ABSTRACT
Objectives
The study aimed to evaluate the impact of grade group (GG) and intraductal carcinoma of the prostate (IDC‐P), as established prognostic factors, on clinical endpoints in metastatic hormone‐sensitive prostate cancer (mHSPC) patients treated with androgen receptor signaling inhibitors (ARSIs).
Methods
We retrospectively analyzed 147 patients with mHSPC treated with androgen deprivation therapy and ARSIs (abiraterone acetate, enzalutamide, or apalutamide). Associations between clinicopathological factors, including GG 5 and IDC‐P, and prostate‐specific antigen progression‐free survival (PSA‐PFS), cancer‐specific survival (CSS), and overall survival (OS) were evaluated by Kaplan–Meier analysis and Cox proportional hazards models.
Results
GG 5 was identified in 66% of patients, and IDC‐P was present in 51% of patients. GG 5 was an independent predictor of PSA‐PFS, whereas IDC‐P was not. In contrast, IDC‐P was independently associated with poorer CSS, while GG was not. Neither IDC‐P nor GG was significantly associated with OS. The combined evaluation of GG 5 and IDC‐P showed the best prognostic predictive ability for PSA‐PFS, CSS, and OS.
Conclusions
In patients with ARSI‐treated mHSPC, both GG 5 and IDC‐P are important prognostic factors, although they play distinct roles in predicting clinical outcomes.
Keywords: androgen receptor pathway inhibitor, androgen receptor signaling inhibitor, grade group, intraductal carcinoma of the prostate, metastatic hormone‐sensitive prostate cancer
1. Introduction
Several randomized clinical trials demonstrated that adding androgen deprivation therapy (ADT) to androgen receptor pathway inhibitors (ARSIs) significantly improves overall survival in metastatic prostate cancer [1, 2, 3]. However, patients who had received ARSIs eventually progressed to castration‐resistant prostate cancer (CRPC), which is associated with a poor prognosis [4]. There is a growing need to establish robust and clinically meaningful prognostic factors even in the era of ARSIs. The Gleason grading system, currently reported as grade group (GG) and intraductal carcinoma of the prostate (IDC‐P), has emerged as an important prognostic factor in prostate cancer [5, 6, 7].
As defined by the 2022 World Health Organization classification, IDC‐P is a malignant epithelial proliferation confined to pre‐existing prostatic ducts and acini, characterized by marked architectural and cytological atypia exceeding that of high‐grade prostatic intraepithelial neoplasia, as well as retained basal cells [8]. IDC‐P represents a biologically aggressive disease that is strongly associated with adverse clinical outcomes [6], warranting its separate reporting from GG [8].
In patients treated with conventional ADT alone, the presence of IDC‐P is consistently associated with shorter time to CRPC and poorer survival [6, 9]. However, its prognostic significance in patients with ARSI‐treated mHSPC remains unclear.
Considering the distinct biological and clinical significance of prostate‐specific antigen progression‐free survival (PSA‐PFS), cancer‐specific survival (CSS), and overall survival (OS), the prognostic impact of GG and IDC‐P may vary according to the evaluated endpoint [10]. Thus, assessing the prognostic impact of the GG and IDC‐P is clinically important. Accordingly, this study retrospectively evaluated the prognostic impact of GG and IDC‐P on survival, such as PSA‐PFS, CSS, and OS, in mHSPC patients treated with ADT and ARSIs, aiming to clarify their distinct roles in the contemporary treatment era.
2. Patients and Methods
2.1. Patients
A total of 147 patients with mHSPC who were treated with ARSIs, including abiraterone acetate (ABI), enzalutamide (ENZA), and apalutamide (APA), from June 2018 to March 2024 at the Kansai Medical University and its affiliated hospitals were retrospectively analyzed. The Institutional Review Board of Kansai Medical University Medical Center approved this study (No. 2026083), which was conducted according to the Declaration of Helsinki.
