Olaparib efficacy in patients with metastatic castration-resistant prostate cancer (mCRPC) carrying circulating tumor (ct) DNA alterations in <i>BRCA1</i>, <i>BRCA2</i> or <i>ATM</i>: Results from the PROfound study.
Bibliographic record
Abstract
27 Background: ctDNA testing offers additional opportunities for homologous recombination repair (HRR) gene alteration determination in patients who are not able to access tumor tissue testing. Alteration testing in ctDNA, for BRCA1, BRCA2 and ATM alterations was performed retrospectively in the PROfound study (phase 3 trial of olaparib versus physician’s choice of abiraterone or enzalutamide in men with HRR gene-mutated mCRPC [NCT02987543]). Methods: ctDNA samples were sequenced at FMI, using the FoundationOne Liquid CDx assay for alterations in BRCA1, BRCA2 (BRCA) and ATM, using plasma samples collected during screening in PROfound. Only patients who consented and provided plasma samples from Cohort A (BRCA/ ATM alteration positive by tissue testing) were tested for ctDNA alterations. Radiographic progression-free survival (rPFS) assessed by blinded independent central review (BICR) in patients positive for alterations in ctDNA was analysed via stratified log-rank test. Additional efficacy endpoints (Objective Response Rate [ORR], Overall Survival[OS]) were also assessed. Results: In total, 181/245 (73.9%) Cohort A patients consented and provided a plasma sample for ctDNA testing, of which 139/181 (76.8%) had a ctDNA result reported (either mutation positive or mutation negative) and 42 patient samples failed testing due to insufficient DNA yield or a technical failure of the test.BRCA/ ATM alterations were identified in111/139 (79.9%) patients and 28/139 patients did not report a BRCA/ATM mutation either due to lack of ctDNA shedding from the tumour or ctDNA levels below the sensitivity of the assay. Patients who carried BRCA/ ATM ctDNA alterations had comparable demography, baseline characteristics and proportions of BRCA1, BRCA2 and ATM mutated patients to the overall Cohort A patients. rPFS by BICR results, in patients with BRCA/ ATM alterations in ctDNA, are presented in the Table. Key secondary efficacy endpoints (ORR, OS) will also be reported for ctDNA alteration positive patients. Conclusions: ctDNA testing in patients with mCRPC is feasible and most, but not all patients have concordant results. Patients who were positive for alterations in BRCA1, BRCA2 or ATM showed a consistent rPFS improvement (hazard ratio [HR] 0.33 [0.21, 0.53]) when compared with the ITT population identified by tumor tissue testing (HR 0.34 [0.25, 0.47]). This suggests that using ctDNA to identify patients carrying BRCA1, BRCA2 or ATM alterations who will benefit from olaparib may be beneficial. Clinical trial information: NCT02987543. [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 | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| 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".