Abstract
PURPOSE
A six-gene panel involved in androgen production, uptake, and conversion (APUC-6: HSD3B1, HSD3B2, CYP3A43, CYP11A1, CYP11B1, CYP17A1) may define distinct clinical outcomes in metastatic prostate cancer. This study evaluated the prognostic and predictive value of APUC-6 expression in metastatic castration-sensitive prostate cancer (mCSPC).
METHODS
Transcriptomic data from 160 patients in the phase III Eastern Cooperative Oncology Group-ACRIN E3805 CHAARTED trial were analyzed. Patients were stratified into four subgroups based on APUC-6 and androgen receptor (AR) gene expression. Clinical outcomes including time to clinical progression (ttCP), time to castration resistance (ttCR), and overall survival (OS) were assessed within the androgen deprivation therapy (ADT) and docetaxel plus ADT (D-ADT) arms. Interaction testing evaluated the predictive value of APUC-6/AR status. Subgroup analyses were also performed by Decipher genomic risk.
RESULTS
Patients with APUC-6-high/AR-low expression showed significantly improved ttCP (hazard ratio [HR], 0.43 [95% CI, 0.22 to 0.82]; P = .0092), ttCR (HR, 0.56 [95% CI, 0.32 to 1]; P = .049), and OS (HR, 0.31 [95% CI, 0.16 to 0.61]; P = .0003), but did not appear to benefit from the addition of docetaxel. Conversely, APUC-6–low/AR-low patients demonstrated significantly improved outcomes with D-ADT (ttCP: HR, 0.37 [95% CI, 0.21 to 0.65]; P = .00036; ttCR: HR, 0.38 [95% CI, 0.23 to 0.64]; P = .00017; OS: HR, 0.39 [95% CI, 0.21 to 0.72]; P = .0019). Statistical interaction analysis supported that patients with APUC-6–low/AR-low expression were more likely to benefit from docetaxel (HR, 0.36 [95% CI, 0.19 to 0.66]; P = .001). For patients with a high Decipher genomic classifier score, those in the APUC-6–low subgroup had improved survival with D-ADT, whereas those in the APUC-6–high subgroup did not gain any additional benefit from docetaxel.
CONCLUSION
APUC-6 expression and AR gene expression define clinically relevant subgroups in mCSPC and may enhance precision medicine treatment approaches in combination with other transcriptomic biomarkers.
INTRODUCTION
Metastatic prostate cancer (mPC), whether arising synchronously at diagnosis or developing metachronously after initial localized treatment, remains an incurable disease despite advances in systemic therapies.1,2 Androgen receptor (AR) is a central driver of prostate cancer progression, activated through multiple mechanisms even under androgen deprivation therapy (ADT). These mechanisms include AR mutations, alterations in coregulatory proteins, and variations in androgen availability, all contributing to sustained tumor growth and disease progression.3 Androgens activate AR, either by entering tumor cells from circulation or through intratumoral synthesis. This AR-driven signaling axis plays a pivotal role in early-stage prostate cancer and its progression to aggressive forms, including metastatic castration-sensitive prostate cancer (mCSPC) and castration-resistant prostate cancer (mCRPC).4 Bergom et al5 identified a subset of six key genes—HSD3B1, HSD3B2, CYP3A43, CYP11A1, CYP11B1, and CYP17A1—from more than 20 genes that regulate androgen production, uptake, and conversion (APUC-6) within tumor cells, which exhibited coordinated expression patterns, suggesting a role in defining a distinct subset of mPC with unique clinical and molecular characteristics. Given the importance of androgen metabolism in prostate cancer progression, understanding the impact of APUC-6 gene expression on disease trajectory is of significant clinical interest. To our knowledge, our study is the first to evaluate the association between APUC-6 gene expression and clinical outcomes in mCSPC using the pivotal phase III Eastern Cooperative Oncology Group (ECOG)-ACRIN E3805 CHAARTED trial and assess its potential to predict therapeutic responses to refine treatment selection in mCSPC.
