This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical results on this page are restricted to the trial data posted on ClinicalTrials.gov for BOLERO-6.
1. Trial at a Glance
BOLERO-6 was a randomized phase 2 trial in advanced breast cancer with three parallel treatment groups. Its registered primary endpoint was progression-free survival comparing everolimus plus exemestane with everolimus alone, with the primary analysis framed as a non-inferiority comparison.
| Feature | BOLERO-6 |
|---|---|
| Phase | Phase 2 |
| Condition | Breast Cancer |
| Brief title | A Phase II Study of Everolimus in Combination With Exemestane Versus Everolimus Alone Versus Capecitabine in Advance Breast Cancer. |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | None |
| Primary purpose | Treatment |
| Enrollment | 309.0 |
| Primary endpoint | Progression Free Survival (PFS) - Everolimus Plus Exemestane Versus Everolimus Alone |
| Results posted | Yes |
| Outcome measures posted | 9 |
| Statistical analyses posted | 16 |
| Lead sponsor | Novartis Pharmaceuticals |
| Sponsor type | Industry |
2. Clinical Question
The primary statistical question was whether progression-free survival with everolimus plus exemestane could be evaluated as non-inferior to everolimus alone in advanced breast cancer. A secondary PFS comparison evaluated the combination against capecitabine alone.
Population
Patients enrolled in a phase 2 study of advanced breast cancer.
Intervention
Everolimus 10 mg plus exemestane 25 mg.
Comparators
Everolimus 10 mg alone and capecitabine 1250 mg/m2.
Primary question
Is progression-free survival with everolimus plus exemestane non-inferior to everolimus alone?
3. Trial Design
Everolimus + Exemestane
- Everolimus 10 mg
- Exemestane 25 mg
- Primary comparator for the PFS non-inferiority analysis
Everolimus Alone
- Everolimus 10 mg
- Primary comparison group for PFS
- Also used in secondary OS, ECOG deterioration, and TSQM comparisons
Capecitabine
- Capecitabine 1250 mg/m2
- Secondary comparison group for PFS, OS, ECOG deterioration, and TSQM analyses
4. Trial Timeline
| Milestone | Date |
|---|---|
| Trial start | 2013-02-26 |
| Primary completion | 2018-07-02 |
| Status | Completed |
The ClinicalTrials.gov record identifies the study as completed, with a start date of February 26, 2013 and primary completion on July 2, 2018. The statistical interpretation below focuses on the analyses and endpoint definitions reported in the ClinicalTrials.gov record rather than reconstructing additional analyses from external publications.
5. Primary Endpoint
| Endpoint | Registered definition / time frame | Analysis population | Primary comparison |
|---|---|---|---|
| Progression Free Survival (PFS) - Everolimus Plus Exemestane Versus Everolimus Alone | Date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first | Full Analysis Set (FAS), which consisted of all randomized patients | Everolimus 10 mg + Exemestane 25 mg vs Everolimus 10 mg |
The registry definition further specifies that PFS is the time from randomization to the date of first radiologically documented progression or death due to any cause. If a patient did not have an event, PFS was censored at the date of the last adequate tumor assessment.
6. Primary Result: Progression-Free Survival
The registry contains a formal statistical analysis for the primary endpoint. The effect measure was a hazard ratio, with a two-sided 90% confidence interval. The analysis was identified as a non-inferiority analysis.
Everolimus + exemestane vs everolimus
Two-sided 90% CI: 0.57–0.97
Hypothesis type: Non-inferiority
| Primary endpoint | Estimate | Confidence interval | Analysis population | Method information |
|---|---|---|---|---|
| Progression-free survival | HR 0.74 | 90% two-sided CI: 0.57–0.97 | Full Analysis Set; all randomized patients | Hazard ratio obtained from a stratified Cox model, stratified by presence/absence of visceral metastasis as per IWRS |
What the estimate means: an HR of 0.74 means that the estimated instantaneous rate of progression or death was 0.74 times that of the everolimus-alone group under the fitted time-to-event model. Expressed as a relative model-based quantity, this corresponds to a 26% lower estimated hazard, calculated as 1 − 0.74.
