This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. The numerical results on this page are restricted to the statistical analyses posted in the ClinicalTrials.gov record.
1. Trial at a Glance
TITAN is a randomized phase 3, parallel-group trial evaluating apalutamide plus androgen deprivation therapy versus androgen deprivation therapy in participants with metastatic hormone-sensitive prostate cancer. The registry reports two primary time-to-event endpoints and four secondary time-to-event analyses, all comparing the randomized groups using log-rank methodology and hazard ratios.
| Feature | TITAN |
|---|---|
| Trial name | TITAN |
| Phase | Phase 3 |
| Condition | Prostate Cancer |
| Population | Participants with metastatic hormone-sensitive prostate cancer (mHSPC) |
| Design | Randomized, parallel-group, triple-masked |
| Primary purpose | Treatment |
| Enrollment | 1052 |
| Arms | 2 |
| Primary endpoints | Radiographic progression-free survival (rPFS) and overall survival (OS) |
| Primary endpoint type | Time-to-event |
| Primary analysis method | Log-rank test |
| Effect measure | Hazard ratio |
| Hypothesis type | Superiority |
| Status | Active, not recruiting |
| Start | 2015-11-27 |
| Primary completion | 2020-09-07 |
| Lead sponsor | Aragon Pharmaceuticals, Inc. |
| Sponsor type | Industry |
2. Clinical Question
The central statistical question is whether adding apalutamide to androgen deprivation therapy improves time-to-event outcomes compared with androgen deprivation therapy alone in participants with metastatic hormone-sensitive prostate cancer.
Population
Participants with metastatic hormone-sensitive prostate cancer (mHSPC).
Intervention
Apalutamide plus androgen deprivation therapy (ADT).
Comparator
Placebo plus androgen deprivation therapy (ADT).
Primary question
Does apalutamide plus ADT improve radiographic progression-free survival and overall survival relative to placebo plus ADT?
3. Trial Design
Apalutamide + ADT
- Apalutamide
- Androgen deprivation therapy (ADT)
Placebo + ADT
- Placebo
- Androgen deprivation therapy (ADT)
The trial uses a parallel-group randomized design. This means each participant is assigned to one treatment strategy and the groups are followed for the prespecified outcomes. Randomization provides the foundation for comparing outcomes according to assigned treatment rather than according to treatment actually received.
The registry classifies the study as triple-masked. Masking can reduce the influence of knowledge of treatment assignment on participant behavior, investigator assessment, and other aspects of trial conduct. For an endpoint such as investigator-assessed radiographic progression, masking is particularly relevant because the timing of an event can otherwise be vulnerable to assessment expectations.
4. Endpoints
| Endpoint | Time frame | Registry definition | Endpoint type |
|---|---|---|---|
| Radiographic Progression-free Survival (rPFS) | Up to 35 months | rPFS as assessed by the investigator was defined as the duration from the date of randomization to the date of first documentation of radiographic progressive disease or death due to any cause, whichever occurred first. Radiographic progressive disease was defined as progression of soft tissue lesions measured by computed tomography (CT) or magnetic resonance imaging (MRI) as defined by modified Response evaluation criteria in solid tumors (RECIST) 1.1. | Time-to-event |
| Overall Survival (OS) | Up to 57 months | OS was defined as the time from date of randomization to date of death from any cause. | Time-to-event |
Both primary endpoints begin at randomization. That common time origin is important statistically because the treatment comparison is anchored to the randomized allocation. The endpoints differ in the event being observed: rPFS reaches an event at radiographic progression or death, whereas OS reaches an event only at death from any cause.
rPFS
Combines radiographic progression and death into a time-to-first-event endpoint. A participant can therefore experience an rPFS event without having died.
OS
Uses death from any cause as the event. Participants who remain alive at the relevant follow-up are treated as censored observations for survival analysis.
5. Primary Results: Radiographic Progression-free Survival
The registry reports a formal superiority analysis of rPFS in the ITT population. Participants were classified according to their assigned treatment group regardless of the actual treatment received.