METHODS
We performed a post hoc exploratory analysis on APUC-6 and AR gene expression (APUC-6/AR) using the transcriptomic data from a previously reported subset of patients from the CHAARTED trial (N = 160).6,7 In this cohort, archival formalin-fixed paraffin-embedded primary prostate tumor tissues obtained before systemic therapy underwent RNA profiling and 160 of 790 randomly assigned patients passed quality control for analysis.6,7 The APUC-6 score was calculated as a weighted linear combination of the normalized expression values of the six APUC genes, with weights derived from the distribution of gene expression in the data set. Patients were stratified into four subgroups based on APUC-6/AR levels: APUC-6 high/AR low (n = 34), APUC-6 high/AR high (n = 6), APUC-6 low/AR low (n = 86), and APUC-6 low/AR high (n = 34). High expression was defined as APUC-6 scores or AR expression in the top 25th percentile, whereas the remaining 75% was classified as low expression. Clinical outcomes, including time to clinical progression (ttCP), time to castration resistance (ttCR), and overall survival (OS), were defined according to the criteria established in the original CHAARTED trial6 and evaluated using the Kaplan-Meier analysis and log-rank tests. Prognostic value of APUC-6/AR was evaluated in all samples and within each treatment arm: ADT alone versus docetaxel + ADT (D-ADT). Additional multivariable Cox proportional hazards models for OS were fitted for selected APUC-6 and APUC-6/AR subgroup comparisons, adjusting for treatment arm, timing of metastasis, disease volume, Decipher genomic classifier (GC), Gleason score, and ECOG performance status. Further stratification was performed with the Decipher GC, a candidate predictor of docetaxel in mCSPC7,8 and disease volume. Interaction test using a Cox proportional hazards model, adjusted for key clinical covariates including timing of metastasis, disease volume, Decipher GC, Gleason score, and ECOG performance status, was used to assess APUC-6/AR as a predictive biomarker for docetaxel response. The interaction hazard ratio (HR) represents the ratio of the treatment HR in the specified subgroup to the treatment HR in the reference subgroup. All P values reported in this study are nominal as the analyses were post hoc and not prespecified in the original CHAARTED trial protocol. A P value <.05 was considered statistically significant.
RESULTS
APUC-6/AR Expression Defines Distinct Prognostic Subgroups in mCSPC
Standard clinicopathologic factors were well-balanced across subgroups, except for a lower proportion of patients with Gleason score ≥8 in APUC-6–high/AR-low subgroup (61.8%) compared with others (79.1%−88.2%; Appendix Table A1). APUC-6 expression was significantly negatively correlated with AR expression (R = −0.26, P = .001, data not shown), aligning with previously reported findings.5 Significant differences in clinical outcomes were observed between the four subgroups (ttCP: P < .0001; ttCR: P = .0011; OS: P < .0001; Figs 1A and 1C). The APUC-6–high/AR-low subgroup showed the most favorable survival outcomes, with significantly longer ttCP, ttCR, and OS when directly compared with the APUC-6–low/AR-high subgroup (median ttCP 47.3 v 17.7 months, HR, 0.43 [95% CI, 0.22 to 0.82]; P = .0092; median ttCR 17.3 v 12.0 months, HR, 0.56 [95% CI, 0.32 to 1]; P = .049; median OS 58.1 v 29.4 months, HR, 0.31 [95% CI, 0.16 to 0.61]; P = .00032; Figs 1A and 1C).
FIG 1.
Kaplan-Meier curves of clinical end points of patients within APUC-6/AR subgroups. (A) ttCP, (B) ttCR, and (C) OS of patients stratified by APUC-6/AR expression. P values are shown as log-rank P values. ADT, androgen deprivation therapy; APUC, androgen production, uptake and conversion genes; AR, androgen receptor; D-ADT, docetaxel + androgen deprivation therapy; OS, overall survival; ttCP, time to clinical progression; ttCR, time to castration resistance.