What it does not mean: it does not mean that 26% of patients avoided progression, that every patient had a 26% reduction in risk, or that median PFS differed by 26%. A hazard ratio is a relative time-to-event measure, not an absolute risk difference.
Precision: the two-sided 90% confidence interval of 0.57–0.97 describes uncertainty around the estimated hazard ratio under the analysis framework. It does not describe the range of effects that individual patients experienced.
The p-value: the registry analysis does not provide a p-value for the primary endpoint. A p-value should not be reconstructed from the reported confidence interval, particularly because this was explicitly framed as a non-inferiority analysis.
Non-inferiority is the key issue: the registry identifies the hypothesis type as non-inferiority, but the ClinicalTrials.gov record does not provide the prespecified non-inferiority margin. Therefore, the HR and confidence interval can be described precisely, but the non-inferiority criterion itself cannot be independently evaluated from the ClinicalTrials.gov record.
Model caution: the reported HR came from a stratified Cox model. Interpretation of a single Cox HR is most straightforward when the proportional-hazards representation is reasonably appropriate over the analyzed period. The ClinicalTrials.gov record does not provide diagnostics for that assumption.
7. What the Primary Hazard Ratio Tells Us
The primary HR of 0.74 is a relative comparison of the event rate over time. Because the endpoint combines two possible events—first documented tumor progression or death from any cause—the hazard ratio summarizes the randomized treatment comparison for this composite time-to-event endpoint rather than separately quantifying progression and death.
For the reported estimate, HR 0.74 indicates a lower estimated instantaneous event rate in the combination group relative to the everolimus-alone group within the fitted model.
The confidence interval adds information that the point estimate alone cannot provide. The reported interval extends from 0.57 to 0.97, so the registry-supported description should remain centered on the estimated HR and its uncertainty rather than treating 0.74 as a fixed underlying biological quantity.
8. Statistical Methodology
Time-to-event analysis
PFS, overall survival, ECOG performance deterioration, and definitive deterioration in global health status / quality of life were all represented as time-to-event outcomes in the analyses posted on ClinicalTrials.gov. Time-to-event methods are designed for situations in which participants can be followed for different lengths of time and some participants may not experience the event during observation.
Right censoring
The registered PFS definition explicitly states that participants without an event were censored at the date of the last adequate tumor assessment. Censoring allows information available before the last adequate assessment to contribute to the analysis without treating the participant as having experienced progression.
Stratified Cox model
The registry states that the reported hazard ratio was obtained from a stratified Cox model, with stratification by presence or absence of visceral metastasis as per IWRS. Stratification allows the baseline hazard to differ across the specified strata while estimating the treatment comparison within the Cox framework.
The coefficient associated with treatment is translated into a hazard ratio through exp(β). In the BOLERO-6 analysis, the reported treatment effect was presented as a hazard ratio rather than as a difference in survival probabilities.
Intention-to-treat analysis
The registry-reported analysis explicitly identifies the Full Analysis Set as consisting of all randomized patients and notes the intention-to-treat analysis concept. This preserves the treatment assignment created by randomization and avoids redefining the comparison according to treatment exposure or completion.
Continuous outcome analysis
Treatment satisfaction was analyzed using a mean difference between groups for several TSQM domains. Unlike a hazard ratio, a mean difference operates on the scale of the questionnaire outcome and is interpreted as an average difference between the compared groups among participants meeting the analysis requirement.
Incomplete patient-reported measurements
For the TSQM analyses, the registry definition states that only participants who had both post-baseline assessments were included. This is an important distinction from the PFS analysis, which used all randomized patients in the Full Analysis Set. The ClinicalTrials.gov record does not specify an imputation method for missing TSQM assessments.
9. Non-Inferiority Design
Non-inferiority changes the statistical question. Instead of asking simply whether the treatment groups are different, a non-inferiority analysis asks whether the new treatment's effect is not unacceptably worse than the comparator according to a prespecified margin.
