2.1

Patients

This retrospective multicenter study enrolled consecutive patients with mCSPC treated with ADT alone, CAB, or ARSIs with ADT at 4 university hospitals and 15 affiliated general hospitals from February 2018 to June 2023 (JIKEI-YAYOI Collaborative Group). ADT included orchiectomy and luteinizing hormone-releasing hormone agonists and antagonists. CAB was defined as surgical or medical ADT combined with bicalutamide. ARSI patients received enzalutamide, apalutamide, or AAP in combination with ADT. After first-line therapies, sequential treatments were administered at the discretion of physicians. We excluded patients whose clinical details were incomplete (n = 15), those who received upfront docetaxel or triplet therapy (n = 29), and patients who did not undergo prostate biopsy (n = 113). The study protocol was approved by the Institutional Review Board of Jikei University (approval number 33–260[10878]).

2.2

Clinicopathological data and study outcomes

Patient demographics, clinicopathological characteristics, treatment strategies, and follow-up results were collected. Abdominal and pelvic computed tomography and bone scans were used to stage prostate cancer. The primary efficacy endpoint was the time to development of castration-resistant prostate cancer (CRPC). The secondary endpoints were progression-free survival 2 (PFS2), cancer-specific survival (CSS), and overall survival (OS). These outcomes are defined in the Supplementary Information. The prostate-specific antigen (PSA) concentration and serum hematological and biochemical marker levels were recorded, and liver function tests performed at baseline, monthly during the first year, and at least every 2 months thereafter. Timing commenced on the date of ADT initiation. The extent of disease (EOD) score was categorized into 5 distinct levels based on the degree of bone metastasis observed on imaging. The grading system is as follows: 0 indicates a normal scan; 1 represents fewer than 6 bone metastases, each measuring ≤50% of the size of a vertebral body (a single lesion equivalent in size to a vertebral body is considered as 2 lesions); 2 comprises 6 to 20 bone metastases; 3 includes more than 20 metastases but does not meet the criteria for a “superscan”; and 4 is defined as either a “superscan” or bone metastases affecting >75% of the ribs, vertebrae, and pelvic bones. Radiation therapy to the primary tumor was administered at the physician’s discretion.

2.3

Statistical analysis

Continuous parameters are presented as medians with interquartile ranges (IQRs). Chi-squared, Kruskal–Wallis, and Mann–Whitney U-tests were used as appropriate to evaluate associations between histological types and clinicopathological variables.

Two separate analyses were conducted. First, we evaluated the prognostic significances of various metastatic sites. Patients were categorized into the following groups: M1a (nonregional lymph node metastases only); M1b (bone metastases only; no visceral metastases); M1c_lung_only (lung metastases with no bone metastases and no other visceral metastases, such as liver, with or without nonregional lymph node metastases); M1c_lung_bone (lung metastases with bone metastases, with or without nonregional lymph node metastases); and M1c_other (nonpulmonary visceral metastases, with or without lung, bone, or nonregional lymph node metastases). Next, we focused on patients with bone metastases; they were stratified by volume of bone metastases and lung metastasis status. Comparisons of these groups revealed the clinical significance of lung metastases in patients with bone metastases. In accordance with the CHAARTED criteria [ ], high-volume bone metastases are defined as the presence of 4 or more bone metastases, including at least 1 metastasis outside of the vertebral column or pelvis.

All survivals were estimated using the Kaplan–Meier method. Differences between treatment strategies were assessed using the log-rank test. Further comparisons employed multivariate Cox’s regression models, which yielded hazard ratios (HRs) with 95% confidence intervals (95% CIs). Interactions among subgroups were tested by adding multiplicative terms to the relevant Cox’s model. A P -value < 0.05 was considered statistically significant. All statistical analyses were performed using Stata software version 13.1 (StataCorp LP, College Station, TX, USA) and R software (The R Foundation for Statistical Computing, Vienna, Austria).

3.1

Patient demographics

The study population included 716 patients as follows: 43 (6.0%) in the M1a group, 531 (74.2%) in the M1b group, 28 (3.9%) in the M1c_lung_only group, 94 (13.1%) in the M1c_lung_bone group, and 20 (2.8%) in the M1c_other group ( Fig. 1 and Table 1 ). The median age was 75 years (IQR: 69–80 years) and the median follow-up was 23 months (IQR: 12–37 months). Significant among-group differences were observed in terms of the baseline PSA level, EOD score, and radiation to primary site ( P < 0.05; Table 1 ). Of the 20 cases in the M1c_other group, 17 had liver metastases. Other visceral metastases included adrenal metastases in 3 cases and brain metastases in 1. Of the total cohort, 336 (46.9%) received ARSI doublet therapy. Supplementary Table 1 summarizes the baseline characteristics of patients in the ARSI cohort (thus mCSPC patients who received ARSI doublet therapy).

Flow diagram of patient selection. We first examined the clinical significance of metastatic sites on oncological outcome (A). Next, we explored the clinical effects of lung metastases on patients with bone metastases (B).

ADT = androgen deprivation therapy; ARSI = androgen receptor-signaling inhibitor; Bome met = bone metastasis; CAB = combined androgen blockade; mCSPC = metastatic castration-sensitive prostate cancer.

3.2

Oncological outcomes

Of all patients, 286 (39.9%) developed CRPC, 183 (25.6%) exhibited disease progression after second-line therapy, 89 (12.4%) suffered cancer-specific deaths, and a total of 143 (20.0%) died. The Kaplan-Meier curves indicated significantly shorter times to CRPC and PFS2 in the M1c _other group ( Fig. 2 ). The castration-resistant prostate cancer-free survival (CRPCFS) Kaplan-Meier curves for the M1a and M1c_lung_only groups almost overlapped, as did the curves for the M1b and M1_lung_bone groups ( Fig. 2 ). Such trends were also observed in patients receiving ARSI doublet therapy ( Fig. 2 ). In contrast, neither the CSS nor OS differed significantly among the groups ( Supplementary Figure 1 ). Multivariate analysis revealed that the M1c_other groups had significantly shorter times to CRPC and PFS2 in both the overall and ARSI cohorts ( Table 2 and Supplementary Table 2 ). Supplementary Tables 3 and 4 present 3-year data for CRPC, PFS2, CSS, and OS, stratified by the metastatic sites of the total and ARSI cohorts, respectively.

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