to impact survival in men with non-metastatic CRPC (non-mCRPC). MATERIALS AND METHODS Endothelin (ET)-mediated signalling has been implicated in the Patients progression of prostate cancer and the development of bone Adult males with histologically or cytologically confirmed adenocarcinoma 5,6 metastases. Specifically, binding of ET-1 to the ETA receptor of the prostate who were surgically or continuously medically castrated (stable treatment for X8 weeks before study initiation) with serum facilitates various processes that promote prostate cancer growth, À 1 À 1 including tumour angiogenesis and invasion, inhibition of testosterone levels p2.4 nmol l or 70 ng dl (lower limit of quantifica- apoptosis and metastasis.5,6 Zibotentan (ZD4054), an oral, tion in many centres participating in this trial) and no evidence of metastatic disease, local recurrence or pelvic lymph node disease based on specific ETA receptor antagonist, has demonstrated survival 7,8 scans of the chest, abdomen/pelvis or bone were eligible for study benefit in a phase II study of patients with mCRPC. These inclusion. Patients were also required to have biochemical progression of promising findings led to the initiation of a large international prostate cancer, documented while castrate and defined as X2 stepwise phase III trial programme (ENTHUSE; ENdoTHelin A USE) increases in PSA over a period of X1 month, with X14 days between each

1Department of Urology, Charite´–Universita¨tsmedizin Berlin, Berlin, Germany; 2Division of Urology, Department of Surgery and Duke Prostate Center, Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA; 3Vancouver Prostate Center, University of British Columbia, Vancouver, British Columbia, Canada; 4Institut Gustave Roussy, University of Paris Sud, Villejuif, France; 5Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; 6AstraZeneca, Macclesfield, UK; 7AstraZeneca Pharmaceuticals LP, Wilmington, DE, USA and 8Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, Seattle, WA, USA. Correspondence: Professor K Miller, Department of Urology, Charite´–Universita¨tsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, Berlin 12200, Germany. E-mail: [email protected] Received 7 September 2012; revised 15 November 2012; accepted 10 December 2012; published online 5 February 2013 Zibotentan in non-metastatic CRPC K Miller et al 188 measurement. The final PSA value had to be X1.2 ng ml À 1 (patients with level; (ii) 485% power to demonstrate a statistically significant difference radical prostatectomy) or 5.0 ng ml À 1 (all other patients), representing an in PFS indicated by a HR of 0.75, assuming a median PFS for the placebo increase in X50% or absolute increase in X10 ng ml À 1 over the first of the group of 24 months, at the 1% significance level. Based on a recruitment three PSA values selected for assessment. Further details on patient period of 18 months and an OS of 47 months, it was estimated that 590 eligibility criteria have been reported previously.9 deaths would occur approximately 52 months after the first patient All patients provided written informed consent before participation in entered the study. the study. Approval of the study protocol and consent forms was obtained The HR for the co-primary objectives of OS and PFS formed the basis for from the relevant ethical review board or committee at each investiga- the continue-stop decision matrix that was developed for the interim tional site. analysis. Thus, continuation of the study would occur if HR p0.75 for OS, or 0.75oHRp1.1 for OS plus HR o0.8 for PFS. Conversely, discontinuation of the study would occur if HR 41.1 for OS, or 0.75oHRp1.1 for OS plus HR Study design X0.8 for PFS. However, if positive trends were observed in both OS This was a multicentre, randomized, double-blind, phase III study. Patients (0.75pHRp0.85) and PFS (0.8pHRp0.85), the study could continue. were stratified by centre and randomized 1:1 to receive oral zibotentan Analyses of efficacy end points (OS and PFS) were performed on an 10 mg or placebo once daily (Figure 1a). At the investigator’s discretion, intent-to-treat basis using a log-rank test, and are presented by means of patients were permitted additional standard prostate cancer therapies in Kaplan–Meier survival curves. The numbers of events at the time of the conjunction with study treatment, including regular follow-up; sympto- interim analysis are presented with corresponding HR estimates, 95% matic therapy for pain control or urinary obstruction; chemotherapy; and confidence intervals (CIs) and P-values. Safety data from all randomized secondary hormonal manipulations such as oestrogen-based preparations, patients who received at least one dose of study treatment (safety anti-androgens, ketoconazole, megestrol or prednisolone. Patients were population) are presented descriptively. allowed to continue oral bisphosphonate therapy if the dose was stabilized X4 weeks before the start of study treatment, and maintained for the duration of the study. RESULTS The absence of a significant survival benefit in the phase III ENTHUSE M1 study (NCT00554229),10 prompted an interim analysis of data in this study Study population to assess the feasibility of achieving the co-primary objectives of the study, Overall, 2577 patients were enrolled in the study between January the findings of which precipitated early termination of the study (data 2008 and May 2011 (Figure 1b). A total of 1155 (45%) patients cutoff (DCO): 1 October 2010). As a consequence, all patients were failed screening, most commonly because of detection of metasta- discontinued from study treatment, with collection of data limited tic disease (32% of all enroled patients; 71% of screening failures).9 thereafter to safety end points until final DCO (27 June 2011). Consequently, 1421 patients were randomized and 1415 patients received treatment with zibotentan (n ¼ 703) or placebo (n ¼ 712). Study end points and evaluations The majority of patients were Caucasian (70.4%), with a median Co-primary end points. Overall survival (OS), defined as time from age of 73 years (range 44–93). Demographics and baseline randomization to death from any cause, and progression-free survival characteristics (Table 1) and anticancer treatments received post (PFS) were the co-primary end points of this study. PFS was defined as the randomization (Table 2) were similar between the two treatment time from randomization to documentation of progressive metastatic arms. disease, with progression classified as any of the following: X1 new bone lesions on bone scan (confirmed by computed tomography, magnetic All patients were discontinued from treatment following the resonance imaging or X-ray); development of malignant visceral disease outcome of the interim analysis. Patients discontinued study on computed tomography/magnetic resonance imaging; or death in the treatment because of AEs (n ¼ 208; 14.6%), withdrawal of consent absence of progression. All patients underwent a bone scan and computed (n ¼ 88; 6.2%), non-compliance (n ¼ 15; 1.1%) and loss to follow- tomography or magnetic resonance imaging scan of the abdomen and up (n ¼ 4; 0.3%); the remaining 1100 (77.4%) patients discontinued pelvis (and additional regions, where clinically indicated) at study entry treatment following the outcome of the interim analysis and and then every 32 weeks until progression. subsequent study termination.