APUC-6/AR Identifies Differential Benefit From Docetaxel Intensification
We next evaluated whether APUC-6/AR expression was associated with differential benefit from docetaxel. For patients with APUC-6–high/AR-low expression, adding docetaxel to ADT did not improve survival (median ttCP not reached [NR] v 23.1 months, HR, 0.47 [95% CI, 0.16 to 1.4]; P = .16; median ttCR 15.8 v 17.3 months, HR, 0.95 [95% CI, 0.4 to 2.2]; P = .90; median OS 57.6 versus 62.6 months, HR, 2.1 [95% CI, 0.71 to 6.3]; P = .17; Figs 2A and 2C). By contrast, APUC-6–low/AR-low patients derived significant survival benefit from D-ADT (median ttCP 34.9 v 15.0 months, HR = 0.37 [95% CI, 0.21 to 0.65]; P = .00036; median ttCR 22.8 v 6.4 months, HR, 0.38 [95% CI, 0.23 to 0.64]; P = .00017; median OS 69.5 v 29.8 months, HR, 0.39 [95% CI, 0.21 to 0.72]; P = .0019; Figs 2D and 2F). These benefits were also observed across all patients with low APUC-6 expression, regardless of AR status (median ttCP 29.8 v 13.5 months, HR, 0.39 [95% CI, 0.24 to 0.61]; P < .0001; median ttCR 18.8 v 6.4 months, HR, 0.34 [95% CI, 0.22 to 0.53]; P < .0001; median OS 53.9 v 29.5 months, HR, 0.42 [95% CI, 0.26 to 0.68]; P = .00041; Figs 2G and 2I). In multivariable analyses adjusting for major clinical covariates, the APUC-6–high/AR-low subgroup remained associated with favorable OS without a significant benefit from docetaxel, whereas the APUC-6–low/AR-low subgroup continued to demonstrate a significant benefit from docetaxel (Appendix Table A2). Interaction analysis supported that APUC-6 low/AR low was a significant predictor of improved survival with D-ADT as compared to ADT (ttCP: HR, 0.35 [95% CI, 0.20 to 0.63]; P = .001; ttCR: HR, 0.35 [95% CI, 0.21 to 0.60]; P < .0001; OS: HR, 0.36 [95% CI, 0.19 to 0.66]; P = .001; Appendix Table A3, Fig 3). Among patients with a high Decipher GC score (≥0.6), 81.7% had low APUC-6 expression, whereas 18.3% had high APUC-6 expression (Appendix Table A1).
FIG 2.
Kaplan-Meier curves of clinical end points of patients within APUC-6/AR subgroups receiving ADT versus D-ADT. (A) ttCP, (B) ttCR, and (C) OS of APUC-6–high/AR-low patients. (D) ttCP, (E) ttCR, and (F) OS of APUC-6–low/AR-low patients. (G) ttCP, (H) ttCR, and (I) OS of APUC-6–low patients despite AR status. P values are shown as log-rank P values. ADT, androgen deprivation therapy; APUC, androgen production, uptake and conversion genes; AR, androgen receptor; D-ADT, docetaxel + androgen deprivation therapy; OS, overall survival; ttCP, time to clinical progression; ttCR, time to castration resistance.
FIG 3.
Forest plot of clinical end points of patients within APUC-6/AR subgroups receiving ADT versus D-ADT. (A) ttCP, (B) ttCR, and (C) OS. ADT, androgen deprivation therapy; APUC, androgen production, uptake and conversion genes; AR, androgen receptor; D-ADT, docetaxel + androgen deprivation therapy; HR, hazard ratio; OS, overall survival; ttCP, time to clinical progression; ttCR, time to castration resistance.
APUC-6/AR Provides Additional Stratification Within Decipher-Defined Risk Groups and High-Volume Disease
In an exploratory analysis in the context of high Decipher GC scores, patients with APUC-6–high/AR-low expression did not appear to derive additional survival benefit from adding docetaxel to ADT (median ttCP 42.6 v 13.4 months, HR, 0.44 [95% CI, 0.12 to 1.7]; P = .22; median ttCR 15.6 v 10.3 months, HR, 0.62 [95% CI, 0.2 to 1.9]; P = .4; median OS 48.0 v 79.8 months, HR, 2.4 [95% CI, 0.48 to 12]; P = .28), suggesting a subset of patients who may derive limited additional benefit from chemotherapy despite their high Decipher GC score (Appendix Figs A1A–A1C). This pattern was consistent across all patients with high Decipher GC scores and high APUC-6 expression, regardless of AR status (Appendix Figs A2A–A2C). By contrast, high Decipher GC score patients in the APUC-6–low/AR-low subgroup showed significantly improved survival with D-ADT (median ttCP 34.9 v 15.6 months, HR, 0.4 [95% CI, 0.21 to 0.75]; P = .0033; median ttCR 17.9 v 6.2 months, HR, 0.45 [95% CI, 0.25 to 0.79]; P = .005; median OS 69.5 v 29.5 months, HR, 