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.
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.
Department of Urology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.
Tomomi
T
Kamba
Department of Urology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake-cho, Miyazaki, 889-1692, Japan.
Toshiyuki
T
Kamoto
Translational Research Informatics Center, 1-5-4 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan.
Shinichiro
S
Maruo
Translational Research Informatics Center, 1-5-4 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan.
Takashi
T
Kikuchi
Department of Urology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.
Yosuke
Y
Shimizu
Department of Urology, Osaki Citizen Hospital, 3-8-1 Furukawa-Honami, Osaki, 989-6183, Japan.
Shunichi
S
Namiki
Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, 634-8522, Japan.
Kiyohide
K
Fujimoto
Department of Urology, Osaka Red Cross Hospital, 5-30 Fudegasaki-cho, Tennoji-ku, Osaka, 543-8555, Japan.
Hiroaki
H
Kawanishi
Department of Urology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hazama-cho, Yufu, Oita, 879-5593, Japan.
Fuminori
F
Sato
Department of Urology, Graduate School of Medicine, Akita University, 1-1-1 Hondo, Akita, 010-8543, Japan.
Shintaro
S
Narita
Department of Urology, School of Medicine, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Japan.
Takefumi
T
Satoh
Department of Urology, Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.
Hideo
H
Saito
Department of Urology, School of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan.
Mikio
M
Sugimoto
Department of Urology, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
Jun
J
Teishima
Department of Urology, School of Medicine, Sapporo Medical University, S1 W16, Chuo-ku, Sapporo, 060-8543, Japan.
Naoya
N
Masumori
Department of Urology, School of Medicine, The Jikei University, 3-25-8 Nishi-Shimbashi, Minato-Ku, Tokyo, 105-8461, Japan.
Shin
S
Egawa
Department of Urology, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
Hideki
H
Sakai
Department of Urology, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, 520-2192, Japan.
Yusaku
Y
Okada
Department of Urology, School of Medicine, Tokai University, 143 Shimokasuya, Isehara, 259-1193, Japan.
Toshiro
T
Terachi
Department of Urology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan. ogawao@kuhp.kyoto-u.ac.jp.
Osamu
O
Ogawa
D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000556:secondary; D004164:Diphosphonates / Q000008:administration & dosage*; D018572:Disease-Free Survival; D005500:Follow-Up Studies; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D015996:Survival Rate; D013997:Time Factors; D017211:Treatment Failure; D000077211:Zoledronic Acid
D000726:Androgen Antagonists; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D017430:Prostate-Specific Antigen
Antitumor activity; Castration sensitive; Primary androgen deprivation; Prostate cancer; Zoledronic acid