2.2. Treatments and Measurements
Patients were treated with ADT plus ABI, ENZA, or APA (initial dose: 1000 mg, 160 mg, and 240 mg, respectively). The agent was selected at the discretion of the treating physician. Treatment was continued until clinical disease progression, unacceptable adverse events, withdrawal of consent, or death. ABI was preferentially administered to patients with high‐risk mHSPC according to the LATITUDE criteria [1]. Patients were diagnosed with mHSPC via bone scintigraphy, and visceral metastases were evaluated by computed tomography. Data on age, Eastern Cooperative Oncology Group performance status (ECOG‐PS), PSA, hemoglobin (Hb), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), C‐reactive protein (CRP), presence of GG 5, IDC‐P status based on prostate biopsy findings, metastatic sites, PSA‐PFS, CSS, and OS were extracted from medical records. All histopathological parameters were re‐assessed by dedicated genitourinary pathologists at each institution (Junichi Ikeda and Katsunori Uchida). IDC‐P was evaluated according to the 2022 World Health Organization classification [8], primarily using hematoxylin and eosin–stained slides, and was not incorporated into the grade group. No cases of pure IDC‐P were identified in our cohorts. PSA progression was defined as a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL from the PSA nadir, as confirmed by a second measurement at least 3 weeks later [11]. CSS was defined as the time from the initiation of ARSI treatment to death due to prostate cancer, whereas OS was defined as the time from the initiation of ARSI treatment to death from any cause.
2.3. Statistical Analysis
Continuous variables are summarized as medians with ranges, whereas categorical variables are expressed as frequencies and percentages. Kaplan–Meier analysis was used to estimate survival curves for PSA‐PFS, CSS, and OS. Differences between groups were evaluated using the log‐rank test. Multivariable Cox proportional hazards models were applied to estimate hazard ratios with 95% confidence intervals. A two‐sided p‐value of < 0.05 indicated statistical significance. Model performance was evaluated using receiver operating characteristic (ROC) curves and the area under the curve (AUC). All statistical analyses were performed using EZR software version 1.61 (Saitama Medical Center, Jichi Medical University, Saitama, Japan) [12].
3. Results
3.1. Patient Characteristics
Table 1 summarizes baseline patient characteristics. Out of 147 patients, 70 patients received ABI, 71 patients received ENZA, and 6 patients received APA. The GG was < 5 in 50 patients and 5 in 97 patients. IDC‐P was present in 75 patients. Visceral metastases were observed in 18.4% of patients with distant metastases. Thirty‐nine patients died, of whom 28 died from prostate cancer. Patients' characteristics stratified by GG and IDC‐P presence are shown in Table S1 and Table S2. Table S3 exhibits the relationship between GG5 and IDC‐P.
TABLE 1.
Baseline patient characteristics (n = 147).
| Variables | n (%) |
|---|---|
| Age, median (IQR) | 75.0 (70.0–80.0) |
| ECOG‐PS | |
| 0 | 120 (81.6) |
| 1 | 25 (17.0) |
| 2 | 2 (1.4) |
| Androgen receptor signaling inhibitor type | |
| Abiraterone acetate | 70 (47.6) |
| Enzalutamide | 71 (48.3) |
| Apalutamide | 6 (4.1) |
| Baseline PSA level (ng/ml), median (IQR) | 434 (111–1305) |
| Baseline blood examination, median (IQR) | — |
| Hb, g/dL | 13.4 (11.8–14.5) |
| LDH, U/L | 197 (171–243) |
| ALP, g/dL | 155 (88.5–363.5) |
| CRP, mg/dL | 0.2 (0.06–18.9) |
| Grade group | |
| 3 | 7 (4.8) |
| 4 | 43 (29.3) |
| 5 | 97 (66.0) |
| Presence of IDC‐P | 75 (51.0) |
| Extent of disease | |
| Bone | 129 (87.8) |
| Lung | 22 (15.0) |
| Liver | 5 (3.4) |
| CHAARTED criteria | |
| Low‐volume | 29 (19.7) |
| High‐volume | 118 (80.3) |
| LATITUDE criteria | |
| Low‐risk | 29 (19.7) |
| High‐risk | 118 (80.3) |
| PSA progression | |
| No | 102 (69.4) |
| Yes | 45 (30.6) |
| Cancer‐specific mortality | 28 (19.1) |
| Overall mortality | 39 (26.5) |
| Follow‐up periods (months), median (IQR) | 37.9 (24.0–51.1) |
Abbreviations: ALP, alkaline phosphatase; CRP, C‐reactive protein; ECOG‐PS, Eastern Cooperative Oncology Group performance status; Hb, hemoglobin; IDC‐P, intraductal carcinoma of the prostate; IQR, interquartile range; LDH, lactate dehydrogenase; PSA, prostate‐specific antigen.