0.37 [95% CI, 0.18 to 0.74]; P = .0034; Appendix Figs A1D–A1F). This survival benefit was observed in the D-ADT arm across all high Decipher GC score patients with low APUC-6 expression, regardless of AR status (median ttCP 27.3 v 13.0 months, HR, 0.44 [95% CI, 0.27 to 0.72]; P = .00085; median ttCR 17.5 v 6.2 months, HR, 0.41 [95% CI, 0.26 to 0.65]; P < .0001; median OS 53.9 v 28.8 months, HR, 0.47 [95% CI, 0.28 to 0.79]; P = .0035; Appendix Figs A2D–A2F). For patients with synchronous high-volume disease (70%, n = 113), high APUC-6 and low AR expression exhibited a significantly improved ttCP with D-ADT (median NR v 11.7 months, HR, 0.25 [95% CI, 0.076 to 0.8]; P = .0119) but did not show significant benefits in ttCR or OS (median ttCR 22.4 v 9.9 months, HR, 0.41 [95% CI, 0.16 to 1.1]; P = .0585; median OS 57.6 v 62.6 months, HR, 1.8 [95% CI, 0.51 to 6.1]; P = .36; Appendix Figs A3A–A3C). By contrast, patients with low APUC-6 and low AR expression experienced significant improvements in ttCP, ttCR, and OS (median ttCP 31.5 v 11.8 months, HR, 0.39 [95% CI, 0.20 to 0.74]; P = .0028; median ttCR 15.7 v 6.2 months, HR, 0.41 [95% CI, 0.23 to 0.75]; P = .0025; median OS 57.4 v 26.8 months, HR, 0.39 [95% CI, 0.20 to 0.78]; P = .0057; Appendix Figs A3D–A3F).
DISCUSSION
This study identifies APUC-6/AR as a potentially prognostic and predictive transcriptomic signature in mCSPC, which warrants further evaluation in larger, prospective clinical trials. Our CHAARTED trial analysis indicated that APUC-6–high/AR-low patients had favorable outcomes with ADT and did not appear to derive additional benefit from docetaxel, even among those with high Decipher GC scores, a group with poor OS that has been shown to benefit from adding docetaxel to ADT.7–9 These findings suggest that APUC-6/AR may help identify a subset of patients who are less likely to benefit from chemotherapy. It is possible that tumors with high APUC-6 and low AR expression are more sensitive to ADT in mCSPC, potentially reducing the need for intensification with chemotherapy. By contrast, low APUC-6/AR may predict a positive response to docetaxel, indicating reduced reliance on AR signaling and increased dependence on alternative survival pathways. One possible interpretation is that these results reflect distinct androgen-axis transcriptional states, where tumors with low APUC-6 and AR may shift toward androgen-independent drivers, whereas those with high APUC-6 may sustain AR activity via intratumoral androgen synthesis and remain ADT-responsive. In addition, although docetaxel disrupts microtubules and inhibits AR activity, its efficacy may be influenced by androgen dynamics and APUC-6 expression. For instance, in a mCRPC model, high androgen levels impaired docetaxel tumor accumulation by competing for the drug transporter OATP1B3.10 The androgen depletion induced by ADT may trigger complex cancer cell reprogramming, ultimately affecting response to subsequent chemotherapy.11 Understanding these interactions could inform treatment sequencing strategies in mCSPC. Certain genomic alterations, such as ERG overexpression and KDM5D loss, have been linked to docetaxel resistance.12,13 The relationship between APUC-6/AR expression; genomic alterations such as TP53, RB1, and PTEN; and other molecular features of mCSPC requires further investigation and could help explain their differential responses to chemotherapy. Recent work by Grist et al9 identified Decipher and transcriptome-based PTEN inactivity as important classifiers associated with docetaxel benefit in mCSPC, whereas APUC-6 was not among the signatures evaluated. While a high Decipher GC score predicts docetaxel sensitivity in the STAMPEDE cohort (HR = 0.64, P = .039),8,9 APUC-6/AR signatures in our study offer additional value in identifying patients who are more or less likely to benefit from chemotherapy. These findings highlight the potential of using combinatorial transcriptomic biomarkers such as Decipher GC and APUC-6/AR expression to guide precision medicine treatment approaches and should be further validated in independent cohorts.
