Blood biomarkers and association with clinical outcomes in metastatic castration-resistant prostate cancer (mCRPC): prespecified longitudinal analysis from the ACIS study of apalutamide (APA) or placebo combined with abiraterone acetate plus prednisone (AAP).
Bibliographic record
Abstract
142 Background: In ACIS, APA + AAP improved radiographic progression-free survival in mCRPC vs AAP; difference in overall survival (OS) was not statistically significant. We report a prespecified analysis of androgen receptor (AR) or non-AR genomic/transcriptional aberrations, known to be associated with poor prognosis, and their associations with OS in patients (pts) with mCRPC. Methods: Circulating tumor (ct)DNA and aberrations in 17 PC-relevant genes were assessed using next-generation sequencing at baseline (BL; n = 197) and at end of study treatment (EOST; n = 140) (biomarker population). ctDNA was summarized qualitatively; genomic aberrations were normalized by ctDNA detection. AR splice variant version 7 (ARv7) was detected by quantitative RT-PCR. Cox proportional hazards model assessed association of OS with biomarkers in univariate/multivariate analyses overall and in pts receiving subsequent treatment (tx). Results: BL characteristics of biomarker and total study populations were similar. From BL to EOST: ctDNA detection did not differ (123/196 [63%] to 92/140 [66%], p=0.6); significant increases occurred in ARv7, AR mutations, and any AR aberration (Table). Prevalence of aberrations in PI3K and homologous recombination repair (HRR) pathways did not change from BL to EOST (40/123 [33%] to 34/92 [37%], p=0.5 and 18/123 [15%] to 14/92 [15%], p>0.9, respectively). Worse OS was associated with ctDNA detection or HRR pathway inactivation at BL (HR, 2.5 or 2.2; all p < 0.001) or presence of ctDNA, ARv7, AR amplification or inactivation of TP53, RB1, or RB1/TP35 pathway at EOST (2.2, p < 0.001; 2.1, p < 0.001; 2.6, p < 0.001; 1.5, p < 0.05; 1.7, p < 0.05; 2.1, p < 0.001, respectively) in univariate analyses. EOST ARv7, AR amplification, and inactivation of RB1, TP53, or RB1/TP53 pathway was associated with worse OS in pts receiving subsequent tx. Detection of ctDNA and RB1 inactivation at BL and RB1/TP53 pathway inactivation at EOST was strongly associated with worse OS (2.1, 3.3, 2.9, respectively, all p < 0.01) in multivariate analyses. Conclusions: In ACIS, AAP or APA + AAP tx was associated with increased AR mutations and ARv7 expression. Detection of ctDNA and select AR/non-AR aberrations may predict poor survival in mCRPC. These markers may be used to improve tx selection following confirmation of their predictive value. Clinical trial information: NCT02257736. [Table: see text]
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".