Substudy G of the Canadian cancer trials group (CCTG) IND.234: PC_BETS (V)—A circulating tumor DNA (ctDNA)–directed phase II study of carboplatin in patients (Pts) with previously treated metastatic castration-resistant prostate cancer (mCRPC).
Bibliographic record
Abstract
5058 Background: PC-BETS registered pts with mCRPC for ctDNA-based genomic screening. A molecular tumor board (MTB) assigned pts to sub-studies (SS) based on prespecified biomarker (BM) criteria: BM-positive (BM+), or by randomization if BM-negative (BM-). IND.234G investigated carboplatin in 2 cohorts (C): C1 included BM+ pts with deleterious DNA damage response (DDR) gene alterations and C2 included BM- pts. Methods: Key inclusion criteria were: mCRPC, ECOG 0-1, evaluable disease, biochemical and/or radiological disease progression, received prior next-generation AR pathway inhibitor; prior chemotherapy allowed (max I regimen for mCRPC). The primary endpoint was clinical benefit rate (CBR: PSA50 response, RECIST CR/PR, or SD ≥12 weeks). Secondary endpoints included time to PSA progression (TTP-PSA), and overall survival (OS). Plasma ctDNA and matched leukocyte DNA underwent deep targeted sequencing with a prostate cancer specific panel that included ATM, BRCA1/2, and 22 other DDR genes. Patients with ctDNA <1% were not eligible unless they carried a germline DDR gene alteration. Pts received IV carboplatin (AUC5) on day 1 of 21-day cycles. Results: From 09/2020 to 02/2024, 36 pts were enrolled: 19 and 17 in C1 and 2, respectively. All pts were evaluable for safety while 1 pt was not evaluable for CBR (biochemical only disease). Median age was 69y (55-83) and 66y (54-77); 67%/82% had prior chemotherapy; 21%/6% had prior PARPi, and 6%/0% had liver metastases in C 1/2, respectively. In C1, qualifying gene alterations were: ATM (n=8 pts), BRCA2 (8), BRCA1 (1) and ATR (1). Median number of cycles was 4 (1-31). The most common adverse events (AEs) were anemia (97%), thrombocytopenia (89%), lymphopenia (69%), nausea (58%), neutropenia (42%), diarrhea (22%), vomiting (22%), and constipation (33%). Grade ≥3 non-hematologic AEs occurred in 28% of patients; 1 pt died from an unrelated myocardial infarction. 22 pts had dose delays and 15 pts had dose reductions for hematologic AEs. A summary of results is shown in Table 1. For C1, CBR was observed in 5/8 pts with BRCA2 alterations (4 pts had PSA response), 2/8 pts with ATM alterations (0 PSA responses), and 0/2 pts with ATR/BRCA1 alterations. CBR (with PSA response) was observed in 1 pt enrolled to C2 who did not have DDR gene alterations. Conclusions: Carboplatin was associated with meaningful clinical benefit in mCRPC pts with DDR alterations detected in ctDNA, but not in pts without DDR alterations. Carboplatin warrants further evaluation in mCRPC pts with DDR gene alterations. Clinical trial information: NCT03385655 . Cohort 1 (BM +) N=18 Cohort 2 (BM -)N=17 Median ctDNA% at baseline 16.5% 20% Clinical Benefit (n, %) 7 (39%) 1 (6%) TTP-PSA (mo; 95% CI) 2.0 (1.4-9.9) 1.7 (0.8-2.6) mOS (mo; 95% CI) 21 (9.3-NR) 9.6 (6.5-NR)
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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 | 0.003 | 0.004 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.010 | 0.002 |
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".