Study limitations include a smaller sample size because of specimen availability although the observed treatment effects aligned with overall trial findings.7 However, given the small sample size, heterogeneity in Decipher GC distribution across subgroups, and the nature of post hoc exploratory analysis, further validation in a larger prospective cohort is needed. In addition, ADT alone is no longer the standard backbone therapy for mCSPC. Although the CHAARTED trial does not directly address contemporary treatment strategies such as doublet (ADT + androgen receptor pathway inhibitor [ARPI])14,15 versus triplet therapy (ADT + ARPI + docetaxel),16,17 it remains a foundational trial with robust long-term follow-up and well-annotated biospecimens, making it a valuable resource for initial biomarker discovery. Our findings are hypothesis-generating and highlight the need for further evaluation of APUC-6/AR expression in treatment settings, such as in trials like PEACE-116 and ARASENS17 as well as the ASPIRE trial (ClinicalTrials.gov identifier: NCT06931340), which evaluate the benefit of adding docetaxel to doublet therapy (ADT + apalutamide). While the role of the Decipher GC score in mCSPC remains investigational, emerging data including post hoc analyses from CHAARTED6 and STAMPEDE8 support its potential utility in risk stratification and predicting benefit from docetaxel.
In conclusion, our exploratory analysis of the CHAARTED trial suggests that APUC-6 high/AR low may identify a mCSPC subgroup with a favorable prognosis who appears less likely to benefit from docetaxel, even when high Decipher GC scores are present. Conversely, patients with APUC-6–low/AR-low expression appeared to derive notable survival benefits from docetaxel intensification, supporting its potential role in identifying docetaxel-responsive patients particularly in combination with Decipher GC score.
CONTEXT.
Key Objective
To evaluate whether androgen production, uptake, and conversion (APUC-6) and androgen receptor (AR) gene expression, derived from transcriptomic profiling, define subgroups of metastatic castration-sensitive prostate cancer (mCSPC) with differential benefit from docetaxel in the CHAARTED trial.
Knowledge Generated
APUC-6/AR expression stratified patients into subgroups with significantly different clinical outcomes, with the APUC-6–high/AR-low subgroup demonstrating favorable outcomes with androgen deprivation therapy (ADT) and no additional survival benefit from docetaxel. The APUC-6–low/AR-low subgroup was associated with significantly improved outcomes with docetaxel plus ADT, supported by multivariable and interaction analyses.
Relevance
APUC-6/AR expression may help identify patients more or less likely to benefit from docetaxel intensification, with potential complementary value alongside the Decipher genomic classifier, supporting more personalized treatment selection in mCSPC.
SUPPORT
P.T.T. is supported by an anonymous donor, Movember Foundation-Distinguished Gentleman’s Ride-Prostate Cancer Foundation, the National Institutes of Health, National Cancer Institute (1R01CA271540 and U54CA273956), and Department of Defense (W81XWH-21-1-0296). X.S. is supported by the NIH/NCI T32 Training Grant in Cancer Biology (T32CA154274). J.H. is supported by NIH/NCI (5R37CA288972). The ECOG-ACRIN E3805 CHAARTED trial was conducted by the ECOG-ACRIN Cancer Research Group (Peter J. O’Dwyer, MD and Mitchell D. Schnall, MD, PhD, group cochairs) and supported by the National Cancer Institute of the National Institutes of Health under award Nos.: U10CA180820, UG1CA189828, U10CA180868, UG1CA233180, UG1CA233230, UG1CA233329, UG1CA233196, and UG1CA233290. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. E.S.A. is partially supported by NCI grant P30 CA077598 and DOD grant W81XWH-22-2-0025. C.J.R. is supported by NIH grant R01 CA249279 (PI: Ryan, C; Halabi S; Sharifi N).
APPENDIX
TABLE A1.
Patient Characteristics of the Analytic Cohort
| Variable | APUC-6 High/AR High | APUC-6 High/AR Low | APUC-6 Low/AR High | APUC-6 Low/AR Low |
|---|---|---|---|---|
| Total | 6 | 34 | 34 | 86 |
| Age, years, median (range) | 63 (50–66) | 64 (47–88) | 64 (49–79) | 61 (39–90) |
| Timing of metastasis, No. (%) | ||||
| Synchronous | 6 (100.0) | 28 (82.4) | 28 (82.4) | 79 (91.9) |
| Metachronous | 0 (0) | 6 (17.6) | 6 (17.6) | 7 (8.1) |
| Tumor volume, No. (%) | ||||
| High | 5 (83.3) | 28 (82.4) | 26 (76.5) | 66 (76.7) |
| Low | 1 (16.7) | 6 (17.6) | 8 (23.5) | 20 (23.3) |
| Gleason score, No. (%) | ||||
| <8 | 0 (0) | 10 (29.4) | 3 (8.8) | 16 (18.6) |
| ≥8 | 5 (83.3) | 21 (61.8) | 30 (88.2) | 68 (79.1) |
| Unavailable | 1 (16.7) | 3 (8.8) | 1 (2.9) | 2 (2.3) |
| Treatment, No. (%) | ||||
| ADT alone | 3 (50.0) | 17 (50.0) | 15 (44.1) | 41 (47.7) |
| D-ADT | 3 (50.0) | 17 (50.0) | 19 (55.9) | 45 (52.3) |
| High decipher GC score, No. (% of all high score patients) | 3 (2.5) | 19 (15.8) | 30 (25.0) | 68 (56.7) |
Abbreviations: ADT, androgen deprivation therapy; AR, androgen receptor; D, docetaxel; GC, genomic classifier.
