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A phase III multicenter, randomized, controlled study of combined androgen blockade with versus without zoledronic acid in prostate cancer patients with metastatic bone disease: results of the ZAPCA trial

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International Journal of Clinical Oncology Aims and scope Submit manuscript

Abstract

Objective

To examine the antitumor activity of zoledronic acid (ZA) combined with androgen deprivation therapy (ADT) for men with treatment-naive prostate cancer and bone metastasis.

Methods

We enrolled 227 men with treatment-naive prostate cancer and bone metastasis. Participants were randomly assigned (1:1 ratio) to receive combined androgen blockade alone (CAB group) or ZA with combined androgen blockade (CZ group). Time to treatment failure (TTTF), time to the first skeletal-related event (TTfSRE), and overall survival (OS) rates were estimated using the Kaplan–Meier method. Hazard ratios (HRs) were calculated using the Cox proportional hazards model. Median follow-up duration was 41.5 months.

Results

Median TTTFs were 12.4 and 9.7 months for the CZ and CAB groups, respectively (HR 0.75; 95 % CI 0.57–1.00; p = 0.051). For men with baseline prostate-specific antigen levels <200 ng/mL, median TTTFs were 23.7 and 9.8 months for the CZ and CAB groups, respectively (HR 0.58; 95 % CI 0.35–0.93; p = 0.023). Median TTfSREs were 64.7 and 45.9 months for the CZ and CAB groups, respectively (HR 0.58; 95 % CI 0.38–0.88; p = 0.009). OS was similar between the groups.

Conclusions

This study failed to demonstrate that combined use of ZA and ADT significantly prolonged TTTF in men with treatment-naive prostate cancer and bone metastasis. However, it generates a new hypothesis that the combined therapy could delay the development of castration resistance in a subgroup of patients with low baseline prostate-specific antigen values <200 ng/mL. The treatment also significantly prolonged TTfSRE but did not affect OS.

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References

  1. Green JR (2004) Bisphosphonates: preclinical review. Oncologist 9(Suppl 4):3–13

    Article  CAS  PubMed  Google Scholar 

  2. Gnant M (2012) Zoledronic acid in the treatment of early-stage breast cancer: is there a final verdict? Curr Oncol Rep 14:35–43

    Article  CAS  PubMed  Google Scholar 

  3. Michaelson MD, Kaufman DS, Lee H et al. (2007) Randomized controlled trial of annual zoledronic acid to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer. J Clin Oncol 25:1038–1042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Saad F, Gleason DM, Murray R et al. (2002) A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 94:1458–1468

    Article  CAS  PubMed  Google Scholar 

  5. Saad F, Gleason DM, Murray R et al. (2004) Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 96:879–882

    Article  CAS  PubMed  Google Scholar 

  6. Gnant M, Mlineritsch B, Schippinger W et al. (2009) Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 360:679–691

    Article  CAS  PubMed  Google Scholar 

  7. Coleman R, de Boer R, Eidtmann H et al. (2013) Zoledronic acid (zoledronate) for postmenopausal women with early breast cancer receiving adjuvant letrozole (ZO-FAST study): final 60-month results. Ann Oncol 24:398–405

    Article  CAS  PubMed  Google Scholar 

  8. Coleman R, Cameron D, Dodwell D et al. (2014) Adjuvant zoledronic acid in patients with early breast cancer: final efficacy analysis of the AZURE (BIG 01/04) randomised open-label phase 3 trial. Lancet Oncol 15:997–1006

    Article  CAS  PubMed  Google Scholar 

  9. Wirth M, Tammela T, Cicalese V et al. (2015) Prevention of bone metastases in patients with high-risk nonmetastatic prostate cancer treated with zoledronic acid: efficacy and safety results of the Zometa European Study (ZEUS). Eur Urol 67:482–491

    Article  CAS  PubMed  Google Scholar 

  10. Dearnaley DP, Mason MD, Parmar MK et al. (2009) Adjuvant therapy with oral sodium clodronate in locally advanced and metastatic prostate cancer: long-term overall survival results from the MRC PR04 and PR05 randomised controlled trials. Lancet Oncol 10:872–876

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Smith MR, Halabi S, Ryan CJ et al. (2014) Randomized controlled trial of early zoledronic acid in men with castration-sensitive prostate cancer and bone metastases: results of CALGB 90202 (alliance). J Clin Oncol 32:1143–1150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. James ND, Sydes MR, Clarke NW et al. (2016) Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 387:1163–1177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Soloway MS, Hardeman SW, Hickey D et al. (1988) Stratification of patients with metastatic prostate cancer based on extent of disease on initial bone scan. Cancer 61:195–202