Secondary end points. Secondary objectives included time to PSA or symptomatic progression, health-related quality of life (functional assess- Efficacy ment of cancer therapy for prostate cancer) and safety. Owing to the early All patients who were randomized up to and including 1 termination of this study, the secondary efficacy objectives were not September 2010 were included in the interim analysis of efficacy subjected to analysis. (zibotentan: n ¼ 592; placebo: n ¼ 589). Originally, the primary Safety and tolerability were monitored throughout the study, and analysis was to be carried out when 410 deaths and 690 assessment encompassed the incidence and severity of adverse events progression events had occurred. At the interim analysis, 79 (AEs; graded according to the National Cancer Institute for Common Terminology Criteria for Adverse Events (CTCAE) version 3.0), laboratory deaths and 293 progression events had occurred. data (clinical chemistry, haematology, and urinalysis parameters), electro- cardiograms, vital signs and other physical examination findings. AEs were Co-primary objectives: OS and PFS. In total, 79 deaths (zibotentan: monitored at study entry and then every 28 days throughout the study. If a n ¼ 40 (6.8%); placebo: n ¼ 39 (6.6%)) and 293 progression events patient discontinued study treatment before a progression criterion was (zibotentan: n ¼ 131 (22.1%); placebo: n ¼ 162 (27.5%)) were met, AEs were monitored for the first 28 days off study treatment. The recorded at DCO (27 June 2011). patient was subsequently followed-up every 16 weeks until progression. The HR for OS did not meet the decision criteria for For patients who stopped study treatment after progression, AEs continuation of the study (HR: 1.13; 95% CI: 0.73–1.76, P ¼ 0.59; continued to be collected for the first 28 days off study treatment. For X patients who continued study treatment after progression, AEs continued Figure 2a). The HR for the co-primary end point of PFS was 0.8 to be monitored every 6 months. Patients were actively questioned by (HR: 0.89; 95% CI: 0.71–1.12, P ¼ 0.33; Figure 2b) and, in means of a possible congestive heart failure (CHF) questionnaire at every combination with the HR for OS, did not meet the decision visit, to identify possible signs and symptoms of cardiac failure. criteria for continuation of the study. Using predictive power calculations, we determined the Statistical analysis probabilities of the trial ultimately achieving a positive outcome based on the results obtained at the early analysis. For OS, given No interim analysis was planned before the trial was activated. Before the decision to perform the interim analysis, the statistical plan required the early analysis results, there was a 7% chance of the trial recruitment of 1500 patients. Originally, the study was sized to have (i) 90% ultimately achieving a significant result had the trial completed power to demonstrate a statistically significant effect in OS indicated by a according to the original size. For PFS, based on the early analysis hazard ratio (HR) for zibotentan vs placebo of 0.75, assuming a median OS results, there was a 4% chance of ultimately achieving a HR o0.75, for the placebo group of approximately 47 months at the 4% significance which would have been assessed as a successful outcome.

