Substudy F of the Canadian Cancer Trials Group (CCTG) IND.234: PC_BETS (Prostate Cancer Biomarker Enrichment and Treatment Selection)—A biomarker-selected phase II study of durvalumab and tremelilumab (DT) in patients (pts) with previously treated metastatic castration-resistant prostate cancer (mCRPC) resistant to AR pathway inhibitors (ARPI).
Bibliographic record
Abstract
5057 Background: mCRPC with high neoantigen burden due to DNA mismatch repair deficiency (MMRd) and somatic hypermutation, or CDK12 mutations, may respond best to immune checkpoint inhibition (ICI). CCTG IND.232 suggested that combination ICI with DT has efficacy in a subset of mCRPC but should be biomarker-directed. In this sub-study (SS) of the PC-BETS master protocol, we explored DT in ARPI-resistant mCRPC stratified by circulating tumor DNA (ctDNA) analysis. Methods: Pts had ECOG PS 0–1, evaluable disease, biochemical or radiographic progression, prior ARPI ± cytotoxic chemotherapy (max 1 in castrate resistant setting). Genomic screening tested plasma ctDNA and matched leukocyte DNA via deep targeted sequencing with a prostate cancer-specific panel including coding regions and introns of selected mismatch repair genes and estimating tumor mutational burden. Only pts with evidence of ctDNA ≥1% were eligible. Pts with a positive biomarker (BM+) on ctDNA were assigned to a specific SS by a molecular tumor board (MTB); BM- pts were randomized between SS. SS- F tested DT in 2 cohorts of pts: cohort 1: BM+ pts had either somatic hypermutation (HM) ± concomitant MMR gene alterations, or CDK12 mutations, cohort 2: BM- pts without these alterations, in a 2-stage design. Primary endpoint was clinical benefit rate (CBR), defined by PSA50 response, RECIST CR/PR, or SD ≥12 weeks. Pts received T 225mg IV once on cycle 1, day 1 and D 1500mg IV day 1 every 4 weeks. Results: From January 2020 to February 2024, 25 pts were enrolled: 15 and 10 to cohort 1 and 2, respectively. Median age was 69y (63-84). Five pts had liver mets, 15 pts had had prior cytotoxics. 9 pts in cohort 1 had HM and the remainder had CDK12 mutations only. Median N cycles given was 4 (1-45). 12 pts had a delayed or interruption of DT dosing. The most common related AEs were fatigue (36%), rash (36%), and diarrhea (32%). CBR was seen in 53% of BM+ pts: all also had PSA response and significantly higher median ctDNA% (34% vs 5%; 5-69%); no patient selected as BM+ due to CDK12 mutations had CBR, while 8 of 9 pts selected based on HM had CBR. Conclusions: Liquid biopsy biomarker-informed treatment with DT demonstrated very promising efficacy in mCRPC pts with HM and merits further evaluation. CDK12 mutations were not predictive of CBR. Toxicities experienced were characteristic of ICI. Clinical trial information: NCT03385655 . BM + BM - CBR 8 (53%) 0 Median ctDNA% 25% 12.5% TTP-PSA* (mo; 95% CI) 6.7 (1-NR) 1.9 (1.1-NR) mOS** (mo; 95% CI) 15.2 (11.8-NR) 7.5 (2.1-NR) *PSA time to progression; **median overall survival.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.002 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.007 | 0.001 |
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".