Hazard ratio for radiographic progression or death
95% CI: 0.391–0.600 · P <0.0001
Analysis time frame: Up to 35 months
| Endpoint | Comparison | Analysis population | Method | Effect estimate | 95% CI | P-value |
|---|---|---|---|---|---|---|
| Radiographic Progression-free Survival (rPFS) | Placebo + ADT vs Apalutamide + ADT | ITT | Log-rank test | HR 0.484 | 0.391–0.600 | <0.0001 |
An HR of 0.484 means that the estimated instantaneous rate of an rPFS event was about 48% of the corresponding rate in the comparison group under the reported time-to-event analysis. Equivalently, the estimate corresponds to an approximately 52% lower estimated hazard for the apalutamide-plus-ADT group relative to placebo plus ADT.
The hazard ratio does not mean that 52% of participants avoided progression, nor does it mean that every participant experienced exactly a 52% reduction in risk. It is a relative time-to-event measure summarizing the treatment comparison over follow-up.
The 95% CI of 0.391–0.600 describes statistical uncertainty around the estimated hazard ratio. It does not describe the range of outcomes for individual participants. The entire interval is below 1, which is consistent with the direction of the reported superiority comparison.
The P-value of <0.0001 addresses the strength of evidence against the relevant null hypothesis under the specified statistical framework. It is not a measure of the magnitude or clinical importance of the treatment effect. Effect size is conveyed by the hazard ratio and its confidence interval.
Because this is a time-to-event analysis, interpretation also depends on censoring and the assumptions underlying the survival model used to express the hazard ratio. The ClinicalTrials.gov record identifies the log-rank test and hazard ratio but does not provide a proportional-hazards diagnostic or additional model specification.
Why the rPFS result is a time-to-event result
rPFS is not simply the percentage of participants who eventually progressed. The analysis incorporates when progression or death occurs and accommodates participants whose event status is not observed by the end of their available follow-up. This is why a hazard ratio is a natural effect measure for the endpoint.
The complementary interpretation is approximately a 51.6% relative reduction in the estimated instantaneous hazard, calculated as 1 − 0.484.
6. Primary Results: Overall Survival
The second primary endpoint was overall survival, defined from randomization to death from any cause. The registry reports a formal superiority analysis in the ITT population.
Hazard ratio for death
95% CI: 0.534–0.793 · P <0.0001
Analysis time frame: Up to 57 months
| Endpoint | Comparison | Analysis population | Method | Effect estimate | 95% CI | P-value |
|---|---|---|---|---|---|---|
| Overall Survival (OS) | Placebo + ADT vs Apalutamide + ADT | ITT | Log-rank test | HR 0.651 | 0.534–0.793 | <0.0001 |
An OS HR of 0.651 means that the estimated instantaneous rate of death in the apalutamide-plus-ADT group was approximately 65.1% of that in the placebo-plus-ADT group under the reported analysis. The complementary interpretation is an approximately 34.9% lower estimated hazard of death.
This does not mean that 34.9% of participants survived or that an individual participant's probability of death was reduced by exactly 34.9%. A hazard ratio is a relative time-to-event measure, not an absolute survival probability.
The 95% CI of 0.534–0.793 quantifies uncertainty around the estimated hazard ratio. It remains below 1 throughout the reported interval, so the point estimate and its uncertainty interval are both in the direction of lower estimated mortality hazard for apalutamide plus ADT.
The P-value of <0.0001 indicates strong statistical evidence against the corresponding null hypothesis under the reported superiority analysis. It should not be interpreted as the probability that the null hypothesis is true, nor as a measure of how large the treatment effect is.
OS is particularly important statistically because the endpoint is death from any cause rather than an investigator-assessed disease event. Nevertheless, the hazard-ratio interpretation remains model- and censoring-dependent, and the ClinicalTrials.gov record does not report additional information about proportional-hazards diagnostics or alternative survival estimands.
Comparing the two primary hazard ratios
| Primary endpoint | HR | 95% CI | P-value | Time frame |
|---|---|---|---|---|
| rPFS | 0.484 | 0.391–0.600 | <0.0001 | Up to 35 months |
| OS | 0.651 | 0.534–0.793 | <0.0001 | Up to 57 months |
The two estimates address different events and use different reported time frames, so they should not be treated as interchangeable measures. The rPFS endpoint captures radiographic progression or death, while OS captures death from any cause. A treatment effect on rPFS can therefore be observed without requiring the same numerical hazard ratio for OS.
