This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Trial-specific numerical results on this page are restricted to the ClinicalTrials.gov record.
1. Trial at a Glance
PrE0102 was a randomized, parallel-group, quadruple-masked phase 2 trial evaluating fulvestrant plus everolimus versus fulvestrant plus placebo in post-menopausal patients with hormone-receptor positive metastatic breast cancer resistant to aromatase inhibitor therapy.
| Feature | PrE0102 |
|---|---|
| Phase | Phase 2 |
| Condition | Metastatic Breast Cancer |
| Population | Post-menopausal patients with hormone-receptor positive metastatic breast cancer resistant to aromatase inhibitor therapy |
| Design | Randomized, parallel |
| Masking | Quadruple |
| Primary purpose | Treatment |
| Enrollment | 131 |
| Primary endpoint | Progression-free Survival |
| Primary endpoint type | Time-to-event |
| Primary hypothesis | Superiority |
| ClinicalTrials.gov | NCT01797120 |
| Lead sponsor | PrECOG, LLC. |
2. Clinical Question
The primary statistical question was whether adding everolimus to fulvestrant would improve progression-free survival compared with fulvestrant alone, represented in the registry by a comparison of fulvestrant plus everolimus with fulvestrant plus placebo.
Population
Post-menopausal patients with hormone-receptor positive metastatic breast cancer resistant to aromatase inhibitor therapy.
Intervention
Fulvestrant plus everolimus.
Comparator
Fulvestrant plus placebo.
Primary question
Does fulvestrant plus everolimus improve progression-free survival relative to fulvestrant plus placebo?
3. Trial Design
Experimental combination
- Fulvestrant
- Everolimus
- Randomized comparison against fulvestrant plus placebo
Control combination
- Fulvestrant
- Placebo
- Randomized comparison against fulvestrant plus everolimus
4. Trial Timeline
Trial start
The PrE0102 study began on May 31, 2013.
Primary completion
The registry lists March 22, 2017 as the primary completion date.
Registry status
The trial is listed as completed, with results posted on ClinicalTrials.gov.
5. Endpoints
| Endpoint | Registry definition / time frame | Type |
|---|---|---|
| Progression-free Survival | Progression-free survival documented by Physical Exam, CT Scan or MRI in post-menopausal patients with hormone-receptor positive metastatic breast cancer that is resistant to aromatase inhibitor therapy treated with fulvestrant and everolimus compared to fulvestrant alone from randomization to documented disease progression or death. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | Time-to-event |
| Clinical Benefit Rate | Every 3 months until progression or up to 3 years | Binary |
| Objective Response Rate | Every 3 months until progression or up to 3 years | Binary |
6. Analysis Populations and Statistical Framework
The posted primary analysis used all randomized patients. This is important because randomized treatment assignment is the basis for the primary efficacy comparison and preserves the principal protection created by randomization.
| Endpoint / analysis | Population | Comparison | Method |
|---|---|---|---|
| Progression-free Survival | All randomized patients | Fulvestrant & Everolimus vs Fulvestrant & Placebo | Stratified log-rank test; hazard ratio |
| Clinical Benefit Rate | All randomized patients | Fulvestrant & Everolimus vs Fulvestrant & Placebo | Fisher exact test |
| Objective Response Rate | All randomized patients | Fulvestrant & Everolimus vs Fulvestrant & Placebo | Fisher exact test |
7. Primary Result: Progression-free Survival
The primary endpoint was a time-to-event outcome measured from randomization to documented disease progression or death. The registry reports a stratified log-rank analysis comparing fulvestrant plus everolimus with fulvestrant plus placebo.
Hazard ratio for progression or death
95% CI: 0.40–0.92 · P = 0.02
Analysis population: all randomized patients
| Endpoint | Fulvestrant & Everolimus | Fulvestrant & Placebo | Effect estimate | P-value |
|---|---|---|---|---|
| Progression-free Survival | Reported as the treatment group in the randomized comparison | Reported as the comparator group | HR 0.61 (95% CI 0.40–0.92) | 0.02 |
The reported hazard ratio of 0.61 means that the estimated instantaneous rate of progression or death was approximately 39% lower in the fulvestrant-plus-everolimus group than in the fulvestrant-plus-placebo group, under the time-to-event analysis represented by the reported hazard ratio.
The HR does not mean that 39% of patients avoided progression, that every patient experienced a 39% reduction in risk, or that the median progression-free survival was reduced or increased by 39%. A hazard ratio is a relative time-to-event measure, not an absolute probability.