What the registry provides
The primary PFS analysis is explicitly classified as non-inferiority, and the estimated HR is 0.74 with a two-sided 90% CI of 0.57–0.97.
What is needed for the formal decision
The ClinicalTrials.gov record does not state the prespecified non-inferiority margin. Without that margin, the formal non-inferiority boundary cannot be independently reconstructed.
10. Secondary Progression-Free Survival
The trial also evaluated PFS for everolimus plus exemestane versus capecitabine alone. This comparison used the same broad time-to-event definition and the Full Analysis Set.
Everolimus + exemestane vs capecitabine
Two-sided 90% CI: 0.96–1.66
Hypothesis type: Non-inferiority
| Endpoint | Estimate | 90% two-sided CI | Population | Stratification |
|---|---|---|---|---|
| PFS: everolimus + exemestane vs capecitabine | HR 1.26 | 0.96–1.66 | Full Analysis Set; all randomized patients | Presence/absence of visceral metastasis as per IWRS |
An HR of 1.26 means that the estimated instantaneous rate of progression or death was 1.26 times the corresponding rate in the capecitabine group under the reported Cox-model framework. Unlike the primary comparison, the point estimate is above 1.
The two-sided 90% CI of 0.96–1.66 communicates substantial uncertainty around the point estimate. The interval extends on both sides of 1, so the reported interval itself should not be converted into a simple statement that one treatment has a definitively higher or lower event rate.
The registry labels this analysis as non-inferiority, but the ClinicalTrials.gov record again do not state the non-inferiority margin. No p-value is reported. Therefore, the formal non-inferiority conclusion cannot be reconstructed solely from the ClinicalTrials.gov record.
11. Overall Survival
Overall survival was evaluated as a secondary time-to-event endpoint. The registered time frame was every 3 months following the end of treatment visit, assessed for approximately 54 months.
| Comparison | Hazard ratio | Two-sided 90% CI | Analysis population |
|---|---|---|---|
| Everolimus + exemestane vs everolimus | 1.27 | 0.95–1.70 | Full Analysis Set |
| Everolimus + exemestane vs capecitabine | 1.33 | 0.99–1.79 | Full Analysis Set |
Both OS analyses used hazard ratios from a stratified Cox model, with stratification by presence or absence of visceral metastasis as per IWRS. The ClinicalTrials.gov record classifies both analyses as non-inferiority hypotheses.
For the everolimus-plus-exemestane versus everolimus comparison, the HR of 1.27 corresponds to a higher estimated instantaneous rate of death in the combination group under the fitted model. The 90% CI of 0.95–1.70 reflects uncertainty around that estimate.
For the comparison with capecitabine, the HR was 1.33 with a two-sided 90% CI of 0.99–1.79. This is again a relative model-based estimate, not a percentage of patients who died or a direct measure of absolute survival.
No p-values are posted on ClinicalTrials.gov for either OS analysis, and the non-inferiority margins are not included in the ClinicalTrials.gov record. Accordingly, the estimates should be reported without constructing an unsupported formal hypothesis-test conclusion.
12. ECOG Performance Deterioration
The registry included time to Eastern Cooperative Oncology Group (ECOG) Performance Deterioration as a secondary endpoint. The registered assessment schedule was baseline, every 6 weeks up to about 43 months.
| Comparison | Hazard ratio | Two-sided 90% CI | Hypothesis type |
|---|---|---|---|
| Everolimus + exemestane vs everolimus | 1.09 | 0.72–1.66 | Non-inferiority |
| Everolimus + exemestane vs capecitabine | 1.18 | 0.78–1.77 | Non-inferiority |
Both comparisons were analyzed in the Full Analysis Set. The registry-reported analysis text again identifies a stratified Cox model with stratification by presence/absence of visceral metastasis as per IWRS.
An HR of 1.09 for the comparison with everolimus alone represents a relatively small point estimate above 1, while its 90% CI of 0.72–1.66 is substantially wider than the point estimate. The comparison with capecitabine has an HR of 1.18 and a 90% CI of 0.78–1.77.