TABLE A2.
Multivariable Cox Regression Analysis for Overall Survival According to APUC-6 and APUC-6/AR Biomarker Subgroups
| Variable | HR (95% CI) | P | HR (95% CI) | P | HR (95% CI) | P |
|---|---|---|---|---|---|---|
| APUC-6 High v Low | APUC-6 High/AR Low v APUC-6 Low/AR High | APUC-6 Low/AR Low v APUC-6 Low/AR High | ||||
| Biomarker subgroup | 0.62 (0.35 to 1.09) | .099 | 0.32 (0.14 to 0.71) | .005 | 0.54 (0.32 to 0.91) | .021 |
| Treatment: D-ADT v ADT | 0.51 (0.33 to 0.78) | .002 | 0.77 (0.38 to 1.56) | .471 | 0.43 (0.25 to 0.71) | .001 |
| Timing of metastasis: De novo v metachronous | 0.70 (0.36 to 1.34) | .277 | 0.77 (0.30 to 2.00) | .595 | 0.75 (0.35 to 1.58) | .446 |
| Disease volume: High v low | 2.30 (1.25 to 4.24) | .008 | 2.12 (0.78 to 5.74) | .139 | 2.17 (1.13 to 4.16) | .020 |
| Decipher GC: Intermediate v low | 1.05 (0.39 to 2.85) | .925 | 0.53 (0.08 to 3.48) | .505 | 1.18 (0.27 to 5.10) | .826 |
| Decipher GC: High v low | 1.56 (0.71 to 3.42) | .268 | 1.59 (0.49 to 5.15) | .442 | 1.51 (0.49 to 4.59) | .471 |
| Gleason score: 8–10 v 1–7 | 1.27 (0.69 to 2.35) | .443 | 6.23 (1.43 to 27.07) | .015 | 0.80 (0.41 to 1.59) | .533 |
| ECOG PS: 1–2 v 0 | 1.84 (1.18 to 2.86) | .007 | 1.12 (0.52 to 2.45) | .768 | 1.79 (1.08 to 2.98) | .025 |
Boldface was intended to indicate statistical significance at P < .05.
Abbreviations: ADT, androgen deprivation therapy; AR, androgen receptor; D, docetaxel; ECOG, Eastern Cooperative Oncology Group; GC, genomic classifier; HR, hazard ratio; PS, performance status.
TABLE A3.
