Effect of concomitant medications on treatment response and survival in de novo metastatic prostate cancer: Secondary analysis of the LATITUDE study.
Bibliographic record
Abstract
120 Background: Prior studies have shown that exposure to concomitant medications such as metformin and statins influences survival in metastatic castrate resistant prostate cancer treated with androgen receptor pathway inhibitors (ARPI). However, it is unclear if such exposure to concomitant medications influences treatment response and survival in metastatic hormone sensitive prostate cancer (mHSPC) treated with ARPI. Methods: We performed a secondary analysis of the LATITUDE trial to determine whether exposure to concomitant medications influenced the effect from abiraterone, in addition to ADT, on overall survival (OS) and prostate cancer specific mortality (PCSM) in men with de novo high risk mHSPC. We focused on 7 commonly prescribed classes of medications: metformin, statins, proton pump inhibitors, cyclooxygenase 2 (COX-2) inhibitors, aspirin, acetaminophen, and NSAIDs (nonselective COX inhibitors except aspirin). To identify effect modification, we applied Cox regression models for OS with an interaction term between the medication classes and the randomized treatment regimen. To determine the independent association of each medication with OS and PCSM, we applied separate multivariable Cox regression and competing risk regression models, respectively. To account for multiple testing, 2-sided p<0.0024 was set as the threshold for statistical significance. Results: Overall, 1135 men were eligible. There was a non-significant evidence of differential effect from abiraterone on OS among men with concomitant exposure to aspirin (Hazard ratio [HR]: 0.93; 95% CI: 0.63-1.36) vs. those who did not (HR: 0.61 [0.51-0.73]) (interaction p=0.04). Similarly, there was a non-significant evidence of a differential effect from abiraterone on OS among men exposed to NSAIDs (HR: 0.54 [0.42-0.70]) vs. those who did not (HR: 0.74 [0.60-0.91]) (interaction p=0.05). Exposure to concurrent NSAIDs was associated with a significantly inferior OS (HR: 1.37 [1.15-1.62]; p<0.001) and higher relative incidence of PCSM (subdistribution HR: 1.47 [1.21-1.78]; p<0.001) in the overall cohort. There was a significantly higher relative excess risk of grade ≥3 cardiovascular adverse events by interaction of concomitant exposure to aspirin with abiraterone (RERI: 3.39 [0.68-6.11]). Conclusions: In this secondary analysis, concomitant exposure to 7 classes of medications was not associated with any statistically significant modification of abiraterone effect on OS in de novo high risk mHSPC. Men who received concurrent NSAIDs had a higher risk of PCSM and inferior OS even after adjustment for skeletal metastases burden and pain score. The excess risk of serious cardiovascular adverse events by interaction of abiraterone and exposure to aspirin could be due to reverse causality due to underlying burden of cardiovascular comorbidity in the exposed group.
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How this classification was reachedexpand
Direct model labels (unvalidated)
Per-model category and study-design labels from the labeling rounds. They are machine output, unvalidated, and the disagreement between models ships as data. No study design here is MEDLINE-validated yet.
| Model arm | Categories | Study design | Confidence |
|---|---|---|---|
| gemma | no category Domain: not available · Genre: Empirical About the Canadian research system: no · About a Canadian topic: no | Observational | low |
| gpt | no category Domain: not available · Genre: Empirical About the Canadian research system: no · About a Canadian topic: no | Observational | low |
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 | 0.004 | 0.006 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.005 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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, unvalidatedLabeled directly by 2 models reading the full record.
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".