These intervals illustrate why a point estimate should not be interpreted in isolation. The confidence intervals encompass a range of plausible relative effects under the model, and no p-values or non-inferiority margins are posted on ClinicalTrials.gov for these analyses.
13. Time to Definitive Deterioration in Global Health Status / Quality of Life
The registry evaluated time to 10% definitive deterioration in the Global Health Status / Quality of Life, measured from baseline every 6 weeks up to about 43 months.
| Comparison | Hazard ratio | Two-sided 90% CI | Hypothesis type |
|---|---|---|---|
| Everolimus + exemestane vs everolimus | 0.64 | 0.46–0.88 | Non-inferiority |
| Everolimus + exemestane vs capecitabine | 1.33 | 0.93–1.91 | Non-inferiority |
The HR of 0.64 for the combination versus everolimus alone corresponds to a 36% lower estimated hazard of the specified definitive deterioration, using the reported hazard-ratio framework. The corresponding 90% CI was 0.46–0.88.
For the capecitabine comparison, the HR was 1.33 with a two-sided 90% CI of 0.93–1.91. Because these are time-to-event patient-reported outcomes, the interpretation concerns the timing of the prespecified deterioration event, not an average change in questionnaire score.
The two quality-of-life time-to-event comparisons illustrate an important statistical distinction. The combination's HR of 0.64 versus everolimus alone describes the relative timing of a prespecified deterioration event. It does not mean that quality of life was 36% higher, nor does it quantify the average magnitude of a patient's change in quality of life.
For both comparisons, the confidence interval is more informative than the point estimate alone because it expresses uncertainty around the estimated hazard ratio. The ClinicalTrials.gov record does not provide p-values or the non-inferiority margin for these analyses.
14. Treatment Satisfaction: TSQM
The Treatment Satisfaction Questionnaire for Medication (TSQM) was assessed at Week 3 and Week 12. The registry analysis used mean change between those assessments. Only participants with both post-baseline assessments were included.
| TSQM domain | Comparison | Mean Difference (Net) | Two-sided 90% CI |
|---|---|---|---|
| Side-effects | Everolimus + exemestane vs everolimus | 4.3 | -3.3 to 11.9 |
| Side-effects | Everolimus + exemestane vs capecitabine | -2.2 | -9.9 to 5.5 |
| Effectiveness | Everolimus + exemestane vs everolimus | -3.3 | -10.4 to 3.8 |
| Effectiveness | Everolimus + exemestane vs capecitabine | -3.3 | -9.7 to 3.0 |
| Convenience | Everolimus + exemestane vs everolimus | -1.6 | -5.8 to 2.5 |
| Convenience | Everolimus + exemestane vs capecitabine | -1.1 | -5.5 to 3.3 |
| Global Satisfaction | Everolimus + exemestane vs everolimus | -2.7 | -8.3 to 2.9 |
| Global Satisfaction | Everolimus + exemestane vs capecitabine | -3.3 | -8.4 to 1.9 |
These are mean differences rather than hazard ratios. The sign therefore depends on the direction of the questionnaire scale and the definition of the reported net difference; it should not be interpreted using the same rules as an HR below or above 1.
15. Safety Results
The ClinicalTrials.gov record reports serious adverse events by randomized treatment arm using affected participants divided by the corresponding number at risk.
| Treatment arm | Serious adverse events | Affected / at risk |
|---|---|---|
| Everolimus 10 mg + Exemestane 25 mg | Serious adverse events | 37/104 |
| Everolimus 10 mg | Serious adverse events | 30/103 |
| Capecitabine 1250 mg/m2 | Serious adverse events | 30/102 |
Combination arm
37 of 104 participants were affected by serious adverse events.
Everolimus arm
30 of 103 participants were affected by serious adverse events.
Capecitabine arm
30 of 102 participants were affected by serious adverse events.
Interpretive caution
These are serious-adverse-event counts by arm; the ClinicalTrials.gov record does not provide a formal between-group statistical test for these safety data.
Safety should be considered separately from efficacy. The serious-adverse-event figures describe observed safety events among the reported at-risk populations; they do not provide a single numerical measure that can be combined with the PFS hazard ratio.
