Baseline ctDNA analyses and associations with outcomes in taxane-naive patients with mCRPC treated with <sup>177</sup>Lu-PSMA-617 versus change of ARPI in PSMAfore.
Bibliographic record
Abstract
5008 Background: [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) prolonged radiographic progression-free survival (rPFS) versus androgen receptor pathway inhibitor (ARPI) change in taxane-naive patients with metastatic castration-resistant prostate cancer (mCRPC) in PSMAfore (NCT04689828). In this exploratory analysis, associations between baseline circulating tumor DNA (ctDNA) and outcomes were assessed. Methods: Patients were randomized 1:1 to 177Lu-PSMA-617 (7.4 GBq Q6W; 6 cycles) or ARPI change (abiraterone/enzalutamide). Patients known to have actionable mutations (e.g. BRCA) were excluded. The primary endpoint was rPFS. Baseline plasma ctDNA was analyzed using a customized 585-gene sequencing assay. ctDNA fraction was assessed in all samples passing quality control. Alterations in key prostate cancer drivers (prevalent in >10% participants) were assessed in samples with ctDNA fraction >1%. Univariate Cox regression (reference: ARPI change) was used to assess association of ctDNA fraction or alterations with rPFS, prostate-specific antigen response (≥50% decline; PSA50) and RECIST response (RR) at the June 21, 2023 data cutoff. Results: Of 360 samples from 468 patients, 255 passed quality control and 156 had ctDNA fraction >1% (median 5.85%; range 0–85). Detection of ctDNA alterations was comparable between arms and with published data. Median rPFS was shorter for patients with ctDNA fraction > versus ≤1% (HR 2.753; 95% CI 1.957–3.872; p<0.0001) (Table); ctDNA fraction >1% was also associated with worse RR and PSA50 response. Median rPFS was shorter for patients with detected versus undetected AR(HR 1.954; 95% CI 1.333–2.865; p<0.001), TP53(1.655; 1.13–2.426; p<0.01) and PTEN(1.62; 1.018–2.578; p<0.05) alterations. Median rPFS was longer with 177Lu-PSMA-617 versus ARPI change in patients with detected AR, TP53, PTEN(Table) , PI3K pathway and DNA repair pathway alterations. There was no significant association between ctDNA alterations and PSA50 or RR. Conclusions: ctDNA fraction >1% and AR, TP53and PTENalterations were associated with worse outcomes in PSMAfore regardless of treatment. Nonetheless, patients with these negative prognostic biomarkers did better with 177Lu-PSMA-617 than with ARPI change. Clinical trial information: NCT04689828 . [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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".