Personalized use of metronomic cyclophosphamide for DNA repair deficient castration-resistant prostate cancer: A phase II trial.
Bibliographic record
Abstract
TPS346 Background: There is a continued need to identify novel targets for the treatment of metastatic, castration-resistant prostate cancer (mCRPC). DNA damage repair (DDR) aberrations are emerging as such a target: 20%-30% of mCRPCs harbor DDR gene aberrations, rendering tumors particularly sensitive to DNA damaging agents and poly ADP-ribose polymerase inhibitor (PARPi) therapy. 88% of men with DDR deficient mCRPC responded to the PARPi olaparib in a phase II trial, whereas in unselected mCRPC patients the metronomic use of the DNA damaging agent cyclophosphamide (CPA) resulted in response rates of 25-60%. Intriguingly, in randomized phase II trials of unselected ovarian and triple-negative breast cancer (ie tumor types enriched for DDR defects), metronomic CPA alone was as active as metronomic CPA plus the PARPi veliparib. Based on this we hypothesize that DDR deficient mCRPC is particularly sensitive to metronomic CPA. To the best of our knowledge this is the first attempt to utilize metronomic CPA in a personalized manner. Our study has the potential to define metronomic CPA as an affordable and well-tolerated alternative to PARPi therapy in men with DDR deficient mCRPC. Methods: To study if metronomic CPA achieves a similar response rate (ie ≥85%) in DDR deficient mCRPC as seen with olaparib, men with mCRPC progressing after 1-2 lines of systemic therapy will undergo circulating tumor DNA based testing for BRCA1/2 or ATM aberrations. Patients with such aberrations will proceed with metronomic CPA (50 mg po daily). Primary endpoint: RECIST 1.1 and/or ≥50% PSA response rate at 12 weeks. Secondary endpoints include biochemical, radiological and clinical progression-free survival. Applying the Optimal Simon's Two-Stage design, and using a type I error rate of 0.05 and a power of 0.8, in the first stage we plan to enroll 14 patients. If there are ≤10 or fewer responses, the study will be stopped. Otherwise, another 19 patients will be accrued as part of the second stage.
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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 | 0.000 |
| 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 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.006 | 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".