Radiographic progression-free survival (rPFS) and time to radiographic progression (TTrP) as surrogate endpoints in docetaxel-naïve metastatic castrate resistant prostate cancer (mCRPC): A pooled analysis of COU-AA-302 and ACIS.
Bibliographic record
Abstract
136 Background: rPFS is often used as an intermediate clinical endpoint (ICE) for overall survival (OS) in randomized trials in mCRPC. However, the current literature shows conflicting results on the surrogacy of rPFS for OS. Moreover, it remains unknown if TTrP, which does not consider death as an event, is an ICE for OS. We performed a combined analysis of COU-AA-302 and ACIS to determine if TTrP and rPFS can be used as ICE. Methods: In COU trial, docetaxel-naïve mCRPC patients were randomized to abiraterone (abi) versus placebo. In ACIS, a similar patient population was randomized to abi alone or abi with apalutamide (abi+apa). We applied weighted Cox regression models to evaluate the effect of treatment on TTrP and OS and used landmark analyses to determine the if the treatment effect on OS is mediated by that on radiographic progression. We estimated a semiparametric Spearman correlation between the ICE and OS at the patient level. We determined the trial level correlation of treatment effect on the ICE and OS in the 2 trials where each of them was subdivided into 9 pseudo-trial centers and then calculating the adjusted R2 between center level estimates of treatment effect for ICE and OS. The procedure of creating pseudo-trial centers was repeated 500 times and the presented R2 is the average across 500 repetitions after excluding those with negative association. Results: Overall, 2016 patients were eligible for this study – 1053 from COU and 963 from ACIS. Abi was associated with superior TTrP (HR 0.55 [95%CI 0.45-0.66]) and OS (HR 0.80 [0.70-0.92]). Similar results were seen with abi+apa (0.51 [0.41-0.64], 0.77 [0.65-0.91]). Radiographic progression was associated with significantly higher hazard of death in the state arrival extended Markov proportional hazard model (3.64 [1.54-8.62]) while longer TTrP was associated with reduced hazard of death (0.94 [0.93-0.95]). At the patient level, the correlation between TTrP & OS and rPFS & OS was 0.58 [0.54-0.63] and 0.68 [0.65-0.71], in the overall cohort. In the abi and abi+apa group, the correlation between TTrP and OS was 0.60 [0.53-0.66] and 0.73 [0.66-0.79] and that for rPFS and OS was 0.72 [0.67-0.75] and 0.79 [0.74-0.83], respectively. At the trial level, the treatment effect on rPFS & OS and TTrP & OS were correlated with average R2 of 0.84, 0.84, 0.85, and 0.86, respectively. The mean surrogate threshold effect over 500 permutations for HRrPFS and HRTTrP was 0.78 and 0.70 in ACIS and 0.54 and 0.45 in the COU-AA-302 trials, respectively. Conclusions: TTrP and rPFS were found to have significant association with OS in chemo-naïve mCRPC patients. We noted a modest to strong correlation between the treatment effect on both the ICE and OS at the trial level. Larger meta-analytic studies are needed to validate these findings.
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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 | 0.021 | 0.014 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.006 | 0.018 |
| Bibliometrics | 0.002 | 0.002 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| 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".