Efficacy of olaparib (ola) plus abiraterone (abi) versus placebo (pbo) plus abi in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with a germline or somatic BRCA mutation in the PROpel trial.
Bibliographic record
Abstract
219 Background: PROpel (NCT03732820) met its primary endpoint showing statistically significant investigator-assessed (INV) radiographic progression-free survival (rPFS) benefit with ola + abi vs pbo + abi in first-line mCRPC in pts enrolled irrespective of homologous recombination repair gene mutation (HRRm) status (intention-to-treat [ITT] hazard ratio [HR] 0.66, 95% CI 0.54–0.81; P <0.001). At final prespecified analysis (ITT), median overall survival (OS) with ola + abi vs pbo + abi was 42.1 vs 34.7 months (HR 0.81, 0.67–1.00; P =0.054). In pts assigned to HRRm subgroups using aggregated tumor tissue and circulating tumor DNA (ctDNA) test results ( post hoc analyses), the greatest benefit for ola + abi vs pbo + abi was in pts with BRCAm (rPFS HR 0.23, 0.12–0.43; OS HR 0.29, 0.14–0.56). Concordance based on HRRm status between tumor tissue and ctDNA testing was also high (80% +ve, 87% -ve predictive agreement). We report post hoc efficacy analyses in pts with BRCAm of germline (g) or somatic (s) origin. Methods: PROpel was a double-blind Phase III trial. Pts were randomized 1:1 to ola (300 mg twice daily [bid]) or pbo, and abi (1000 mg once daily) + prednisone/prednisolone (5 mg bid) until disease progression, unacceptable toxicity, or withdrawal of consent. Tumor BRCAm status was determined using aggregated results from tumor tissue (FoundationOne CDx) and ctDNA (FoundationOne Liquid CDx) tests, and g/s status by blood test (Myriad MyRisk). Results: Of the 85 BRCAm pts, 77 were evaluable for g/s status by blood test. Of these, 32% (n=25) had a BRCAm of g origin and 68% (n=52) of s origin. HRs for pts with g and s BRCAm for rPFS (INV 0.13 and 0.19, BICR 0.15 and 0.17) and OS (0.23 and 0.26) all favored ola + abi vs pbo + abi (Table). Conclusions: Ola + abi showed clinical benefit vs pbo + abi for rPFS and OS in pts with g or s BRCAm, supporting earlier findings in the overall BRCAm population of PROpel. Also, as g testing alone does not detect s mutations, these results highlight the importance of robust biomarker testing (which is currently underutilized in real-world practice), including tumor tissue or ctDNA testing, to inform treatment options. Clinical trial information: NCT03732820 . Germline BRCAm, (n=25) Somatic BRCAm, (n=52) Ola + Abi(n=15) Pbo + Abi (n=10) Ola + Abi (n=27) Pbo + Abi (n=25) rPFS* (INV, primary endpoint) Events, n (%) 5 (33.3) 10 (100) 7 (25.9) 17 (68.0) Median rPFS NR 6.9 NR 11.1 HR 0.13 (0.04–0.38) 0.19 (0.07–0.45) rPFS*(BICR, sensitivity analysis) Events 5 (33.3) 10 (100) 6 (22.2) 18 (72.0) Median rPFS NR 5.9 NR 9.1 HR 0.15 (0.05–0.45) 0.17 (0.06–0.41) OS † (key secondary endpoint) Events, n (%) 5 (33.3) 9 (90.0) 6 (22.2) 15 (60.0) Median OS NR 18.4 NR 27.5 HR 0.23 (0.07–0.67) 0.26 (0.09–0.65) *Primary analysis, DCO 30 July 2021; † Final prespecified analysis, DCO 12 Oct 2022. BICR, blinded independent central review; DCO, data cutoff; NR, not reached.
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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 | 0.000 |
| 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".