3.2. Impact of GG 5 and IDC‐P on Survival
Kaplan–Meier curves for PSA‐PFS, CSS, and OS were generated according to the GG: PSA‐PFS demonstrated a significant difference (p = 0.02), whereas CSS and OS showed no significant differences (p = 0.26 and 0.68, respectively) (Figure 1A–C). Furthermore, Kaplan–Meier curves for PSA‐PFS, CSS, and OS were generated according to IDC‐P status: PSA‐PFS and OS exhibited no significant differences (p = 0.07 and 0.17, respectively), whereas CSS showed a significant difference (p = 0.03) (Figure 2A–C). Patients were stratified according to the number of adverse pathological features (GG5 and IDC‐P) into those with 0, 1, or 2 positive features. A significant difference was observed in PSA‐PFS, whereas other survival endpoints demonstrated no significant differences (Figure 3A–C).
FIGURE 1.
Kaplan–Meier curves comparing PSA progression‐free survival (A) cancer‐specific survival (B) and overall survival (C) between patients with and without intraductal carcinoma of the prostate.
FIGURE 2.
Kaplan–Meier curves comparing PSA progression‐free survival (A) cancer‐specific survival (B) and overall survival (C) between patients with grade group < 5 and 5.
FIGURE 3.
Kaplan–Meier curves comparing PSA progression‐free survival (A) cancer‐specific survival (B) and overall survival (C) between patients with the number of positive factors (IDC‐P and GS5): 0, 1, or 2.
Comparing the combination of GG5 and IDC‐P, GG5 alone, and IDC‐P alone for predicting PSA‐PFS, CSS, and OS, the AUC for PSA‐PFS was the highest for GG5 and IDC‐P combination (0.653), followed by GG5 alone (0.617) and IDC‐P alone (0.579) (Figure 4A). For the CSS, the AUCs were 0.645 for GG5 and IDC‐P combination, 0.578 for GG alone, and 0.626 for IDC‐P alone (Figure 4B). For the OS, the AUCs were 0.574 for GG5 and IDC‐P combination, 0.540 for GG5 alone, and 0.572 for IDC‐P alone (Figure 4C).
FIGURE 4.
Comparison of the area under the receiver operating characteristic curve (AUC) for predicting progression‐free survival (A) cancer‐specific survival (B) and overall survival (C) evaluation for GG5 plus IDC‐P, GG5 alone, and IDC‐P alone.
3.3. Univariate and Multivariate Analysis of Prognostic Factors
The univariate analysis revealed that ARSI type, GG, PSA, Hb, LDH, and CRP were significantly associated with PSA‐PFS, while IDC‐P was not. In the multivariate analysis, only GG was an independent predictor of PSA‐PFS (Table 2). Furthermore, the univariate analysis showed that ARSI type, Hb, CRP, and IDC‐P significantly influenced CSS. The multivariate analysis identified CRP and IDC‐P as independent predictors of CSS (Table 3). Additionally, the univariate analysis demonstrated a significant association with OS for age, Hb, and CRP, whereas GG and IDC‐P had no significant association (Table 4). The multivariate analysis identified age as an independent predictor of OS.
TABLE 2.
