Phase III study of the efficacy and safety of zibotentan (ZD4054) in patients with bone metastatic castration-resistant prostate cancer (CRPC).
Bibliographic record
Abstract
117 Background: Endothelin-1 and the endothelin A (ETA) receptor have been implicated in prostate cancer progression in bone. Zibotentan, a specific ETA receptor antagonist, had a promising signal for prolonged overall survival (OS) in a phase II study of patients with CRPC and bone metastases who were pain free or mildly symptomatic for pain. The aim of this phase III study was to confirm the efficacy and safety of zibotentan in a similar but larger population. Methods: Patients with CRPC and bone metastases were randomized 1:1 to zibotentan 10 mg/day po or placebo, plus standard of care including chemotherapy. The primary endpoint was OS. Secondary endpoints included times to pain progression, chemotherapy use, new bone metastases, and safety. Efficacy endpoints were analyzed using a log-rank test. At least 263 deaths were required for formal analysis. If the true hazard ratio (HR) for zibotentan versus placebo was 0.67, the analysis would have 90% power to demonstrate a statistically significant effect in OS at the 5% level. Results: A total of 594 patients were randomized (299 to zibotentan; 295 to placebo). Baseline group demographics were similar. Mean age was ∼71 yrs, and 64% were Caucasian. Although median OS was longer in zibotentan-treated patients than those receiving placebo (median 24.5 vs 22.5 months), the difference did not reach significance (HR [95.2% confidence interval]; 0.87 [0.69–1.10]: P=0.240). No significant differences were observed for any secondary endpoints. The most commonly reported AEs in the zibotentan group, peripheral edema and headache, were consistent with the pharmacologic action of zibotentan as a vasodilator. Cardiac failure events, actively solicited following a phase II signal, were higher in the zibotentan group (any grade, 5.7%; Common Terminology Criteria for Adverse Events [CTCAE] grade ≥3, 3.0%) than placebo (any grade, 1.7%; CTCAE grade ≥3, 1.0%), but were manageable and reversible. Conclusions: In this placebo-controlled phase III trial treatment with zibotentan 10 mg/day did not lead to a significant improvement in OS in patients with CRPC and bone metastases. Zibotentan had an acceptable safety profile. [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 | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.005 | 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".