    Article  CAS  PubMed  Google Scholar 

  14. Eisenberger MA, Blumenstein BA, Crawford ED et al. (1998) Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Engl J Med 339:1036–1042

    Article  CAS  PubMed  Google Scholar 

  15. Kotake T, Usami M, Akaza H et al. (1999) Goserelin acetate with or without antiandrogen or estrogen in the treatment of patients with advanced prostate cancer: a multicenter, randomized, controlled trial in Japan. Jpn J Clin Oncol 29:562–570

    Article  CAS  PubMed  Google Scholar 

  16. Usami M, Akaza H, Arai Y et al. (2007) Bicalutamide 80 mg combined with a luteinizing hormone-releasing hormone agonist (LHRH-A) versus LHRH-A monotherapy in advanced prostate cancer: findings from a phase III randomized, double-blind, multicenter trial in Japanese patients. Prostate Cancer Prostatic Dis 10:194–201

    Article  CAS  PubMed  Google Scholar 

  17. Schoenfeld DA (1983) Sample-size formula for the proportional-hazards regression model. Biometrics 39:499–503

    Article  CAS  PubMed  Google Scholar 

  18. Dearnaley DP, Sydes MR, Mason MD et al. (2003) A double-blind, placebo-controlled, randomized trial of oral sodium clodronate for metastatic prostate cancer (MRC PR05 Trial). J Natl Cancer Inst 95:1300–1311

    Article  CAS  PubMed  Google Scholar 

  19. Vale CL, Burdett S, Rydzewska LH et al. (2016) Addition of docetaxel or bisphosphonates to standard of care in men with localised or metastatic, hormone-sensitive prostate cancer: a systematic review and meta-analyses of aggregate data. Lancet Oncol 17:243–256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Thompson IM, Tangen C, Basler J et al. (2002) Impact of previous local treatment for prostate cancer on subsequent metastatic disease. J Urol 168:1008–1012

    Article  PubMed  Google Scholar 

  21. Morgan GJ, Davies FE, Gregory WM et al. (2010) First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet 376:1989–1999

    Article  CAS  PubMed  Google Scholar 

  22. Noguchi M, Kikuchi H, Ishibashi M et al. (2003) Percentage of the positive area of bone metastasis is an independent predictor of disease death in advanced prostate cancer. Br J Cancer 88:195–201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Smith MR, Saad F, Coleman R et al. (2012) Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet 379:39–46

    Article  CAS  PubMed  Google Scholar 

  24. Vahtsevanos K, Kyrgidis A, Verrou E et al. (2009) Longitudinal cohort study of risk factors in cancer patients of bisphosphonate-related osteonecrosis of the jaw. J Clin Oncol 27:5356–5362

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The ZAPCA trial was supported by Grant for Urologic Research No. 200040700148 from Kyoto University Hospital. We thank all members of the ZAPCA Study Group for their cooperation. We also thank Dr. Masanori Fukushima in TRI for his valuable advice and critical reading of the manuscript and Mr. Koichi Yamashiro in TRI for his administrative and clerical support of this study. The affiliated members are Hakodate Goryokaku Hospital, Sunagawa City Medical Center, Sapporo Medical University, Akita University, Osaki Citizen Hospital, Tohoku University, Kesen-numa City Hospital, Yamagata Prefectural Central Hospital, Mito Medical Center, Jikei University School of Medicine, Jikei University Katsushika Medical Center, Kitasato University, Tokai University, Shimada Municipal Hospital, Shizuoka General Hospital, Shizuoka Hospital, Otsu Red Cross Hospital, Otsu Municipal Hospital, Shiga Medical Center for Adults, Shiga University of Medical Science, Kyoto University, Kyoto-Katsura Hospital, Kyoto City Hospital, Nara Medical University, Yamato Koriyama Hospital, Tenri Hospital, Osaka Red Cross Hospital, Kansai Electric Power Hospital, Osaka Kaisei Hospital, Kitano Hospital, Nishikobe Medical Center, Toyo-oka Hospital, Kurashiki Central Hospital, Kure Medical Center, Hiroshima University, JA Hiroshima General Hospital, Chugoku Rosai Hospital, Kagawa University, Oita University, Tsurumi Hospital, Nakamura Hospital, Yamaga Hospital, Ureshino Medical Center, Nagasaki University, and University of Miyazaki.