The 95% confidence interval of 0.40–0.92 describes statistical uncertainty around the estimated hazard ratio. It does not describe the range of outcomes that individual patients might experience. The interval also does not establish that the true treatment effect is equally large at every point in follow-up.
The P-value of 0.02 addresses the statistical evidence against the null hypothesis under the analysis framework. It does not measure the size or clinical importance of the treatment effect. The magnitude of the estimated effect is conveyed by the HR and its confidence interval.
The analysis was stratified on ECOG performance status, measurable disease, and prior chemotherapy for metastatic disease. Stratification incorporates these prespecified factors into the comparison without treating them as separate treatment effects.
8. Secondary Result: Clinical Benefit Rate
Clinical Benefit Rate was a secondary binary endpoint assessed every 3 months until progression or up to 3 years. The registry reports a Fisher exact test comparing the two randomized treatment groups.
Fisher exact test
Analysis population: all randomized patients
Comparison: Fulvestrant & Everolimus vs Fulvestrant & Placebo
The registry reports P = 0.01 for the Clinical Benefit Rate comparison. Because the ClinicalTrials.gov record does not provide the group-specific proportions, event counts, or a confidence interval for this endpoint, the numerical magnitude of the difference cannot be quantified from the ClinicalTrials.gov record.
Fisher's exact test is appropriate for comparing a binary outcome between two treatment groups, particularly when exact rather than large-sample inference is desired. The test evaluates the evidence for an association between treatment assignment and the binary endpoint; it does not itself provide the size of the treatment effect.
The P-value should therefore not be interpreted as a percentage benefit. A fuller clinical interpretation would require the observed Clinical Benefit Rate in each randomized group together with an effect measure such as an absolute difference, risk ratio, or odds ratio and its confidence interval.
9. Secondary Result: Objective Response Rate
Objective Response Rate was another secondary binary endpoint assessed every 3 months until progression or up to 3 years. The registry reports a Fisher exact test for the comparison.
Fisher exact test
Analysis population: all randomized patients
Comparison: Fulvestrant & Everolimus vs Fulvestrant & Placebo
The registry reports P = 0.47 for Objective Response Rate. The ClinicalTrials.gov record does not provide the response proportions or corresponding confidence interval, so the magnitude of any observed difference cannot be determined from the ClinicalTrials.gov record.
A P-value of 0.47 does not establish that the two treatments have identical Objective Response Rates. It indicates that the reported data do not provide strong statistical evidence against the null hypothesis under this test. The distinction matters because absence of statistical evidence for a difference is not the same as proof of equivalence.
Fisher's exact test evaluates the binary response comparison, while the clinical magnitude would normally be communicated using the response proportions and an effect measure with uncertainty.
10. Statistical Methodology
Kaplan-Meier estimation
Progression-free survival is a time-to-event endpoint. A standard descriptive approach for such data is the Kaplan-Meier estimator, which accounts for patients whose follow-up ends before the event occurs through right censoring.
where di is the number of events at time ti and ni is the number at risk immediately before that time.
The registry statistical-analysis record specifically reports a log-rank test and hazard ratio for Progression-free Survival. It does not explicitly state that a Kaplan-Meier estimate was posted as part of the statistical-analysis record, so Kaplan-Meier is discussed here as the standard descriptive framework for this endpoint rather than attributed as a reported registry method.
Stratified log-rank test
The primary Progression-free Survival comparison used a stratified log-rank test. The registry specifies that the analysis was stratified on ECOG performance status, measurable disease, and prior chemotherapy for metastatic disease.
Stratification allows the time-to-event comparison to account for these prespecified factors when comparing the randomized treatment groups. This is different from claiming that any one of those factors is itself a treatment-effect modifier.
Hazard ratio
The primary effect measure was a hazard ratio. In this trial, the reported HR of 0.61 compares the estimated event hazard for progression or death between the fulvestrant-plus-everolimus group and the fulvestrant-plus-placebo group.
The HR is a relative time-to-event measure. It is not the same as a risk ratio, an absolute risk difference, a median-survival ratio, or the percentage of patients who benefit.
Fisher exact test
Clinical Benefit Rate and Objective Response Rate were analysed using Fisher exact tests. Both are binary outcomes in the ClinicalTrials.gov record, making a two-group exact test a natural method for evaluating the association between treatment assignment and the observed binary outcome.
Fisher's exact test evaluates a categorical comparison. It does not account for the timing of events and therefore answers a different statistical question from the log-rank test used for progression-free survival.