Prostate Cancer and Prostatic Disease (2013), 187 – 192 & 2013 Macmillan Publishers Limited Zibotentan in non-metastatic CRPC K Miller et al 189

Figure 1. (a) Study flow. aScans were only performed every 32 weeks. After the first analysis, which occurred when approximately 410 deaths had occurred (and it had been anticipated that there would be 690 progression events), the assessments undertaken every 32 weeks for progression were no longer required. Patients were followed for progression, only as clinically indicated, and survival. bPatients continuing on study treatment after the final analysis (approximately 590 deaths) had occurred were to be followed for serious adverse events (SAE) data only. cPatients who were discontinued from study treatment for safety and tolerability reasons. (b) CONSORT diagram.

& 2013 Macmillan Publishers Limited Prostate Cancer and Prostatic Disease (2013), 187 – 192 Zibotentan in non-metastatic CRPC K Miller et al 190 and headache (3.1% vs 0.1%). Overall, 14 (2.0%) patients Table 1. Patient demographics and baseline characteristics experienced fatal AEs in each treatment group. Cardiac failure events, actively solicited following a signal in a Zibotentan 10 mg Placebo 8 (n ¼ 705) (n ¼ 716) previous phase II study, and other related terms suggestive of CHF AEs (cardiac failure congestive, left ventricular dysfunction, Median age (range), 73.0 (44–93) 73.0 (44–93) cardiac failure acute or chronic) occurred in 28 (4.0%) zibotentan- years treated patients compared with 10 (1.4%) receiving placebo. Time to onset for CHF AEs was within 60 days of initiation of treatment Race, n (%) for 19 of the 28 patients in the zibotentan group. Heart failure White 496 (70.4) 504 (70.4) tended to occur within the first 3 months of dosing with Black 13 (1.8) 21 (2.9) Asian 172 (24.4) 168 (23.5) zibotentan (range, 1–502 days). CHF events resolved in the Other 24 (3.4) 23 (3.2) majority (21 of 26) of zibotentan-treated patients who received Serum testosterone, 1.1a 1.1b treatment. CHF AEs resulted in death in the placebo group alone nmol l À 1 (n ¼ 2; cardiac failure and chronic cardiac failure). In total, 12 of 28 patients who had CHF AEs in the zibotentan group had events Previous anticancer treatment, n (%) that were considered to be serious AEs. Of the 28 patients who c Hormone therapy 668 (94.8) 669 (93.4) reported CHF AEs in the zibotentan group, 26 patients received Anti-androgens 544 (77.2) 547 (76.4) treatment for this event, and the majority of events (21 patients) Radiotherapy 258 (36.6) 273 (38.1) resolved, either without interrupting zibotentan treatment (8 Radical prostatectomy 107 (15.2) 108 (15.1) Chemotherapy 10 (1.4) 6 (0.8) patients), or after temporary (2 patients) or permanent (11 Immunotherapy 2 (0.3) 4 (0.6) patients) discontinuation of zibotentan treatment. With the Other therapies 73 (10.4) 76 (10.6) exception of reductions in haemoglobin, platelet count and white Bisphosphonates 36 (5.1) 39 (5.4) cell count in zibotentan-treated patients, no clinically relevant Ketoconazole 22 (3.1) 17 (2.4) changes in laboratory safety parameters were observed between treatment groups. an ¼ 696. bn ¼ 707. cOrchiectomy had been performed in a minority of patients. DISCUSSION Analysis of data from this phase III study of zibotentan 10 mg vs Table 2. Post-randomization anticancer treatment placebo in non-mCRPC was precipitated by the findings from a partner trial (ENTHUSE M1), in which no significant improvement Zibotentan 10 mg Placebo in survival was observed for zibotentan treatment compared with (n ¼ 705) (n ¼ 716) placebo in patients with CRPC that had metastasized to bone.10 Results from this interim analysis revealed that the criteria for n (%) n (%) continuation of this study were not met; consequently, the