16. Statistical Methods Explained
Why was a hazard ratio used for PFS?
PFS is a time-to-event endpoint in which participants can experience progression or death at different times, while some remain event-free at their last adequate tumor assessment. A hazard ratio provides a relative comparison of the instantaneous event rate over time and can accommodate right-censored observations within the Cox framework.
What does HR 0.74 mean?
For the primary comparison, HR 0.74 means that the fitted model estimated the instantaneous rate of progression or death in the everolimus-plus-exemestane group at 0.74 times the rate in the everolimus-alone group. It does not mean that 74% of patients avoided progression or that individual patients experienced a 26% reduction.
Why was the Cox model stratified?
The registry states that the hazard ratio was obtained from a stratified Cox model, stratified by presence or absence of visceral metastasis as per IWRS. Stratification allows the baseline hazard to differ across those strata while estimating the treatment comparison within the model.
Why is non-inferiority judged against a margin?
Non-inferiority asks whether a treatment is not worse than its comparator by more than a prespecified clinically acceptable amount. Therefore, the relevant statistical boundary is the non-inferiority margin, not simply whether a confidence interval crosses 1. The registry-reported BOLERO-6 data identify the hypothesis as non-inferiority but do not provide the margin.
Why use the Full Analysis Set for efficacy?
The registry-reported analysis defines the Full Analysis Set as all randomized patients. An intention-to-treat approach preserves the original randomized comparison and therefore avoids changing the treatment groups according to subsequent treatment exposure or completion.
Why are the TSQM analyses different from PFS?
TSQM is a continuous patient-reported outcome, so the registry reports mean differences rather than hazard ratios. In addition, only participants with both post-baseline assessments were included. That differs from the PFS analysis, which used the Full Analysis Set of all randomized patients.
Why should a p-value not be inferred from the confidence interval?
The ClinicalTrials.gov record provides two-sided 90% confidence intervals but does not provide p-values. The primary endpoint is also explicitly framed as a non-inferiority hypothesis, so a conventional significance interpretation based on a two-sided null value of 1 would not necessarily reproduce the prespecified non-inferiority decision rule.
17. Understanding the Confidence Intervals
BOLERO-6 provides a useful example of why an effect estimate should always be accompanied by its confidence interval.
| Analysis | Estimate | Two-sided 90% CI |
|---|---|---|
| Primary PFS: combination vs everolimus | HR 0.74 | 0.57–0.97 |
| PFS: combination vs capecitabine | HR 1.26 | 0.96–1.66 |
| OS: combination vs everolimus | HR 1.27 | 0.95–1.70 |
| OS: combination vs capecitabine | HR 1.33 | 0.99–1.79 |
| ECOG deterioration: combination vs everolimus | HR 1.09 | 0.72–1.66 |
| ECOG deterioration: combination vs capecitabine | HR 1.18 | 0.78–1.77 |
| Quality-of-life deterioration: combination vs everolimus | HR 0.64 | 0.46–0.88 |
| Quality-of-life deterioration: combination vs capecitabine | HR 1.33 | 0.93–1.91 |
The intervals vary considerably in width. This reflects differences in the amount of information available for each endpoint and comparison. A narrow interval provides greater statistical precision around the estimated effect than a wider interval, although precision is not the same thing as clinical importance.
18. Multiplicity and Multiple Comparisons
The ClinicalTrials.gov record contains one registered primary endpoint and multiple secondary analyses. The primary endpoint is PFS comparing everolimus plus exemestane with everolimus alone. Secondary analyses include PFS and OS comparisons with capecitabine, ECOG deterioration, quality-of-life deterioration, and several TSQM domains.
| Analysis family | Role in the ClinicalTrials.gov record | Effect measure |
|---|---|---|
| PFS: combination vs everolimus | Primary endpoint | Hazard ratio |
| PFS: combination vs capecitabine | Secondary | Hazard ratio |
| OS | Secondary | Hazard ratio |
| ECOG deterioration | Secondary | Hazard ratio |
| Quality-of-life deterioration | Secondary | Hazard ratio |
| TSQM | Secondary | Mean difference |
The ClinicalTrials.gov record does not specify a multiplicity-adjustment procedure or an alpha-allocation hierarchy across the secondary endpoints. Consequently, the secondary estimates should be presented as reported analyses rather than treated as a sequence of independently confirmed hypotheses without additional information about the prespecified testing strategy.
