Salvage Radiotherapy +/- Hormone Therapy versus Hormone Therapy Alone for Prostate-Specific Antigen Failure after Radical Prostatectomy: A Randomised, Multicentre, Open-Label, Phase 3 Trial (JCOG0401)

Abstract

Background: No standard therapy has been established for patients with prostate-specific antigen (PSA) failure after radical prostatectomy (RP). This study was designed to determine whether radiotherapy ± hormone therapy is superior to hormone therapy alone in such patients. Methods: This multicentre, randomised, open-label, unblinded, phase 3 trial included 36 institutions. Patients with localized prostate cancer [T1-2N0M0) treated by RP, pT0/2/3 and pN0/x] whose PSA concentrations had decreased to <0•1 ng/mL after RP, then increased to 0•4-1•0 ng/mL, were randomised to Arm A [hormone therapy 80 mg bicalutamide (BCL) monotherapy followed by luteinizing hormone-releasing hormone agonist in case of BCL failure], or Arm B [64·8 Gy of salvage radiotherapy (SRT) followed by the same regimen as in Arm A in case of SRT failure]. The primary endpoint was time to treatment failure (TTF) of BCL in the intention-to-treat. This trial is registered with UMIN-CTR, 00026. Findings: From May 2004 to May 2011, 210 patients (105 in each arm) were registered, median follow-up being 5·5 years. The TTF of BCL was significantly longer in Arm B (hazard ratio 0aƒ»56, 90% CI (0·40-0·77); one-sided p=0·001). Thirty-two of 102 patients (31%) in Arm B did not have SRT treatment failure. TTF of protocol treatment was significantly longer in Arm B, however, clinical relapse-free and overall survival did not differ between the arms. The most frequent Grade 3-4 adverse event was erectile dysfunction (83 patients [80%] in Arm A vs. 76 [74%] in Arm B). Interpretation: Initial SRT followed by hormone therapy in case of treatment failure should be standard therapy for PSA failure after RP. Funding: Health Sciences Research Grants for Clinical Research for Evidence Based Medicine and Grants-in-Aid for Cancer Research (016) from the Ministry of Health, Labour and Welfare, Japan. Declaration of Interest: AY has received personal fees from Astellas Pharma Inc, AstraZeneca, Bayer, Janssen Pharmaceutical K.K., Sanofi and Takeda Pharmaceutical Company Ltd,. MW has received personal fees from Chugai Pharmaceutical Co., Ltd. and Johnson & Johnson K.K. MEDICAL COMPANY. TF has received personal fees from Bayer AG, Janssen Pharmaceutical K.K., Nihon Medi-Physics Co., Ltd., AstraZeneca, Astellas Pharma Inc., Takeda Pharmaceutical Company Limited and Daiichi Sankyo Company Limited. KH has received personal fees from Kyowa Hakko Kirin Co. Ltd., Chugai Pharmaceutical Co. Ltd. Takeda Pharmaceutical C. Ltd., Sanofi, Bristol-Myers Squibb, MSD K. K., Pfizer, Bayer, and Astellas Pharma Inc. TI has received personal fees from Astellas Pharma Inc, Janssen Pharmaceutical K.K., Astra Zeneca, Takeda Pharmaceutical Company Ltd., Bayer, Sanofi, MSD K.K., Bristol-Myers Squibb, Ono Pharmaceutical Co., Ltd. and Pfizer Pfizer Inc. KF has received personal fees from Chugai Pharmaceutical Co., Ltd., NIppon Kayaku Co., Ltd., Ferring Pharmaceuticals, Pfizer Inc., Bayer, ASKA Pharmaceutical Co., Ltd., Daiichi Sankyo Company Ltd., Novartis International AG, SBI Pharma, KYORIN Pharmaceutical Co.,Ltd., MSD K.K., Tsumura & Co., Taiho Pharmaceutical Co., Ltd., FUJIFILM Corporation, Ono Pharmaceutical Co., Ltd., Sanofi, Asahi Kasei, Janssen Pharmaceutical K.K., Kissei Pharmaceutical Co., Ltd.. SE has received personal fees from Astellas Pharma Inc., Takeda Pharmaceutical Company Ltd., Daiichi Sankyo Company Ltd., FUJIFILM Toyama Chemical Co., Ltd., Olympus Corporation, Asahi Kasei Pharma Corporation, Nihon Medi-Physics Co., Ltd. Nippon Shinyaku Co., Ltd., Pfizer Inc., Sanofi, Janssen Pharmaceutical K.K., Kissei Pharmaceutical Co., Ltd. TH has received personal fees from Takeda Pharmaceutical Company Ltd., AstraZeneca, Astellas Pharma Inc, Janssen Pharmaceutical K.K., Sanofi and Bayer. KK. KK had received personal fees from Astellas Pharma Inc, AstraZeneca, Asahi Kasei Pharma Corporation, AMCO Inc. and Nihon Medi-Physics Co., Ltd. OI has received personal fees from Johnson & Johnson K.K. MEDICAL COMPANY, Kissei Pharmaceutical Co., Ltd., KYORIN Pharmaceutical Co.,Ltd., Pfizer Inc., Taiho Pharmaceutical Co., Ltd., Sanofi, Daiichi Sankyo Company Ltd., Takeda Pharmaceutical Company Ltd., Ono Pharmaceutical Co., Ltd., Novartis Pharma, , Asahi Kasei Pharma Corporation, Hisamitsu Pharmaceutical CO., Inc. Hisamitsu Pharmaceutical Co.,Inc. and AstraZeneca. NS has received grants and personal fees from Astellas Pharma Inc., Ono Pharmaceutical Co., Ltd., personal fees from Janssen Pharmaceutical K.K., Takeda Pharmaceutical Company Ltd., Astra Zeneca, Astellas Pharma Inc, Bayer., Pfizer Inc., Novartis International AG, Chugai Pharmaceutical Co., Ltd., MSD K.K. MS has received personal fees from Janssen Pharmaceutical K.K., Astellas Pharma Inc, Takeda Pharmaceutical Company Ltd. and AstraZeneca. YY has received personal fees from Intuitive Surgical Inc., Bristol-Myers Squibb and Takeda Pharmaceutical Company Ltd. KN has received personal fees from AstraZeneca. HF has received personal fees from Taiho Pharmaceutical Co., Ltd. and Chugai Pharmaceutical Co., Ltd. KT has received personal fees from AstraZeneca. YK has received personal fees from AstraZeneca, Janssen Pharmaceutical K.K., Takeda Pharmaceutical Company Ltd., Astellas Pharma Inc, Nippon Kayaku Co., Ltd. SN has received personal fees from Takeda Pharmaceutical Company Ltd., AstraZeneca, Astellas Pharma Inc, Janssen Pharmaceutical K.K., BrightPath Biotherapeutics, Pfizer Inc., Novartis International AG, Chugai Pharmaceutical Co., Ltd., MSD K.K. and Ono Pharmaceutical Co., Ltd. Ethical Approval: The study protocol was approved by each Institutional Review Board.