Univariable and multivariable analysis of clinicopathological factors for predicting PSA progression‐free survival.
| Variable | Univariate | Multivariate | ||
|---|---|---|---|---|
| HR (CI) | p | HR (CI) | p | |
| Age (years) | — | — | — | — |
| < 70 | 1 | — | — | — |
| ≥ 70 | 1.15 (0.58–2.28) | 0.68 | — | — |
| ECOG‐PS | — | — | — | — |
| 0 | 1 | — | — | — |
| 1,2 | 1.08 (0.52–2.26) | 0.83 | — | — |
| ARSI type | — | — | — | — |
| Abiraterone acetate | 1 | — | — | — |
| Enzalutamide/Apalutamide | 0.52 (0.28–0.96) | 0.04 | — | — |
| Grade group | — | — | — | — |
| < 5 | 1 | — | — | — |
| 5 | 2.43 (1.13–5.22) | 0.02 | 2.73 (1.06–7.03) | 0.04 |
| PSA | — | — | — | — |
| < 434 | 1 | — | — | — |
| ≥ 434 | 1.98 (1.07–3.64) | 0.03 | — | — |
| Hb | — | — | — | — |
| ≥ 13.4 | 1 | — | — | — |
| < 13.4 | 3.11 (1.65–5.86) | < 0.001 | 2.11 (0.99–4.52) | 0.054 |
| LDH | — | — | — | — |
| < 197 | 1 | — | — | — |
| ≥ 197 | 2.28 (1.12–4.43) | 0.01 | 1.59 (0.80–3.16) | 0.18 |
| ALP | — | — | — | — |
| < 155 | 1 | — | — | — |
| ≥ 155 | 1.92 (0.99–3.67) | 0.0502 | — | — |
| CRP | — | — | — | — |
| < 0.2 | 1 | — | — | — |
| ≥ 0.2 | 3.22 (1.60–6.48) | 0.001 | 1.92 (0.88–4.20) | 0.10 |
| Visceral metastasis | — | — | — | — |
| Negative | 1 | — | — | — |
| Positive | 0.75 (0.33–1.70) | 0.49 | — | — |
| Presence of IDC‐P | — | — | — | — |
| Negative | 1 | — | — | — |
| Positive | 1.75 (0.95–3.22) | 0.07 | — | — |
Abbreviations: ALP, alkaline phosphatase; ARSI, androgen receptor signaling inhibitor; CRP, C‐reactive protein; ECOG‐PS, Eastern Cooperative Oncology Group performance status; Hb, hemoglobin; IDC‐P, intraductal carcinoma of the prostate; LDH, lactate dehydrogenase; PSA, prostate‐specific antigen.
TABLE 3.
Univariable and multivariable analysis of clinicopathological factors for predicting cancer‐specific survival.
| Variables | Univariate | Multivariate | ||
|---|---|---|---|---|
| HR (CI) | p | HR (CI) | p | |
| Age (years) | — | — | — | — |
| < 70 | 1 | — | — | — |
| ≥ 70 | 1.89 (0.72–4.99) | 0.20 | — | — |
| ECOG‐PS | — | — | — | — |
| 0 | 1 | — | — | — |
| 1,2 | 1.20 (0.49–2.97) | 0.69 | — | — |
| ARSI type | — | — | — | — |
| Abiraterone acetate | 1 | — | — | — |
| Enzalutamide/Apalutamide | 0.31 (0.12–0.78) | 0.01 | — | — |
| Grade group | — | — | — | — |
| < 5 | 1 | — | — | — |
| 5 | 1.67 (0.67–4.12) | 0.27 | — | — |
| PSA | — | — | — | — |
| < 434 | 1 | — | — | — |
| ≥ 434 | 1.93 (0.89–4.19) | 0.09 | — | — |
| Hb | — | — | — | — |
| ≥ 13.4 | 1 | — | — | — |
| < 13.4 | 3.09 (1.36–7.02) | 0.007 | 1.60 (0.62–4.10) | 0.33 |
| LDH | — | — | — | — |
| < 197 | 1 | — | — | — |
| ≥ 197 | 2.16 (0.93–5.02) | 0.07 | — | — |
| ALP | — | — | — | — |
| < 155 | 1 | — | — | — |
| ≥ 155 | 1.51 (0.66–3.46) | 0.33 | — | — |
| CRP | — | — | — | — |
| < 0.2 | 1 | — | — | — |
| ≥ 0.2 | 4.78 (1.80–12.70) | 0.002 | 3.57 (1.19–10.73) | 0.02 |
| Visceral metastasis | — | — | — | — |
| Negative | 1 | — | — | — |
| Positive | 0.87 (0.33–2.32) | 0.79 | — | — |
| Presence of IDC‐P | — | — | — | — |
| Negative | 1 | — | — | — |
| Positive | 2.46 (1.08–5.59) | 0.03 | 2.48 (1.03–5.94) | 0.04 |
Abbreviations: ALP, alkaline phosphatase; ARSI, androgen receptor signaling inhibitor; CRP, C‐reactive protein; ECOG‐PS, Eastern Cooperative Oncology Group performance status; Hb, hemoglobin; IDC‐P, intraductal carcinoma of the prostate; LDH, lactate dehydrogenase; PSA, prostate‐specific antigen.