Superiority hypothesis
The registry identifies the hypothesis type for the posted analyses as superiority. The statistical question is therefore framed around whether the randomized treatment groups differ in the direction represented by the treatment comparison, rather than whether two treatments satisfy a prespecified equivalence or non-inferiority criterion.
11. Statistical Methods Explained
Why was a stratified log-rank test used for Progression-free Survival?
Progression-free Survival is measured over time, so a simple comparison of proportions would discard information about when progression or death occurred. The log-rank framework compares the observed and expected pattern of events over follow-up. Stratification additionally accounts for the specified ECOG performance status, measurable disease, and prior chemotherapy factors.
What does an HR of 0.61 mean?
An HR of 0.61 indicates a lower estimated instantaneous rate of progression or death in the fulvestrant-plus-everolimus group relative to the fulvestrant-plus-placebo group. The corresponding relative reduction in estimated hazard is 39%. This is not the same as saying that 39% of patients avoided progression or that individual risk was reduced by exactly 39%.
Why does the confidence interval matter?
The 95% CI of 0.40–0.92 communicates uncertainty around the estimated HR. The point estimate is 0.61, but the data are also compatible with smaller or larger relative effects within the interval under the statistical framework. A confidence interval therefore provides information that the P-value alone cannot provide.
Why is the P-value not the effect size?
The P-value measures the compatibility of the observed data with a null hypothesis under the specified testing framework. It does not describe how large the treatment difference is. For Progression-free Survival, the HR and its confidence interval describe the estimated relative treatment effect; for the binary secondary endpoints, the ClinicalTrials.gov record provides P-values but not the underlying effect estimates.
Why use Fisher exact test for Clinical Benefit Rate and Objective Response Rate?
Both endpoints are binary in the registry data. Fisher's exact test evaluates a two-group comparison using the observed counts in a treatment-by-outcome table. Unlike the log-rank test, it does not use event timing.
What does a P-value of 0.47 for Objective Response Rate tell us?
It indicates that the reported comparison did not provide strong statistical evidence against the null hypothesis under the Fisher exact test. It does not prove that the two response rates are equal, nor does it quantify the size of any observed difference. The missing group-specific proportions in the ClinicalTrials.gov record prevent a numerical effect-size interpretation.
12. Stratification and the Primary Analysis
The primary Progression-free Survival analysis was not an unstratified comparison. The registry states that the log-rank test was stratified on three factors:
| Stratification factor | Role in the reported analysis |
|---|---|
| ECOG performance status | Included as a stratification factor in the log-rank analysis. |
| Measurable disease | Included as a stratification factor in the log-rank analysis. |
| Prior chemotherapy for metastatic disease | Included as a stratification factor in the log-rank analysis. |
Stratification is especially relevant when randomization incorporates clinically meaningful baseline factors. Rather than ignoring those factors in the analysis, the stratified test evaluates the treatment comparison while maintaining separate risk-set comparisons across the specified strata.
13. Confidence Intervals and the Primary Estimate
Primary Progression-free Survival estimate
Two-sided 95% CI: 0.40–0.92
Log-rank P = 0.02
Point estimate
The HR of 0.61 is the single best estimate reported in the registry-reported statistical analysis for the relative time-to-event comparison.
Interval estimate
The 95% CI of 0.40–0.92 communicates uncertainty around that point estimate and is more informative than the point estimate alone.
Statistical evidence
The reported P-value of 0.02 provides evidence against the null hypothesis under the reported superiority analysis.
What is not provided
The ClinicalTrials.gov record does not provide median Progression-free Survival, event counts, or Kaplan-Meier time-point estimates.
14. Safety Results
The ClinicalTrials.gov record provides serious adverse-event counts by randomized treatment arm. These figures should be interpreted as the number affected relative to the stated number at risk, rather than as an overall adverse-event rate or as a measure of treatment efficacy.
| Safety measure | Fulvestrant & Everolimus | Fulvestrant & Placebo |
|---|---|---|
| Serious adverse events | 31/64 | 5/65 |
The ClinicalTrials.gov record shows a substantial difference in the number of patients affected by serious adverse events between the two arms. The denominator is important: the registry data specify 31 of 64 in the fulvestrant-plus-everolimus group and 5 of 65 in the fulvestrant-plus-placebo group. These figures should not be generalized to other safety endpoints that are not reported in the ClinicalTrials.gov record.
