Urological Science xxx (2015) 1e5. Contents lists available at ScienceDirect. Urological Science. journal homepage:

Urological Science xxx (2015) 1e5 Contents lists available at ScienceDirect Urological Science journal homepage: www.urol-sci.com Original article The efficacy of abiraterone acetate in treating Taiwanese chemo-refractory metastatic castration-resistant prostate cancer patients Tony Wu a, *, Hsi Chin Wu b, Yen Chuan Ou c, See-Tong Pang d, Yeong-Shiau Pu e, Yen-Hwa Chang f a Department of Surgery, Kaohsiung Veterans General Hospital and School of Medicine, National Yang-Ming University, Taipei, Taiwan b Department of Urology, China Medical University Hospital and School of Medicine, China Medical University, Taichung, Taiwan c Division of Urology, Taichung Veterans General Hospital, Taichung, Taiwan d Department of Urology, Chung Gung Memorial Hospital, Linko, Taiwan e Department of Urology, School of Medicine, National Taiwan University Hospital, Taipei, Taiwan f Department of Urology, Taipei Veterans General Hospital and School of Medicine, National Yang-Ming University, Taipei, Taiwan article info abstract Article history: Received 15 September 2015 Received in revised form 2 November 2015 Accepted 3 November 2015 Available online xxx Keywords: abiraterone acetate docetaxel metastatic castration-resistant prostate cancer prednisolone prostate-specific antigen Objective: To evaluate the efficacy of abiraterone acetate in combination with prednisolone in Taiwanese men with metastatic castrate-resistant prostate cancer (mcrpc) who failed docetaxel-based chemotherapy. Materials and methods: In this single-arm, open label study, 30 mcrpc patients with prostate specific antigen (PSA) progression after docetaxel chemotherapy were enrolled. All patients were treated with abiraterone acetate 1000 mg once daily and prednisolone 5 mg twice daily. The primary end-point was PSA response rate (defined as proportion of patients achieving a PSA decline of 50%). Secondary endpoints were overall survival and time-to-psa progression. Results: Among 28 patients who received one or more cycles of treatment, 15 (53.6%) men achieved PSA response [95% confidence interval (CI) 33.9e72.5]. The median time-to-psa progression was 5.5 months (95% CI 3.1e7.9). The median interval from stopping abiraterone to death was 3.4 months (95% CI 0.1 e21.0), and the median overall survival was 19.2 months (95% CI 13.0e25.4). The PSA responders had better overall survival compared with PSA nonresponders, in both univariate (log rank test, p ¼ 0.007) and multivariate (Cox regression, p ¼ 0.001; relative risk: 0.31; 95% CI: 0.12e0.76) analysis. Both a high Gleason score (8) and viscera involvement did not have an unfavorable response to abiraterone treatment. Conclusion: A combination of abiraterone acetate and prednisolone can improve the overall survival in Taiwanese mcrpc patients who fail prior docetaxel chemotherapy. Copyright 2015, Taiwan Urological Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 1. Introduction Prostate cancer is now the fifth most commonly diagnosed cancer and is the seventh leading cause of cancer deaths in Taiwanese men. In 2012, there were 4740 newly diagnosed patients, with an age-standardized incidence of 29.73/100,000 population. 1 A total of 14,769 prostate cancer patients were registered * Corresponding author. Department of Surgery, Kaohsiung Veterans General Hospital, 382 Ta-Chung First Road, Kaohsiung, Taiwan. E-mail address: tonyw@vghks.gov.tw (T. Wu). into the Taiwan Cancer Registry between 2008 and 2012; among them 4719 patients (31.95%) were Clinical Stage N1 or M1 and were treated with androgen-deprivation therapy according to local guidelines. 2 The majority of N1/M1 patients respond well to androgen-deprivation therapy initially, however, almost all men will eventually have prostate specific antigen (PSA) and/or bone scintiscan progression, despite castrate levels of testosterone. This is referred to as castrate-resistant prostate cancer (CRPC). 3 Historically, the median survival for men with metastatic CRPC (mcrpc) has been <2 years. 3 Recent studies have shown that despite surgical or medical castration, adrenal gland and tumor cells may still produce http://dx.doi.org/10.1016/j.urols.2015.11.003 1879-5226/Copyright 2015, Taiwan Urological Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

