Efficacy of olaparib (O) plus abiraterone (A) versus placebo (P) plus A in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with single homologous recombination repair gene mutations (HRRm) in the PROpel trial.
Bibliographic record
Abstract
165 Background: PROpel (NCT03732820) met its primary endpoint and showed a significant investigator-assessed radiographic progression-free survival (rPFS) benefit with O + A vs P + A in first-line mCRPC (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.54–0.81; P<0.001). At final prespecified analysis, median overall survival (OS) with O + A vs P + A was 42.1 vs 34.7 months (HR 0.81, 95% CI 0.67–1.00; P=0.0544). We report gene-by-gene efficacy of O + A vs P + A for pts from PROpel with a HRRm. Methods: PROpel was a Phase 3 randomized (1:1), double-blind trial. Pts were enrolled irrespective of biomarker status and received O (300 mg twice daily [bid]) or P, plus A (1000 mg once daily) and prednisone/prednisolone (5 mg bid). rPFS by investigator assessment was the primary endpoint (data cutoff [DCO]: 7/30/2021). OS was a key secondary endpoint (DCO: 10/12/2022). Following randomization and before primary analysis, HRRm status was assessed by tumor tissue (FoundationOne CDx) and ctDNA (FoundationOne Liquid CDx) tests and is reported using aggregated results from both tests. Genes assessed were ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L. HR and CIs are not reported in subgroups with <5 events in either arm for both rPFS and OS. Results: 28.4% pts had an HRRm.For most pts with a single gene HRRm, there was a lower proportion of rPFS events and deaths in the O + A arm relative to the P + A arm (Table). The most prevalent gene mutations were BRCA2, ATM and CDK12; HRs for rPFS and OS numerically favored O + A (rPFS: BRCA2, HR 0.20, 95% CI 0.08–0.44; ATM, HR 0.55, 95% CI 0.20–1.38; CDK12, HR 0.51, 95% CI 0.20–1.18. OS: BRCA2, HR 0.20, 95% CI 0.07–0.48; ATM, HR 0.79, 95% CI 0.33–1.77; CDK12, HR 0.57, 95% CI 0.24–1.27). Conclusions: BRCA2, ATM and CDK12 were the most prevalent single gene mutations and clinical benefit was observed with O + A. Other single gene mutations were rare, limiting interpretation. The greatest treatment benefit was observed in pts with BRCA mutations. Clinical trial information: NCT03732820 . [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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| 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, 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".