Prostate cancer is the most common cancer and the second most common cause of death in the United States. The 5-year relative survival rate of patients with metastatic prostate cancer is 30% (1). The U.S. Preventive Services Task Force recommends individualized decision making, not blanked against prostate-specific antigen (PSA) screening for prostate cancer, but the incidence of metastatic prostate cancer has been increasing rapidly since 2012 (2). Metastatic hormone-sensitive prostate cancer (mHSPC) accounts for up to 5% of patients newly diagnosed with prostate cancer in the United States (3). Androgen deprivation therapy (ADT) with a luteinizing hormone-releasing hormone agonist or receptor antagonist or with bilateral orchiectomy has been the standard of care for men with mHSPC. Combined androgen blockade (CAB) therapy with a standard nonsteroidal antiandrogen drug (bicalutamide or flutamide) is not recommended with systemic therapy for castration-naïve disease according to the National Comprehensive Cancer Network clinical practice guidelines in oncology, but it is recommended as grade B in the Japanese Urological Association guidelines. CAB therapy may be superior to other hormone therapies for overall survival (OS) in patients with mHSPC in Japan (4). The rate of CAB therapy in primary hormone therapy is higher in Japan than in Western Europe, and the cancer-specific mortality rate is less than half that in the United States (5). The dosage of bicalutamide in Japan and Western Europe differs (80 and 50 mg, respectively).

In the LATITUDE trial, addition of abiraterone acetate plus prednisone (AAP) to ADT significantly prolonged progression-free survival (PFS) and OS compared with ADT in high-risk mHSPC, who were defined as having at least two of the following three high-risk factors: Gleason score ≥8, visceral metastasis, and ≥3 bone metastases (6). In the ENZAMET trial, addition of enzalutamide to ADT resulted in longer PFS and OS within 3 years than CAB therapy (7). However, whether the addition of AAP to ADT improves PFS and OS in patients with high-risk mHSPC compared with CAB therapy remains unknown. The aim of our study was to compare the effect of AAP+ADT with CAB therapy for upfront treatment in patients with high-risk mHSPC.

This study retrospectively identified 166 patients with high-risk mHSPC at Kindai University and its affiliated hospitals from January 2014 to December 2020. All patients were adult men with pathologically diagnosed prostate adenocarcinomas and had not received prior hormonal therapy. Patients with high-risk HSPC were defined as having at least two of the following three high risk factors: Gleason score ≥8, visceral metastasis, and ≥3 bone metastases. Three patients with no prostate biopsy or unknown prognosis were excluded. The data of 163 patients were retrospectively analyzed. The metastasis burden was evaluated using computed tomography and diffusion-weighted whole-body imaging with background body signal or bone scan. Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score <3. Disease progression was assessed using the Prostate Cancer Working Group 2. PSA progression was defined as a confirmed relative increase in the PSA level from the nadir value by ≥25% and ≥2 ng/ml. The extent of disease (EOD) score was used to classify bone metastases. This study was approved by the institutional ethics committee of Kindai University (R02-247), and written informed consent was waived owing to the retrospective design.

This study retrospectively analyzed the efficacy of AAP+ADT in patients with high-risk mHSPC compared with CAB therapy and found that AAP+ADT significantly improved PFS and OS by propensity score–matched analysis. In the CHAARTED and STAMPEDE (arm C), addition of docetaxel to ADT resulted in beneficial effects on PFS and OS in patients with mHSPC (8, 9). In the LATITUDE and STAMPEDE (arm G) trial, AAP+ADT resulted in beneficial effects on PFS and OS in patients with high-risk mHSPC (6, 10). In the ENZAMET trial, addition of enzalutamide to CAB therapy resulted in beneficial effects on PFS and OS in patients with mHSPC (7). In the ARCHES trial, addition of enzalutamide to ADT resulted in a reduced risk of metastatic progression or death in patients with mHSPC, including after docetaxel chemotherapy (11). In the TITAN trial, addition of apalutamide to ADT resulted in beneficial effects on radiographic PFS and OS in patients with mHSPC (12). Based on these studies, docetaxel, AAP, enzalutamide, and apalutamide are recommended for patients with mHSPC. In the Japanese subgroup analyses of LATITUDE with high-risk mHSPC patients, a reduced risk of radiographic PFS and PSA-PFS in Japanese patients was observed in the AAP group compared with the ADT group and the AAP+ADT group had a favorable treatment effect on OS than the ADT group (13, 14).

Results from LATITUDE and STAMPEDE (arm G) showed that Gleason score, ECOG PS score, and nodal status were not prognostic factors for OS in mHSPC patients treated with AAP+ADT compared with those treated with ADT alone, but the benefit of AAP+ADT was greater in younger men (15). Miyazawa et al. (2021) reported that the prognostic factors for OS in high-risk mHSPC patients treated with CAB therapy were ECOG PS score, hemoglobin, and PSA response after 3 months (<97.0%) (16).

In our study, PFS and OS were significantly longer in the AAP+ADT group than in the CAB group. Ueda et al. retrospectively compared 50 high-risk mHSPC patients with AAP+ADT and 99 patients with CAB therapy, and showed the benefit of AAP+ADT for improvement of overall survival in Japanese patients with high-risk mHPSC (17). However, the sample size was small and further accumulation of evidence is necessary. In their study, LHRH antagonist were used as ADT, while LHRH agonists were used in our study. Our results confirmed the efficacy of AAP+ADT in 74 patients compared with CAB. While Ueda et al. reported that the prognostic factor for PSA-PFS in high-risk mHSPC patients was a high Gleason score, the ECOG PS score and visceral metastasis were poor prognostic factors for OS in our study. Docetaxel may be an alternative option for patients with these factors.

Since 2014, ARSI has been used for CPRC treatment in Japan, and the prognosis of patients with high-risk mHSPC treated with CAB has been prolonged. Our study included cases from 2014, who have received ARSI and taxane after the diagnosis of CRPC. Secondary therapy after progression to CRPC includes enzalutamide and docetaxel in the AAP+ADT group and flutamide, enzalutamide, and docetaxel in the CAB group. The subsequent therapies were docetaxel and ARSI in both groups. Bicalutamide did not improve the OS of patients with high-risk HSPC, regardless of whether most of the patients in the CAB group received ARSI (enzalutamide or abiraterone) after the diagnosis of CRPC. Our results suggest that the upfront use of AAP instead of bicalutamide followed by ARSI resulted in prolonged OS in patients with high-risk mHSPC.

The present study has several limitations. This was retrospective study with a small cohort and a short observation period. Further larger-scale studies should be performed to compare the effect of AAP+ADT with CAB therapy for upfront treatment in patients with high-risk mHSPC.

In this study, AAP+ADT provided better PFS and OS than CAB therapy in patients with high-risk mHSPC. Upfront AAP+ADT would be recommended for patients with high-risk mHSPC.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by the institutional ethics committee of Kindai University (R02-247). The patients/participants provided their written informed consent to participate in this study.

NM and KF performed concept and design of experiments. Acquisition of data was done by NM, MNi, YY, KK, YH, YM, and SU. NM performed manuscript writing and data analysis. KF performed manuscript editing and data analysis. YN, TM, MNo, HT, AE, AH, KY, and HU supervised the work. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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