2 T. Wu et al. / Urological Science xxx (2015) 1e5 androgen that stimulates tumor growth through the androgen receptor signaling pathway. 4,5 The key enzyme involved in adrenal and intratumor androgenic steroid biosynthesis is CYP17. 6 Abiraterone is a strong, irreversible CYP17 inhibitor. By blocking the function of 17, 20-lyase, and 17-alpha-hydroxylase, abiraterone suppresses the biosynthesis of androgen, not only in the adrenal gland but also in tumor and peripheral tissue, resulting in a decrease of serum testosterone levels to <1 ng/ml. 4e9 In a Phase III registration trial, abiraterone in combination with prednisolone or prednisone was shown to prolong overall survival in men with mcrpc who had received prior docetaxel-based chemotherapy. 10e12 An overall survival benefit and radiographic free survival benefit was also shown in a separate Phase III registration trial in chemotherapy-naïve patients. 13,14 Between 2011 and 2013, we carried out a multicenter, openlabel, single-arm, Phase II bridging study in Korea and Taiwan, to evaluate the safety and efficacy of abiraterone acetate plus prednisolone in an Asian population with mcrpc who failed docetaxelbased chemotherapy (PCR 2007 study). 15 A total of 82 patients (52 Korean and 30 Taiwanese) were enrolled. After a median treatment duration of 5.7 months, and a median follow-up time for survival of 8.3 months, 35 (42.7%) patients achieved a PSA response [95% confidence interval (CI) 31.8e54.1]. The median overall survival (from the date of the 1 st dose of abiraterone acetate, until the date of death) was 11.8 months. 15 Despite a relatively short treatment and follow-up duration in this study, we found comparable outcomes with similar studies conducted in Caucasian populations. 5,10 The present study was an extended follow up for the survival outcome of Taiwanese patients in the PCR 2007 study. 2. Materials and methods 2.1. Study population Patients aged 20 years with mcrpc and documented PSA and/ or image progression after docetaxel chemotherapy were enrolled. All had Eastern Cooperative Oncology Group performance status 2, and had histologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell histology. Patients on a stable dose of bisphosphonate were allowed to participate in the study. Key exclusion criteria included: (1) serious or uncontrolled coexistent nonmalignant disease, including active and uncontrolled infection; (2) uncontrolled hypertension, hemoglobin 9.0 g/dl; (3) abnormal liver function [total bilirubin > 1.5 upper limit of normal (ULN), aspartate transaminase or alanine transaminase > 2.5 ULN]; (4) active viral hepatitis or chronic liver disease; (5) serum creatinine > 2.0 ULN; (6) history of adrenal insufficiency or hyperaldosteronism; and (7) clinically significant heart disease. Patients who were treated previously with ketoconazole were also excluded from the study. The study protocol was reviewed and approved by our local institutional review board or ethics committee. All enrolled patients provided written consent for participation in this study. 2.2. Study design Eligible patients received abiraterone acetate 1000 mg once daily and prednisolone 5 mg twice daily, orally. Each treatment cycle consisted of 28 days. Patients continued to receive abiraterone acetate in combination with prednisolone until disease progression, unacceptable toxicity, or withdrawal of informed consent for any reason. 2.3. Efficacy The PSA response rate (defined as the proportion of patients achieving a PSA decline of 50% from Cycle 1 Day 1 level) and the 95% CI were calculated based on the treated population (all patients who received 1 dose of abiraterone acetate). Secondary endpoints included overall survival (defined as the time interval from the date of the 1 st dose of abiraterone acetate, until the date of death due to any cause) and time-to-psa progression (defined as the time interval between the 1 st date of abiraterone acetate treatment and the date of PSA progression). In patients whose PSA level had never decreased, PSA progression was defined as a 25% increase over the baseline and an increase in the absolute value by at least 5 ng/ml; in those whom the PSA had decreased but had not reached response criteria, progressive disease was defined as an increase of PSA level by 25% from the nadir and an absolute value by 5 ng/ml; for PSA responders, PSA progression was defined as an increase of 50% above the nadir and a minimum of 5 ng/ml; all increases in PSA needed confirmation by a second PSA value at least 1 week apart. 10 2.4. Statistical analysis The PSA response rate and the 95% CI were calculated based on patients who received one or more cycles of abiraterone acetate by Clopper-Pearson exact method carried out using Daniel Soper Statistics Calculator version 3 (at DanielScoper.com by Dr. Daniel S. Scoper at California State University, Fullerton, CA, USA). The overall survival and time-to-psa progression was estimated using the KaplaneMeier method and Cox regression analysis, carried out using IBM SPSS Statistics version 20 (IBM Corp., Armonk, NY, USA). 