Interaction Analysis of the Clinical End Points Within the APUC-6/AR Subgroups Receiving D-ADT Versus ADT
| Variable | ttCP | ttCR | OS | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No. | Events | Median (months) |
HR | HR P | No. | Events | Median (months) |
HR | HR P | No. | Events | Median (months) |
HR | HR P | |
| APUC-6 low/AR low and ADT alone | 41 | 30 | 14.95 | Ref | Ref | 41 | 34 | 9.10 | Ref | Ref | 41 | 27 | 29.80 | Ref | Ref |
| APUC-6 low/AR high and ADT alone | 15 | 11 | 12.35 | 1.25 | .524 | 15 | 13 | 6.20 | 1.69 | .113 | 15 | 14 | 25.30 | 1.82 | .072 |
| APUC-6 high/AR low and ADT alone | 17 | 10 | 23.13 | 0.53 | .088 | 17 | 11 | 17.30 | 0.48 | .038 | 17 | 7 | 62.60 | 0.34 | .013 |
| APUC-6 high/AR high and ADT alone | 3 | 3 | 3.25 | 3.41 | .045 | 3 | 3 | 3.30 | 4.23 | .019 | 3 | 3 | 13.10 | 6.99 | .002 |
| APUC-6 low/AR low and D-ADT | 45 | 18 | 50.07 | 0.35 | .001 | 45 | 22 | 29.40 | 0.35 | .0001 | 45 | 17 | 69.50 | 0.36 | .001 |
| APUC-6 low/AR high and D-ADT | 19 | 11 | NR | 0.76 | .645 | 19 | 8 | 27.30 | 0.51 | .199 | 19 | 12 | 34.40 | 1.42 | .486 |
| APUC-6 high/AR low and D-ADT | 17 | 5 | NR | 1.32 | .658 | 17 | 10 | 15.80 | 2.59 | .066 | 17 | 9 | 57.60 | 4.54 | .011 |
| APUC-6 high/AR high and D-ADT | 3 | 3 | 7.39 | 2.72 | .256 | 3 | 3 | 7.40 | 1.40 | .694 | 3 | 3 | 30.60 | 0.72 | .716 |
Abbreviations: ADT, androgen deprivation therapy; APUC, androgen production, uptake, and conversion; AR, androgen receptor; D-ADT, docetaxel plus ADT; HR, hazard ratio; NR, not reached; OS, overall survival; Ref, reference; ttCP, time to clinical progression; ttCR, time to castration resistance.
FIG A1.
Kaplan-Meier curves of clinical end points of high Decipher GC score patients within APUC-6/AR subgroups receiving ADT versus D-ADT. (A) ttCP, (B) ttCR, and (C) OS of APUC-6–high/AR-low patients. (D) ttCP, (E) ttCR, and (F) OS of APUC-6–low/AR-low patients. P values are shown as log-rank P values. ADT, androgen deprivation therapy; APUC, androgen production, uptake, and conversion genes; AR, androgen receptor; D-ADT, docetaxel + androgen deprivation therapy; GC, genomic classifier; OS, overall survival; ttCP, time to clinical progression; ttCR, time to castration resistance.
FIG A2.
Kaplan-Meier curves of clinical end points of high Decipher GC score patients with high or low APUC-6 expression despite AR status with receiving ADT versus D-ADT. (A) ttCP, (B) ttCR, and (C) OS of APUC-6–high patients. (D) ttCP, (E) ttCR, and (F) OS of APUC-6–low patients. P values are shown as log-rank P values. ADT, androgen deprivation therapy; AR, androgen receptor; D-ADT, docetaxel plus ADT; OS, overall survival; ttCP, time to clinical progression; ttCR, time to castration resistance.
FIG A3.
Kaplan-Meier curves of clinical end points of patients with synchronous high-volume disease receiving ADT versus D-ADT. (A) ttCP, (B) ttCR, and (C) OS of APUC-6–high/AR-low patients. (D) ttCP, (E) ttCR, and (F) OS of APUC-6–low/AR-low patients. P values are shown as log-rank P values. ADT, androgen deprivation therapy; AR, androgen receptor; D-ADT, docetaxel plus ADT; OS, overall survival; ttCP, time to clinical progression; ttCR, time to castration resistance.
Footnotes
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.
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Amol C. Shetty
Employment: AstraZeneca (I)
Stock and Other Ownership Interests: AstraZeneca (I)
Philip A. Sutera
Stock and Other Ownership Interests: Pfizer, Merck, Catalent (I)
Krishnan R. Patel
Employment: MD Anderson Cancer Center
Ravi A. Madan
Employment: AstraZeneca
Leadership: AstraZeneca
Stock and Other Ownership Interests: AstraZeneca
Research Funding: Bayer
Chad Tang
Employment: MD Anderson Cancer Center
Consulting or Advisory Role: Boston Scientific, Telix Pharmaceuticals, MOLLI Surgical, Elekta
Research Funding: Noxopharm (Inst), Myriad Genetics (Inst)
Patents, Royalties, Other Intellectual Property: I have a patent on the utilization of a monoclonal antibody and we license this for use. We receive royalties <$1,000 per year on this license