19. Missing Data and Censoring
The primary PFS definition explicitly specifies censoring at the date of the last adequate tumor assessment when no event occurred. This is a central feature of time-to-event analysis: participants can contribute follow-up information even when the event has not been observed.
The TSQM analyses use a different rule: only participants who had both post-baseline assessments were included. This creates an analysis population defined partly by availability of questionnaire measurements.
PFS
Participants without an event were censored at the date of the last adequate tumor assessment.
TSQM
Only participants with both post-baseline assessments were included in the reported analysis.
The ClinicalTrials.gov record does not specify an imputation procedure for missing TSQM values. That distinction matters because complete-case inclusion and statistical imputation answer different missing-data problems and can rely on different assumptions.
20. Randomization and Stratification
Randomization is the structural foundation of the treatment comparison. Because participants were randomized into three parallel groups, the treatment assignments were determined before the outcome comparisons were made.
For the reported hazard-ratio analyses, the registry specifies stratification by presence or absence of visceral metastasis as per IWRS. The stratified Cox model therefore accounts for this stratification variable when estimating the treatment hazard ratio.
Stratification does not turn an observational comparison into a randomized one. Rather, it incorporates the specified stratification structure into the time-to-event model used for the randomized comparison.
21. What This Trial Does Not Establish From the Supplied Data
Several common trial-reporting details are not contained in the registry-reported BOLERO-6 statistical record. They should not be reconstructed from the point estimates alone.
- Non-inferiority margin: the primary and several secondary analyses are labeled non-inferiority, but the ClinicalTrials.gov record does not state the numerical margin.
- P-values: none of the statistical analyses posted on ClinicalTrials.gov provides a p-value.
- Median PFS or OS: the statistical analyses posted on ClinicalTrials.gov provide hazard ratios and confidence intervals, not median survival estimates.
- Kaplan-Meier estimates: no time-specific survival probabilities are reported.
- Formal multiplicity procedure: the ClinicalTrials.gov record does not identify an adjustment strategy for the multiple secondary analyses.
- Interim-analysis procedure: no interim-monitoring rule is provided in the ClinicalTrials.gov record.
- Bayesian analysis: no Bayesian method is identified in the analyses posted on ClinicalTrials.gov.
- Formal missing-data imputation: the TSQM inclusion rule is reported, but no imputation method is identified.
22. Important Limitations and Interpretation Issues
- Non-inferiority margin is essential: without the prespecified margin, the formal non-inferiority decision cannot be independently assessed from the registry-reported HR and confidence interval.
- No p-values are reported: the analyses posted on ClinicalTrials.gov should be described using their estimates and confidence intervals rather than assigning unsupported significance levels.
- Hazard-ratio interpretation: HRs are model-based relative measures and should not be confused with absolute risks, median survival differences, or individual treatment effects.
- Proportional-hazards consideration: a single Cox HR is most naturally interpreted under the model's proportional-hazards framework; the ClinicalTrials.gov record does not provide diagnostics for that assumption.
- Patient-reported outcomes: TSQM analyses included only participants with both post-baseline assessments, so their analysis population differs from the all-randomized PFS population.
- Open-label design: treatment assignment was not masked, which is particularly relevant when interpreting subjective outcomes such as treatment satisfaction.
- Multiple secondary analyses: many secondary comparisons are reported, but the ClinicalTrials.gov record does not identify a multiplicity-adjustment procedure.
- Safety comparisons: serious-adverse-event counts are provided by arm, but the ClinicalTrials.gov record does not provide formal between-arm statistical testing for these events.