3. Results A total of 30 patients were enrolled from August 2011 to July 2012. The median age of patients was 69 years (range: 55e84 years). Median PSA levels on Cycle 1 Day 1 was 328.5 (range: 8.1e3051.3 ng/ml) ng/ml. Twenty-one patients (70%) had a Gleason score of 8. All patients had bone metastasis, 17 (26.7%) had lymph node involvement, six (20%) had lung metastasis, and four (13.3%) had liver metastasis (Table 1). All patients had been treated with a docetaxel-based chemotherapy previously. The median number of cycles and accumulated dosage of docetaxel was eight cycles and 800 mg, respectively. Five patients had received second line chemotherapy; three with cabazitaxel and two with estramustine. One patient was withdrawn from the study because of disease progression, judged by clinical presentation, 1 week after starting medication. He died of prostate cancer 2 weeks after stopping abiraterone acetate treatment. One patient withdrew consent 3 days after starting medication because of severe gastrointestinal discomfort and died 2 months later. The end-points analysis was calculated based on 28 patients who received one or more cycles of abiraterone acetate. At the data cutoff date (31 st May 2015), the median treatment duration was 18 cycles (range: 4e82) and 10 patients (33%) received >13 cycles (approximately 1 year) of treatment. Reasons for discontinuing abiraterone acetate included disease progression (23 patients), adverse events (2 patients), and a serious adverse event (1 patient with left ventricular dysfunction). Two patients remained on treatment (>40 cycles) until the data cut-off date, despite PSA progression. Twenty-three patients (82.1%) had serum PSA levels start to decline after one cycle of abiraterone treatment. The PSA nadir was reached in 13 men (46.4%) on Cycle 3 Day 1 follow up. Overall, 15

T. Wu et al. / Urological Science xxx (2015) 1e5 3 Table 1 Demographic and baseline characteristics (all treated patients). n ¼ 30 Age (y) 69 (55e84) <65 7 (23) 65e74 15 (50) 75 8 (27) Time from initial diagnosis to first dose (mo) 38.9 (16.1e208.4) Baseline PSA on date of first dose (ng/ml) 325.8 (8.1e3051.3) Gleason score at diagnosis <7 1 (3) 7 6 (20) 8e10 21 (70) Unknown 2 (7) Previous androgen deprivation therapy Orchiectomy 10 (33) Medical castration 20 (67) Evidence of disease progression PSA only 27 (90) PSA þ radiographic progression 3 (10) ECOG performance status 0 16 (53) 1 6 (20) 2 8 (27) Data are presented as median (range)or n (%). ECOG ¼ Eastern Cooperative Oncology Group; PSA ¼ prostate specific antigen. (53.6%) patients achieved the primary endpoint (95% CI 33.9e72.5) and seven (25%) patients had 90% reduction of PSA. Three patients never had a PSA decline during treatment with abiraterone acetate. Based on protocol specific criteria, the median time-to-psa progression was 5.5 months (95% CI 3.1e7.9; Figure 1A). Both a high Gleason score (8) and visceral involvement did not have a negative impact on the time-to-psa progression (log rank test, p ¼ 0.738 and p ¼ 0.835, respectively; Figures 1B and 1C). The median follow-up time was 19.3 months (range: 1.9e39.2 months). All 21 deaths were prostate cancer related. The median interval from stopping abiraterone acetate to death was 3.4 months (95% CI 0.1e21.0), and the median overall survival was 19.2 months (95% CI 13.0e25.4). The PSA responders had better overall survival compared with PSA nonresponders, in both univariate (log rank test, p ¼ 0.007; Figure 2A) and multivariate (Cox regression, p ¼ 0.001; hazard ratio: 0.31; 95% CI: 0.12e0.76) analysis. Patients with a Gleason score 8 and visceral involvement had no significant difference in overall survival compared with patients with a Gleason score < 8 and those without visceral involvement (p ¼ 0.738 and p ¼ 0.130, respectively; Figures 2B and 2C). The most common treatment emergent adverse events were cardiac disorders (27%) and increased blood alkaline phosphatase levels (27%), followed by hypertension (23%), hypokalemia (23%), bone pain (20%), and insomnia (20%). Three patients experienced Grade 3 hypertransaminasemia, one recovered after discontinuing abiraterone acetate, and two patients did not recover because of liver metastasis and fatal sepsis. 