study was terminated early. It should be noted that the early cessation of Hormone therapy 591 (83.8) 589 (82.3) the trial (leading to reduced post-randomization power) and low Anti-androgens 252 (35.7) 238 (33.2) numbers of observed mortality and PFS events (as evidenced Radiotherapy 40 (5.7) 54 (7.5) by the large confidence intervals associated with end point Chemotherapy 44 (6.2) 68 (9.5) Other systemic 95 (13.5) 132 (18.4) estimates) represent a major study limitation and preclude therapies definitive conclusions regarding the efficacy of the study Bisphosphonates 51 (7.2) 71 (9.9) treatment. The ENTHUSE programme of phase III clinical trials was designed to evaluate the efficacy and safety of zibotentan as monotherapy in mCRPC (ENTHUSE M1) and non-mCRPC Safety (ENTHUSE M0), and as combination therapy with docetaxel in Safety results are derived from the final DCO (27 June 2011), at patients with mCRPC (ENTHUSE M1C). Results from the two which time all patients had discontinued study treatment and monotherapy studies documented a failure of zibotentan to were no longer enroled on this study. The median total duration demonstrate a significant benefit over placebo, irrespective of of exposure to zibotentan was 7.95 (range: 0–35.8) months and metastasis.10 Encouraging preclinical data and initial clinical 10.69 (0.2–34.3) months for placebo. evidence supported investigation of zibotentan in combination At least one AE was experienced by 611 (86.9%) patients in the with docetaxel in the phase III setting;11–14 however, ENTHUSE zibotentan and 560 (78.7%) patients in the placebo group. The M1C failed to confirm superiority for the zibotentan and docetaxel most commonly reported AEs (all grades) in zibotentan-treated combination in mCRPC.15 Collectively, results from the ENTHUSE patients were peripheral oedema (37.7%), headache (26.2%) and programme, while disappointing, are consistent with those of the nasal congestion (24.9%), each of which occurred with 415% selective ETA receptor antagonist atrasentan, which produced higher incidence than was observed in the placebo group positive phase II data,11,16,17 but which also failed to significantly (Table 3). A similar incidence of CTCAE grade X3 events were impact disease progression in the phase III setting.18–20 reported among zibotentan-treated (172; 24.5%) and placebo- Zibotentan was generally well tolerated in this patient treated (156; 21.9%) patients. In the zibotentan group, the most population, with observed safety and tolerability data consistent frequent grade X3 AEs were headache (1.6% vs 0% for placebo), with the known profile of zibotentan. Pharmacological conse- anaemia (1.3% vs 0.7%), neutropenia (1.3% vs 1.3%) and quences of ETA antagonism by zibotentan are largely the result of peripheral oedema (1.3% vs 0.3%). Serious AEs were reported in vasodilation.21 Thus, events of headache, nasal congestion/rhinitis, 139 (19.8%) and 133 (18.7%) of patients in the zibotentan and peripheral oedema and reductions in blood pressure and placebo groups, respectively. AEs led to treatment discontinuation haemoglobin with zibotentan in this study were not unexpected in more patients receiving zibotentan (162; 23.0%) than those and reflect reports across an extensive clinical receiving placebo (44; 6.2%); primarily due to higher incidences of programme.7,8,10,21,22 CHF is a common and significant cause of peripheral oedema (4.6% vs 0.6%), nasal congestion (3.6% vs 0%) death in patients with prostate cancer;23,24 there was no evidence

Prostate Cancer and Prostatic Disease (2013), 187 – 192 & 2013 Macmillan Publishers Limited Zibotentan in non-metastatic CRPC K Miller et al 191

Figure 2. Kaplan–Meier curves of overall survival (a) and progression-free survival (b).