Travel, Accommodations, Expenses: Vision RT
Other Relationship: Wolters Kluwer, Osler Institute
James Proudfoot
Employment: Veracyte
Stock and Other Ownership Interests: Veracyte
Elai Davicioni
Employment: Veracyte
Stock and Other Ownership Interests: Veracyte
Patents, Royalties, Other Intellectual Property: WO2018205035A1 Decipher prostate cancer genomic classifier gene signature patent-assigned to my employer Veracyte
Arif Hussain
Consulting or Advisory Role: AstraZeneca, Bayer, Exelixis, Janssen Oncology, Merck
Research Funding: Merck (Inst), Bayer (Inst), Orion (Inst), POINT Biopharma (Inst), Regeneron (Inst), Poseida (Inst), AstraZeneca (Inst), FutureChem (Inst)
Paul Nguyen
Stock and Other Ownership Interests: Volatilyx (I), Nanocan Therapeutics, Stratagen Bio, Reversal Therapeutics, Telerad Oncology
Consulting or Advisory Role: Bayer, Blue Earth Diagnostics, Boston Scientific, Janssen Oncology, Myovant Sciences, Nanocan Therapeutics, AIQ Solutions, Novartis, Theranano, Amgen, MDxHealth
Research Funding: Astellas Pharma, Janssen, Bayer
Patents, Royalties, Other Intellectual Property: Wife has a patent on volatile diagnostics of infections (I)
Christopher Sweeney
Stock and Other Ownership Interests: Leuchemix, Parthera
Consulting or Advisory Role: Janssen Biotech, Astellas Pharma, Bayer, Genentech/Roche, AstraZeneca, Pfizer, Lilly, Advancell, Novartis
Research Funding: Janssen Biotech (Inst), Astellas Pharma (Inst), Bayer (Inst), Dendreon, Pfizer (Inst)
Patents, Royalties, Other Intellectual Property: Leuchemix, Parthenolide, Dimethylaminoparthenolide. Exelixis: Abiraterone plus cabozantinib combination, Parthenolide analogues as radiation protectors for non-cancer indications (eg, medical countermeasures) patent owned by University of Adelaide (Inst)
Ella Boytim
Consulting or Advisory Role: Astrin Biosciences, Tempus
Kristine P. Lacuna
Honoraria: Topline Bio, Curio Science, IDEOlogy Health, Dava Oncology, Bayer, Aptitude Health
Consulting or Advisory Role: Topline Bio, Curio Science, IDEOlogy Health, Bayer, Dava Oncology, Aptitude Health
Travel, Accommodations, Expenses: Dava Oncology, Consens/Digital Science Press, IDEOlogy Health, Bayer
Charles J. Ryan
Honoraria: Janssen Oncology, Bayer, Pfizer, Novartis
Consulting or Advisory Role: ORIC Pharmaceuticals, VIR Biotechnology, Tolmar
Other Relationship: Lilly, ArsenalBio, Bayer
Emmanuel S. Antonarakis
Consulting or Advisory Role: Sanofi, Janssen Biotech, Merck, AstraZeneca, Lilly, Bayer (Inst), Amgen, Blue Earth Diagnostics, Curium Pharma, Foundation Medicine, Tempus, AIkido Pharma, Z-Alpha, AADi, Corcept Therapeutics, Hookipa Pharma, Menarini Silicon Biosystems, Pfizer, Tango Therapeutics
Research Funding: Astellas Pharma (Inst), Bayer (Inst), Bristol Myers Squibb (Inst), MacroGenics (Inst), Merck (Inst), Orion Health (Inst)
Patents, Royalties, Other Intellectual Property: Co-inventor of a biomarker technology that has been licensed to Qiagen
Phuoc T. Tran
Honoraria: Reflexion Medical
Consulting or Advisory Role: Astellas Pharma, Regeneron, GenomeDx, Reflexion Medical, Dendreon, Noxopharm, Janssen, Myovant Sciences, AstraZeneca, Bayer Health, Lantheus Medical Imaging, Novartis, Pfizer
Research Funding: Astellas Pharma (Inst), Reflexion Medical (Inst), Bayer Health (Inst)
Patents, Royalties, Other Intellectual Property: Compounds and Methods of Use in Ablative Radiotherapy. Patent filed 3/9/2012. PCT/US2012/028475. PCT/WO/2012/122471
Travel, Accommodations, Expenses: Reflexion Medical
Justin Hwang
Consulting or Advisory Role: Tempus, Astrin Bio
Research Funding: Astrin Biosciences
No other potential conflicts of interest were reported.
DATA SHARING STATEMENT
A data sharing statement provided by the authors is available with this article at DOI https://doi.org/10.1200/PO-25-01012.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
A data sharing statement provided by the authors is available with this article at DOI https://doi.org/10.1200/PO-25-01012.