23. Why This Trial Matters Statistically
BOLERO-6 is a useful teaching case because it combines randomized treatment allocation with a non-inferiority primary question, multiple time-to-event endpoints, stratified Cox modeling, censoring, and patient-reported continuous outcomes.
| Concept | How it appears in BOLERO-6 |
|---|---|
| Randomization | Three-arm randomized parallel design |
| Intention-to-treat analysis | Full Analysis Set consisting of all randomized patients |
| Time-to-event endpoints | PFS, OS, ECOG deterioration, and quality-of-life deterioration |
| Hazard ratio | Primary and secondary time-to-event effect measure |
| Stratified Cox model | HR obtained with stratification by visceral-metastasis status as per IWRS |
| Non-inferiority | Primary PFS and several secondary analyses identified as non-inferiority hypotheses |
| Confidence intervals | Two-sided 90% intervals accompany the reported estimates |
| Censoring | PFS censored at the date of the last adequate tumor assessment when no event occurred |
| Continuous outcomes | TSQM reported using mean differences |
| Analysis populations | All randomized patients for FAS efficacy analyses; TSQM additionally required both post-baseline assessments |
The trial is particularly instructive for non-inferiority education. A hazard ratio below 1 can look favorable in isolation, but the formal question is not simply whether the estimate is below 1. The prespecified non-inferiority margin determines how much worsening would have been considered acceptable, and that margin is not contained in the ClinicalTrials.gov record.
24. Clinical Biostats Interpretation of the Overall Statistical Picture
Primary PFS comparison
The reported HR was 0.74 with a two-sided 90% CI of 0.57–0.97 for everolimus plus exemestane versus everolimus alone.
Comparator PFS analysis
Against capecitabine, the reported HR was 1.26 with a two-sided 90% CI of 0.96–1.66.
Overall survival
The reported HRs were 1.27 versus everolimus and 1.33 versus capecitabine, with corresponding two-sided 90% confidence intervals of 0.95–1.70 and 0.99–1.79.
Quality of life
Time to 10% definitive deterioration had an HR of 0.64 versus everolimus and 1.33 versus capecitabine.
These results should not be compressed into a single overall statistic. The primary PFS comparison, secondary PFS comparison, OS analyses, quality-of-life deterioration analyses, and TSQM measurements represent different estimands and different statistical questions.
The strongest statistical reading is therefore endpoint-specific: identify the population, comparison, effect measure, confidence interval, hypothesis type, and analysis framework for each result. For the non-inferiority analyses in particular, the missing margin prevents the formal decision rule from being reconstructed from the ClinicalTrials.gov record alone.
25. Related Tutorials
Learn more about the methods used in this trial:
26. Related Calculators
27. Sources
- ClinicalTrials.gov: BOLERO-6, NCT01783444. Official registry record containing the trial design, registered endpoint definitions, posted outcome measures, statistical analyses, and safety data used for this page.
- Linked publication: PubMed record for PMID 29862411.
Continue with the statistical methods
Explore the broader methods behind randomized trials, time-to-event analysis, hazard ratios, confidence intervals, and non-inferiority designs.
28. Record Summary
BOLERO-6 was a randomized, parallel phase 2 study of everolimus plus exemestane, everolimus alone, and capecitabine in advanced breast cancer. Its primary endpoint was progression-free survival comparing the combination with everolimus alone, analyzed in the Full Analysis Set using a hazard ratio from a stratified Cox model. The reported primary estimate was HR 0.74 with a two-sided 90% CI of 0.57–0.97.
The trial also reported secondary PFS, OS, ECOG deterioration, quality-of-life deterioration, and TSQM analyses. The time-to-event endpoints were summarized with hazard ratios and two-sided 90% confidence intervals, while TSQM used mean differences. Serious adverse events were reported as 37/104, 30/103, and 30/102 across the three treatment arms.
The central statistical lesson is that the numerical estimate is only one component of the analysis. For BOLERO-6, interpretation also requires attention to the Full Analysis Set, intention-to-treat principle, censoring, stratified Cox modeling, the distinction between hazard ratios and mean differences, and—most importantly for the primary question—the non-inferiority margin. Because the ClinicalTrials.gov record does not provide that margin or p-values, those elements should not be inferred from the reported estimates.