Table 3. Adverse events (any grade; any cause) experienced by X5% patients in either treatment arm (safety population)

Number of patients (%)

Zibotentan 10 mg (n ¼ 703) Placebo (n ¼ 712)

All grades Grade X3 All grades Grade X3

Patients with any adverse event 611 (86.9) 172 (24.5) 560 (78.7) 156 (21.9) Peripheral oedema 265 (37.7) 9 (1.3) 85 (11.9) 2 (0.3) Headache 184 (26.2) 11 (1.6) 79 (11.1) 0 Nasal congestion 175 (24.9) 3 (0.4) 39 (5.5) 0 Fatigue 69 (9.8) 1 (0.1) 76 (10.7) 4 (0.6) Constipation 64 (9.1) 2 (0.3) 76 (10.7) 2 (0.3) Nausea 59 (8.4) 3 (0.4) 59 (8.3) 3 (0.4) Rhinitis 55 (7.8) 0 16 (2.2) 1 (0.1) Dyspnoea 50 (7.1) 6 (0.9) 30 (4.2) 0 Nasal obstruction 47 (6.7) 1 (0.1) 4 (0.6) 0 Anaemia 46 (6.5) 9 (1.3) 24 (3.4) 5 (0.7) Dizziness 46 (6.5) 2 (0.3) 39 (5.5) 2 (0.3) Diarrhoea 43 (6.1) 3 (0.4) 62 (8.7) 1 (0.1) Urinary tract infection 40 (5.7) 5 (0.7) 49 (6.9) 6 (0.8) Decreased appetite 38 (5.4) 4 (0.6) 33 (4.6) 0 Arthralgia 37 (5.3) 0 51 (7.2) 2 (0.3) Asthenia 35 (5.0) 1 (0.1) 42 (5.9) 2 (0.3) Nasopharyngitis 31 (4.4) 0 41 (5.8) 0 Back pain 30 (4.3) 1 (0.1) 47 (6.6) 1 (0.1) to suggest an increased risk in zibotentan-treated patients in this reported incidences from other phase III studies in the ENTHUSE study. Indeed, the incidence of cardiac failure events in the clinical programme (zibotentan: 6%; placebo: 2%) and a phase III zibotentan (4%) and placebo groups (1%) are comparable to trial of atrasentan (atrasentan 10 mg: 5%; placebo: 1%).18 The

