PERSEUS1: An Open-label, Investigator-initiated, Single arm, Phase 2 Trial Testing the Efficacy of Pembrolizumab in Patients with Metastatic Castration-resistant Prostate Cancer with Mismatch Repair Deficiency and Other Immune-sensitive Molecular Subtypes
Bibliographic record
Abstract
BACKGROUND AND OBJECTIVE: Some metastatic castration-resistant prostate cancers (mCRPCs) present mismatch repair deficiency (MMRd) and other molecular subtypes potentially sensitive to immune checkpoint inhibitors (ICIs). The PERSEUS1 trial evaluated the response to pembrolizumab in these subtypes. METHODS: This open-label, investigator-initiated, single-arm, phase 2 trial used a two-stage Simon minimax design. Results from stage 1 are presented here. Tumour biopsies from patients with mCRPC progressing on standard therapies were analysed via targeted next-generation sequencing and immunohistochemistry. Patients with MMRd and/or other molecular subtypes associated with ICI sensitivity were treated with pembrolizumab until disease progression or unacceptable toxicity. The primary outcome was response by 24 wk using a composite of radiological objective response; confirmed decrease in prostate-specific antigen ≥50%; or conversion of circulating tumour cell count. The hypothesised desirable response rate was 40%, with 20% deemed unacceptable; >5/24 responses were required for progression to stage 2. KEY FINDINGS AND LIMITATIONS: In total, 25 patients from two centres received a median of 6 cycles (range 2-13) of pembrolizumab, with a response observed in seven (28.0%, 95% confidence interval 12.1-49.4%). Median progression-free survival was 2.8 mo and median overall survival was 16.0 mo. Nineteen patients (76%) experienced treatment-related adverse events, including three (12%) grade 3-4 events. There were no treatment-related deaths. While the prespecified threshold for futility was not met, slow accrual meant the study did not progress to stage 2. CONCLUSIONS AND CLINICAL IMPLICATIONS: Pembrolizumab showed antitumour activity against MMRd and/or other mCRPC molecular subtypes, with a manageable toxicity profile. Genomic and molecular stratification and further translational research are needed to refine patient selection for this therapy in the mCRPC setting.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| 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 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".