15. What the Primary Result Does — and Does Not — Mean
The reported HR of 0.61 indicates a lower estimated rate of progression or death in the fulvestrant-plus-everolimus group relative to the fulvestrant-plus-placebo group within the reported time-to-event analysis.
It does not mean that 61% of patients were progression-free, that 39% of patients benefited, or that each patient's risk was reduced by exactly 39%.
The 95% CI of 0.40–0.92 indicates uncertainty around the estimated HR. The width of the interval reflects that the point estimate should not be interpreted as an exact measurement of the underlying treatment effect.
The P-value of 0.02 is evidence against the null hypothesis under the reported superiority test. It does not measure the size of the effect and should be read together with the HR and confidence interval.
The registry analysis does not report median Progression-free Survival, survival probabilities at specified time points, or an absolute PFS difference. Those quantities therefore cannot be inferred from the HR alone.
16. Interpreting Time-to-Event Endpoints
Progression-free Survival differs from a simple binary endpoint because both whether an event occurred and when it occurred are relevant. Patients who have not experienced progression or death by the end of observed follow-up are typically censored rather than treated as if the event never will occur.
Time matters
A patient progressing earlier and a patient progressing later do not contribute identical information to a time-to-event analysis.
Censoring matters
Patients without an observed event at the end of their available follow-up contribute information up to their censoring time.
HR is relative
The HR compares event hazards rather than directly reporting an absolute probability of progression or death.
Median is different
A median PFS would describe a time point, whereas an HR describes a relative event rate over the analyzed follow-up.
17. Secondary Endpoints and What Their Tests Tell Us
| Endpoint | Type | Method | Reported result | What can be concluded from the ClinicalTrials.gov record |
|---|---|---|---|---|
| Progression-free Survival | Time-to-event | Stratified log-rank | HR 0.61; 95% CI 0.40–0.92; P = 0.02 | Both an effect estimate and formal statistical comparison are reported. |
| Clinical Benefit Rate | Binary | Fisher exact | P = 0.01 | Statistical evidence is reported, but the ClinicalTrials.gov record does not include the group-specific proportions or an effect estimate. |
| Objective Response Rate | Binary | Fisher exact | P = 0.47 | The ClinicalTrials.gov record does not provide a formal statistical signal under the reported test, but they also do not establish equality of response rates. |
This distinction illustrates why a complete statistical report should provide both effect estimates and uncertainty whenever possible. A P-value without the underlying proportions can identify the result of a test but cannot communicate the magnitude of a binary treatment difference.
18. Multiplicity and Multiple Endpoints
The ClinicalTrials.gov record identifies one registered primary endpoint and two posted secondary endpoint analyses. They also identify the hypothesis type as superiority. The ClinicalTrials.gov record does not provide an alpha-allocation scheme or multiplicity-adjustment procedure for these endpoints.
| Endpoint | Role | Reported test | Multiplicity details reported |
|---|---|---|---|
| Progression-free Survival | Primary | Stratified log-rank | Not provided in the ClinicalTrials.gov record |
| Clinical Benefit Rate | Secondary | Fisher exact | Not provided in the ClinicalTrials.gov record |
| Objective Response Rate | Secondary | Fisher exact | Not provided in the ClinicalTrials.gov record |
This matters because multiple statistical tests can change how individual P-values should be interpreted when a familywise error rate is being controlled. The ClinicalTrials.gov record does not establish such an adjustment, so this page does not infer one.
19. Crossover, Interim Analysis, and Bayesian Methods
Crossover
The ClinicalTrials.gov record does not report a crossover design or crossover analysis. No crossover effect is therefore attributed to PrE0102 here.
Interim analysis
The ClinicalTrials.gov record does not report an interim-analysis procedure, stopping boundary, or alpha-spending method.
Bayesian methods
The registry-reported statistical methods are Fisher exact testing and log-rank testing. No Bayesian method is reported.
Non-inferiority
The hypothesis type is superiority. No non-inferiority margin is reported because the registry-reported analysis is not described as a non-inferiority analysis.
20. Missing Data and Imputation
The ClinicalTrials.gov record identifies the analysis population and methods but does not specify a missing-data or imputation procedure for the posted analyses.
21. Limitations and Interpretation Issues
- Limited numerical reporting: the ClinicalTrials.gov record provides the primary HR, confidence interval, and P-value, but not median Progression-free Survival, event counts, or time-specific PFS estimates.