4. Discussion The present study shows that abiraterone acetate 1000 mg once daily in combination with prednisolone 5 mg twice daily achieved a PSA response rate (50% reduction from the Cycle 1, Day 1 data) in 53.6% of Taiwanese patients with mcrpc postdocetaxel-based chemotherapy. The PSA response rate was better than that reported in the original article by de Bono et al 10 (53.6% vs. 29.1%), despite the fact that the Taiwanese patients had worse prognostic Figure 1. KaplaneMeier curve of time-to-prostate specific antigen progression: (A) all treated patients; (B) Gleason score (Gle) 8 versus Gle 8; and (C) viscera involvement versus bone and lymph nodes only. LNs ¼ lymph nodes; PSA ¼ prostate specific antigen. factors (70% with Gleason score of 8, median PSA level 328.5 ng/ ml). The majority (82.1%) of patients' serum PSA levels began to decline after the first cycle of abiraterone acetate treatment. All patients, except the three previously mentioned who never had a PSA decrease, had PSA levels begin to decline during the first three cycles (12 weeks) of abiraterone acetate treatment. In 14 (50%) patients, the PSA nadir was reached on Cycle 4, Day 1 follow up. Based on these findings, we recommend all patients undergoing abiraterone acetate treatment should have PSA levels checked after 12 weeks of therapy to evaluate the efficacy. For those whose serum PSA had not started to decline, alternative therapy should be

4 T. Wu et al. / Urological Science xxx (2015) 1e5 involvement had a negative impact on the treatment efficacy of abiraterone acetate on mcrpc patients. Taiwanese patients have a higher incidence of treatment-related adverse events in hypokalemia, hypertension, increased serum alkaline phosphatase levels, and transient abnormality in alanine aminotransferase/aspartate aminotransferase levels compared with Korean patients or global studies, however, most were Grade 1 or 2 adverse events. 12,15 Considering the small sample size, the difference might not be clinically significant. We do recommend liver function tests and hepatitis markers to rule out active or chronic liver diseases before prescribing abiraterone acetate. The serum potassium level should be monitored carefully especially in the 1 st 2e3 months of treatment. The present study showed that abiraterone acetate in combination with prednisolone effectively achieved a PSA response rate in 53.6% of Taiwanese mcrpc patients who failed docetaxel chemotherapy. The PSA responders had better overall survival compared with PSA nonresponders. A larger scale study might be necessary to evaluate whether the Asian population had a shorter PSA progression-free interval compared with Caucasians. Conflicts of interest All contributing authors declare no conflicts of interest. Acknowledgments This study is sponsored by Johnson & Johnson Pharmaceutical Research & Development, L.L.C, protocol 212082PCR2007. The authors thank Dr Huey-Shyan Lin at the Department of Health- Business Administration, Fooyin University for data analysis. References Figure 2. KaplaneMeier curve of overall survival: (A) prostate specific antigen responders versus nonresponders; (B) Gleason score 8 versus < 8; and (C) viscera involvement versus bone and lymph nodes only. * Median ± standard error (mo). LNs ¼ lymph nodes; PSA ¼ prostate specific antigen. considered. This is consistent with the recommendation of Prostate Cancer Clinical Trials Working Group-2, because treatment should be continued for at least 12 weeks to ensure adequate drug exposure. 16 Despite a higher PSA response rate, time-to-psa progression in Taiwanese patients was much shorter than that observed in the original COU-AA-301 study (5.5 months vs. 8.5 months). 17 The overall survival in the present study is not inferior to the final analysis of the COU-AA-301 study conducted at a median follow up of 20 months (19.2 months vs. 15.8 months). 17 This discrepancy might be due to ethnic differences or the extremely small sample size in our study. Neither a high Gleason score nor visceral 1. 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T. Wu et al. / Urological Science xxx (2015) 1e5 5 13. Rathkopf DE, Smith MR, de Bono JS, Logothetis CJ, Shore ND, de Souza P, et al. Updated interim efficacy analysis and long-term safety of abiraterone acetate in metastatic castration-resistant prostate cancer patients without prior chemotherapy (COU-AA-302). Eur Urol 2014;66:815e25. 14. Ryan CJ, Smith MR, Fizazi K, Saad F, Mulders PF, Sternberg CN, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomized, double-blind, placebo-controlled phase 3 study. Lancet Oncol 2015;16: 152e60. 15. Kwak C, Wu TL, Lee HM, Wu HC, Hong SJ, Ou YC, et al. Abiraterone acetate and prednisolone for metastatic castration-resistant prostate cancer failing androgen deprivation and docetaxel-based chemotherapy: a phase II bridging study in Korean and Taiwanese patients. Int J Urol 2014;21:1239e44. 16. Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 2008;26:1148e59. 17. Goodman Jr OB, Flaig TW, Molina A, Mulders PF, Fizari K, Suttmann H, et al. Exploratory analysis of the visceral disease subgroup in a phase III study of abiraterone acetate in metastatic castration-resistant prostate cancer. Prostate Cancer Prostatic Dis 2014;17:34e9.