TABLE 4.
Univariable and multivariable analysis of clinicopathological factors for predicting overall survival.
| Variables | Univariate | Multivariate | ||
|---|---|---|---|---|
| HR (CI) | p | HR (CI) | p | |
| Age (years) | — | — | — | — |
| < 70 | 1 | — | — | — |
| ≥ 70 | 2.69 (1.05–6.90) | 0.04 | 2.93 (1.12–7.66) | 0.03 |
| ECOG‐PS | — | — | — | — |
| 0 | 1 | — | — | — |
| 1,2 | 1.31 (0.62–2.77) | 0.48 | — | |
| ARSI type | — | — | — | — |
| Abiraterone acetate | 1 | — | — | — |
| Enzalutamide/Apalutamide | 0.63 (0.32–1.23) | 0.18 | — | — |
| Grade group | — | — | — | — |
| < 5 | 1 | — | — | — |
| 5 | 1.16 (0.58–2.33) | 0.68 | — | — |
| PSA | — | — | — | — |
| < 434 | 1 | — | — | — |
| ≥ 434 | 1.90 (0.99–3.66) | 0.06 | — | — |
| Hb | — | — | — | — |
| ≥ 13.4 | 1 | — | — | — |
| ≥ 13.4 | 1.96 (1.03–3.74) | 0.04 | 1.02 (0.46–2.26) | 0.96 |
| LDH | — | — | — | — |
| < 197 | 1 | — | — | — |
| ≥ 197 | 1.58 (0.81–3.08) | 0.18 | — | — |
| ALP | — | — | — | — |
| < 155 | 1 | — | — | — |
| ≥ 155 | 1.20 (0.62–2.35) | 0.59 | — | — |
| CRP | — | — | — | — |
| < 0.2 | 1 | — | — | — |
| ≥ 0.2 | 2.23 (1.12–4.47) | 0.02 | 2.23 (0.98–5.08) | 0.06 |
| Visceral metastasis | — | — | — | — |
| Negative | 1 | — | — | — |
| Positive | 1.07 (0.49–2.34) | 0.87 | — | — |
| Presence of IDC‐P | — | — | — | — |
| Negative | 1 | — | — | — |
| Positive | 1.56 (0.82–2.97) | 0.18 | — | — |
Abbreviations: ALP, alkaline phosphatase; ARSI, androgen receptor signaling inhibitor; CRP, C‐reactive protein; ECOG‐PS, Eastern Cooperative Oncology Group performance status; Hb, hemoglobin; IDC‐P, intraductal carcinoma of the prostate; LDH, lactate dehydrogenase; PSA, prostate‐specific antigen.
4. Discussion
Gleason grading system (reported as GG) primarily reflects the architectural differentiation and proliferative activity of tumor glands, serving as a surrogate marker of tumor growth kinetics and androgen sensitivity [13]. Higher GGs are associated with distinct transcriptional programs characterized by the increased expression of cell cycle– and proliferation‐related genes and the decreased expression of androgen response–related genes, which are linked to more aggressive tumor behavior and poorer progression outcomes, such as biochemical recurrence and metastatic progression [14, 15]. However, Gleason grade alone does not fully capture the molecular heterogeneity responsible for treatment resistance, particularly in the context of intensified AR‐targeted therapy.