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Authors and Affiliations

  1. Department of Urology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan

    Tomomi Kamba, Yosuke Shimizu & Osamu Ogawa

  2. Department of Urology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake-cho, Miyazaki, 889-1692, Japan

    Toshiyuki Kamoto

  3. Translational Research Informatics Center, 1-5-4 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan

    Shinichiro Maruo & Takashi Kikuchi

  4. Department of Urology, Osaki Citizen Hospital, 3-8-1 Furukawa-Honami, Osaki, 989-6183, Japan

    Shunichi Namiki

  5. Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, 634-8522, Japan

    Kiyohide Fujimoto

  6. Department of Urology, Osaka Red Cross Hospital, 5-30 Fudegasaki-cho, Tennoji-ku, Osaka, 543-8555, Japan

    Hiroaki Kawanishi

  7. Department of Urology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hazama-cho, Yufu, Oita, 879-5593, Japan

    Fuminori Sato

  8. Department of Urology, Graduate School of Medicine, Akita University, 1-1-1 Hondo, Akita, 010-8543, Japan

    Shintaro Narita

  9. Department of Urology, School of Medicine, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Japan

    Takefumi Satoh

  10. Department of Urology, Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan

    Hideo Saito

  11. Department of Urology, School of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan

    Mikio Sugimoto

  12. Department of Urology, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan

    Jun Teishima

  13. Department of Urology, School of Medicine, Sapporo Medical University, S1 W16, Chuo-ku, Sapporo, 060-8543, Japan

    Naoya Masumori

  14. Department of Urology, School of Medicine, The Jikei University, 3-25-8 Nishi-Shimbashi, Minato-Ku, Tokyo, 105-8461, Japan

    Shin Egawa

  15. Department of Urology, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan

    Hideki Sakai

  16. Department of Urology, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, 520-2192, Japan

    Yusaku Okada

  17. Department of Urology, School of Medicine, Tokai University, 143 Shimokasuya, Isehara, 259-1193, Japan

    Toshiro Terachi

Authors
  1. Tomomi Kamba
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  2. Toshiyuki Kamoto
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  3. Shinichiro Maruo
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  20. Osamu Ogawa
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ZAPCA Study Group

Corresponding author

Correspondence to Osamu Ogawa.

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Conflict of interest

Tomomi Kamba accepted an honorarium from Astellas Pharma. Toshiyuki Kamoto accepted research funding and honoraria from Astellas Pharma. Fuminori Sato accepted research funding from Janssen Pharmaceutical and Astellas Pharma. Naoya Masumori accepted honoraria from Novartis Pharma and Daiichi Sankyo, and research funding from Daiichi Sankyo. Shin Egawa accepted research funding from Astellas Pharma and Takeda Pharmaceutical. Hideki Sakai accepted research funding from Astellas Pharma and Takeda Pharmaceutical, and honoraria from Astellas Pharma and AstraZeneca. Osamu Ogawa accepted an honorarium from Astellas Pharma.

Electronic supplementary material

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10147_2016_1037_MOESM1_ESM.tiff

Fig. S1. Kaplan−Meier plots for time to treatment failure in patients with baseline PSA ≥200 ng/mL (A), EOD ≤2 (B), EOD ≥3 (C), GS ≤7 (D) and GS ≥8 (E) (TIFF 5170 kb)

10147_2016_1037_MOESM2_ESM.tiff

Fig. S2. Kaplan−Meier plots for time to first SRE in patients with baseline PSA <200 ng/mL (A), PSA ≥200 ng/mL (B), EOD ≥3 (C) and GS ≤7 (D) (TIFF 4136 kb)

10147_2016_1037_MOESM3_ESM.tiff

Fig. S3. Kaplan–Meier plots for OS in patients with baseline PSA <200 ng/mL (A), PSA ≥200 ng/mL (B), EOD ≤2 (C), EOD ≥3 (D), GS ≤7 (E) and GS ≥8 (F) (TIFF 5596 kb)

Table S1. Correlations between PSA, EOD and Gleason score (DOC 39 kb)

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Kamba, T., Kamoto, T., Maruo, S. et al. A phase III multicenter, randomized, controlled study of combined androgen blockade with versus without zoledronic acid in prostate cancer patients with metastatic bone disease: results of the ZAPCA trial . Int J Clin Oncol 22, 166–173 (2017). https://doi.org/10.1007/s10147-016-1037-2

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  • DOI: https://doi.org/10.1007/s10147-016-1037-2

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