- Secondary endpoint effect sizes: Clinical Benefit Rate and Objective Response Rate have reported P-values, but the ClinicalTrials.gov record does not provide group-specific proportions or confidence intervals.
- P-values are not effect sizes: the secondary-endpoint P-values cannot be converted into percentages of treatment benefit.
- Time-to-event assumptions: hazard-ratio interpretation relies on a model-based comparison of event hazards. A single HR can be less descriptive if the relative hazards vary substantially over time.
- Stratification: the primary analysis was stratified on ECOG performance status, measurable disease, and prior chemotherapy for metastatic disease. The reported HR should therefore be understood as arising from that stratified analysis rather than an unadjusted comparison.
- Multiplicity: the ClinicalTrials.gov record identifies one primary endpoint and two secondary analyses but does not specify a multiplicity-adjustment strategy.
- Safety information: serious adverse-event counts are reported, but the ClinicalTrials.gov record does not provide the broader safety profile needed for a comprehensive adverse-event assessment.
- Registry data scope: this page deliberately restricts trial-specific numerical claims to the ClinicalTrials.gov record rather than importing additional estimates from external sources.
22. Why This Trial Matters Statistically
PrE0102 is a useful teaching example because the trial connects a randomized treatment comparison with two distinct classes of statistical endpoints: a time-to-event primary endpoint and binary secondary endpoints.
| Concept | How it appears in PrE0102 |
|---|---|
| Randomization | The study used randomized allocation across two parallel treatment arms. |
| Blinding | The registry describes the study as quadruple-masked. |
| Time-to-event analysis | Progression-free Survival was the registered primary endpoint. |
| Stratified analysis | The primary log-rank analysis was stratified on ECOG performance status, measurable disease, and prior chemotherapy for metastatic disease. |
| Hazard ratio | The primary treatment effect was reported as HR 0.61. |
| Confidence interval | The primary HR had a two-sided 95% CI of 0.40–0.92. |
| Log-rank test | The primary Progression-free Survival comparison used a stratified log-rank test. |
| Fisher exact test | Clinical Benefit Rate and Objective Response Rate were compared using Fisher exact tests. |
| Superiority testing | The registry identifies the hypothesis type as superiority. |
| Safety analysis | Serious adverse events are reported by randomized treatment arm. |
23. Clinical Interpretation vs Statistical Interpretation
Statistical interpretation
The primary randomized comparison produced a Progression-free Survival HR of 0.61, with a two-sided 95% CI of 0.40–0.92 and a reported P-value of 0.02 from the stratified log-rank analysis.
What the registry supports
The ClinicalTrials.gov record supports describing the estimated relative treatment effect and the uncertainty around it. They do not support adding unreported median PFS values or time-specific survival probabilities.
Secondary endpoints
Clinical Benefit Rate had a reported Fisher exact P-value of 0.01, while Objective Response Rate had a reported Fisher exact P-value of 0.47. Their numerical effect sizes are not reported.
Safety
The ClinicalTrials.gov record reports serious adverse events in 31/64 patients in the fulvestrant-plus-everolimus group and 5/65 in the fulvestrant-plus-placebo group.
24. Statistical Concepts in This Trial
Learn more about the methods used in this trial:
25. Related Statistical Calculators
26. Sources
- ClinicalTrials.gov: PrE0102 — NCT01797120.
- PubMed: Publication associated with PrE0102 — PMID 29664714.
Continue through Clinical Biostats
Explore the statistical methods behind randomized trials, time-to-event endpoints, categorical outcomes, confidence intervals, and hypothesis testing.
27. Record Summary
PrE0102 provides a compact example of how different statistical methods answer different clinical-trial questions. The primary endpoint, Progression-free Survival, was analysed in all randomized patients using a stratified log-rank test and reported with a hazard ratio of 0.61, a two-sided 95% confidence interval of 0.40–0.92, and a P-value of 0.02. The analysis was stratified on ECOG performance status, measurable disease, and prior chemotherapy for metastatic disease. Clinical Benefit Rate and Objective Response Rate were secondary binary endpoints analysed using Fisher exact tests, with reported P-values of 0.01 and 0.47, respectively.
The statistical lesson is broader than any individual number. A hazard ratio communicates a relative time-to-event effect; a confidence interval communicates uncertainty around that estimate; a log-rank test evaluates the time-to-event comparison; and Fisher's exact test addresses a binary treatment comparison. Keeping those quantities conceptually separate prevents P-values from being mistaken for effect sizes and prevents relative measures from being mistaken for absolute clinical probabilities.