& 2013 Macmillan Publishers Limited Prostate Cancer and Prostatic Disease (2013), 187 – 192 Zibotentan in non-metastatic CRPC K Miller et al 192 increase in cardiac failure events is possibly due to fluid overload mildly symptomatic: a double-blind, placebo-controlled, randomized, phase II as ETA antagonism results in vasodilation. Importantly, in most trial. Eur Urol 2009; 55: 1112–1123. cases, cardiac failure events resolved with appropriate 8 James ND, Caty A, Payne H, Borre M, Zonnenberg BA, Beuzeboc P et al. Final management. safety and efficacy analysis of the specific endothelin A receptor antagonist A high screening failure rate was observed in this study, the zibotentan (ZD4054) in patients with metastatic castration-resistant prostate potential reasons for which have been examined and reported cancer and bone metastases who were pain-free or mildly symptomatic for pain: 9 a double-blind, placebo-controlled, randomized phase II trial. BJU Int 2010; 106: separately. The most common reason (comprising 71% of all 966–973. screening failures) was detection of metastatic disease. Although 9 Yu EY, Miller K, Nelson J, Gleave M, Fizazi K, Moul JW et al. Detection of previously the frequency of the most common reasons for screening failure unidentified metastatic disease as a leading cause of screening failure in a phase were similar across investigator specialties (urology vs oncology) III trial of zibotentan versus placebo in patients with nonmetastatic, castration and within geographical regions, greater variation in the overall resistant prostate cancer. J Urol 2012; 188: 103–109. failure rate was observed between geographical areas (from 38% 10 Nelson JB, Fizazi K, Miller K, Higano C, Moul JW, Akaza H et al. Phase III, rando- in the Asia Pacific region to 65% in the Middle East). The mized, placebo-controlled study of zibotentan (ZD4054) in patients with castra- prevalence of asymptomatic metastases in men thought to have tion-resistant prostate cancer metastatic to bone. Cancer 2012; 118: 5709–5718. non-mCRPC should be factored into the recruitment design of 11 Armstrong AJ, Creel P, Turnbull J, Moore C, Jaffe TA, Haley S et al. A phase I-II study of docetaxel and atrasentan in men with castration-resistant metastatic future clinical trials, which should utilize more sensitive markers of prostate cancer. Clin Cancer Res 2008; 14: 6270–6276. progression that ideally obviate the requirement for assessment 12 Banerjee S, Hussain M, Wang Z, Saliganan A, Che M, Bonfil D et al. In vitro and by imaging techniques. in vivo molecular evidence for better therapeutic efficacy of ABT-627 and taxotere To date, there are no approved agents for patients with non- combination in prostate cancer. Cancer Res 2007; 67: 3818–3826. mCRPC despite numerous other attempts to study this disease 13 Rosano` L, Di Castro V, Spinella F, Nicotra MR, Natali PG, Bagnato A. ZD4054, a state with zoledronic acid,25 atrasentan18–20 and, most recently, specific antagonist of the endothelin A receptor, inhibits tumor growth and denosumab;26 of all these phase III studies, only the latter trial enhances paclitaxel activity in human ovarian carcinoma in vitro and in vivo. Mol (denosumab) achieved complete accrual. Although none of these Cancer Ther 2007; 6: 2003–2011. studies were positive in terms of OS, denosumab did delay time 14 Trump DL, Payne H, Miller K, de Bono JS, Stephenson III J, Burris III HA et al. Preliminary study of the specific endothelin a receptor antagonist zibotentan in to bone metastases, yet did not receive Food and Drug 27 combination with docetaxel in patients with metastatic castration-resistant Administration approval for use in this setting. Hence, this prostate cancer. Prostate 2011; 71: 1264–1275. disease state is very challenging to study because of its intrinsic 15 Fizazi K, Higano C, Nelson J, Gleave M, Miller K, Morris T et al. Phase III, rando- heterogeneity, longer natural history and, in recent years, mized, placebo-controlled study of docetaxel in combination with zibotentan the availability of numerous downstream therapies that (ZD4054) in patients with metastatic castration-resistant prostate cancer. modify outcome and could confound the results of a trial in Submitted to J Clin Oncol 2012. non-mCRPC.28 16 Carducci MA, Padley RJ, Breul J, Vogelzang NJ, Zonnenberg BA, Daliani DD et al. In conclusion, this study was terminated early on the basis of Effect of endothelin-A receptor blockade with atrasentan on tumor progression in results from an interim analysis indicating that zibotentan men with hormone-refractory prostate cancer: a randomized, phase II, placebo- À 1 controlled trial. J Clin Oncol 2003; 21: 679–689. 10 mg day was unlikely to meet its co-primary end points of 17 Nelson JB, Nabulsi AA, Vogelzang NJ, Breul J, Zonnenberg BA, Daliani DD et al. OS and PFS. As a result of the lack of efficacy in the ENTHUSE trials, Suppression of prostate cancer induced bone remodeling by the endothelin zibotentan is no longer being investigated as a potential receptor A antagonist atrasentan. J Urol 2003; 169: 1143–1149. treatment for patients with prostate cancer. 18 Carducci MA, Saad F, Abrahamsson PA, Dearnaley DP, Schulman CC, North SA et al. A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer. Cancer 2007; CONFLICT OF INTEREST 110: 1959–1966. KM is a consultant to AstraZeneca (AZ), Astellas and Janssen–Cilag; JWM is a paid 19 Nelson JB, Love W, Chin JL, Saad F, Schulman CC, Sleep DJ et al. Phase 3, ran- consultant of AZ; MG, KF and CSH participated in an AZ advisory board; JBN is a paid domized, controlled trial of atrasentan in patients with nonmetastatic, hormone- consultant of AZ; TM, FEN, SM and KP are all employees of AZ and have stock refractory prostate cancer. Cancer 2008; 113: 2478–2487. ownership. 20 SWOG Press Release. Addition of atrasentan to standard chemotherapy for advanced prostate cancer shows no benefit in phase III clinical trial. SWOG 2012, Internet Communication. ACKNOWLEDGEMENTS 21 Warren R, Liu G. ZD4054: a specific endothelin A receptor antagonist with promising activity in metastatic castration-resistant prostate cancer. Expert Opin We thank Zoe¨ van Helmond, PhD from Mudskipper Bioscience who provided writing Investig Drugs 2008; 17: 1237–1245. assistance funded by AstraZeneca. 22 Liu G, Dreicer R, Hou J, Chen Y, Wilding G. Tolerability profile of ZD4054 is consistent with the effects of endothelin A receptor-specific antagonism. 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