IDC‐P is a distinct pathological entity reflecting intrinsic tumor aggressiveness and advanced tumor biology [6, 7]. Guo and Epstein proposed that IDC‐P comprises well‐circumscribed intraductal proliferations with preserved basal cells and cytologically malignant epithelial populations, most commonly identified in close proximity to an invasive carcinoma [16]. Multiple molecular studies demonstrated that IDC‐P is strongly associated with adverse genomic alterations, including PTEN loss, TP53 mutation, RB1 loss, and BRCA2 alterations, which are hallmarks of aggressive and treatment‐resistant prostate cancer [9]. In turn, these alterations are closely linked to lineage plasticity, impaired DNA damage repair, and reduced dependence on androgen receptor (AR) signaling, providing a biological basis for early treatment resistance and poor cancer‐specific outcomes [17].
PSA‐PFS primarily reflects sensitivity to initial systemic therapy and is strongly influenced by AR dependency and tumor burden at treatment initiation [18, 19]. Because GG is closely associated with intrinsic tumor aggressiveness and AR‐driven biology [20], GG reasonably exerted the strongest impact on PSA‐PFS in our cohort. In contrast, the presence of IDC‐P did not significantly influence PSA‐PFS, suggesting that IDC‐P may not directly reflect early biochemical response to ARSI‐based therapy.
CSS represents an integrated outcome reflecting both the effectiveness of the initial hormonal therapy and the biological propensity of tumors to develop treatment resistance and ultimately progress to a fatal disease state [21]. The significant association between IDC‐P and poorer CSS observed in this study likely represents the intrinsic biological aggressiveness of IDC‐P rather than resistance to initial AR‐targeted therapy alone.
In contrast, OS is influenced by multiple competing factors, including the patient's age, comorbidities, and non‐cancer‐related causes of death such as cardiovascular events [22]. These competing risks might have attenuated the apparent impact of IDC‐P on OS in our cohort.
Taken together, GG predominantly reflects early treatment sensitivity, whereas IDC‐P more accurately captures the lethal potential of prostate cancer in the ARSI era, highlighting their distinct and complementary prognostic roles in mHSPC. Therefore, the presence of IDC‐P warrants genomic testing and consideration of intensive therapy, even in patients who initially respond to ARSI‐based treatment.
Our study has several limitations. First, this was a retrospective study conducted at a single institution and its affiliated hospitals, which might have introduced selection bias and unmeasured confounding factors. Second, the relatively small sample size and limited number of events, particularly for CSS and OS, might have reduced the statistical power of the analyses. Third, different ARSIs were analyzed collectively, and potential differences in treatment efficacy among agents were not separately evaluated. Additionally, the distribution of ARSI agents was imbalanced across the cohort, potentially influencing treatment efficacy. Therefore, our results should be interpreted with caution and warrant confirmation in larger prospective studies.
In conclusion, the GG 5 is important for predicting initial treatment response, whereas the IDC‐P assessment is crucial for predicting long‐term prognosis.
Author Contributions
Yuki Masuo: writing – review and editing. Junichi Ikeda: conceptualization, software, data curation, investigation, formal analysis, writing – original draft. Makoto Taguchi: writing – review and editing. Takahiro Nakamoto: writing – review and editing. Seiji Shimada: writing – review and editing. Hidefumi Kinoshita: writing – review and editing, supervision. Masaaki Yanishi: writing – review and editing. Monta Inoue: writing – review and editing. Hisanori Taniguchi: writing – review and editing. Takao Mishima: writing – review and editing. Katsunori Uchida: writing – review and editing.
Ethics Statement
The protocol for this research project has been approved by a suitably constituted Ethics Committee of the institution and it conforms to the provisions of the Declaration of Helsinki. The Institutional Review Board of Kansai Medical University Medical Center approved this study (No. 2026083).
Consent
An opt‐out approach was used to obtain informed consent on the hospital website.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Table S1: Association grade Group with clinicopathological factors.
Table S2: Association IDC‐P with clinicopathological factors.
Table S3: Association of grade Group 5 with IDC‐P.
Acknowledgments
The authors have nothing to report.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1: Association grade Group with clinicopathological factors.
Table S2: Association IDC‐P with clinicopathological factors.
Table S3: Association of grade Group 5 with IDC‐P.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.