7. Secondary Endpoint Results
The registry also reports four secondary time-to-event analyses. All use the ITT population, compare placebo plus ADT with apalutamide plus ADT, and use the log-rank test with hazard ratio as the effect measure. Each analysis is reported as a superiority hypothesis.
| Secondary endpoint | Time frame | HR | 95% CI | P-value |
|---|---|---|---|---|
| Time to Initiation of Cytotoxic Chemotherapy | Up to 57 months | 0.469 | 0.350–0.630 | <.0001 |
| Time to Pain Progression | Up to 57 months | 0.868 | 0.700–1.076 | 0.1966 |
| Time to Chronic Opioid Use | Up to 57 months | 0.794 | 0.576–1.094 | 0.1563 |
| Time to Skeletal-related Event (SRE) | Up to 57 months | 0.857 | 0.615–1.194 | 0.3608 |
Time to Initiation of Cytotoxic Chemotherapy
Hazard ratio
95% CI: 0.350–0.630 · P <.0001
The HR of 0.469 corresponds to an estimated instantaneous rate of initiation of cytotoxic chemotherapy of about 46.9% of the comparison-group rate under the reported analysis. The complementary interpretation is approximately a 53.1% lower estimated hazard of the event. The confidence interval remains below 1, while the P-value is <.0001.
Time to Pain Progression
Hazard ratio
95% CI: 0.700–1.076 · P = 0.1966
The point estimate corresponds to an estimated event hazard about 86.8% of the comparison-group hazard, but the 95% CI extends from 0.700 to 1.076. The reported P-value is 0.1966. The appropriate statistical description is therefore that the registry reports an estimated hazard ratio below 1 with an uncertainty interval that includes 1; the ClinicalTrials.gov record does not establish a statistically significant superiority result for this secondary endpoint.
Time to Chronic Opioid Use
Hazard ratio
95% CI: 0.576–1.094 · P = 0.1563
The HR of 0.794 corresponds to an estimated event hazard about 79.4% of the comparison-group hazard. However, the 95% CI of 0.576–1.094 crosses 1, and the reported P-value is 0.1563. The point estimate alone should therefore not be interpreted as demonstrating superiority.
Time to Skeletal-related Event (SRE)
Hazard ratio
95% CI: 0.615–1.194 · P = 0.3608
The HR of 0.857 represents an estimated event hazard about 85.7% of the comparison-group hazard. The 95% CI of 0.615–1.194 includes 1, and the P-value is 0.3608. As with the other secondary endpoints, the estimate should be interpreted together with its uncertainty rather than by the point estimate alone.
8. Statistical Methodology
Intention-to-treat analysis
For every posted analysis, the registry identifies the intent-to-treat (ITT) population. It defines this population as including all randomized participants, classified according to their assigned treatment group regardless of the actual treatment received.
The ITT framework preserves the comparison created by randomization. Treatment discontinuation, treatment switching, or other deviations do not ordinarily cause a participant to be reclassified into another randomized group for the primary efficacy comparison.
Log-rank test
The registry identifies the log-rank test as the method used for every posted analysis. The log-rank test is designed to compare time-to-event experience between groups while incorporating the timing of events and allowing for right-censored observations.
Conceptually, the test compares the observed number of events in each group with the number that would be expected if the groups had the same underlying survival experience. It therefore uses the full ordering of event times rather than reducing the outcome to a single binary endpoint.
Hazard ratio
The effect measure reported for every posted analysis is the hazard ratio. A hazard is an instantaneous event rate conditional on remaining event-free up to a particular time. A hazard ratio below 1 indicates a lower estimated event hazard in the apalutamide-plus-ADT group relative to the placebo-plus-ADT group under the reported comparison.
The quantity 1 − HR can be used for a simple relative-hazard interpretation when the HR is below 1, but that calculation should not be confused with an absolute risk reduction or a probability of benefit for an individual participant.
Confidence intervals
Each of the six posted statistical analyses includes a two-sided 95% confidence interval. For the primary endpoints, the intervals are 0.391–0.600 for rPFS and 0.534–0.793 for OS. A confidence interval communicates the statistical precision of the effect estimate; it does not give the probability that the true effect lies inside that particular realized interval.
Time-to-event censoring
Time-to-event analysis is necessary because not every participant necessarily experiences the event during the period in which the outcome is observed. Participants without a recorded event by their available follow-up can contribute information up to the time they are censored. This is one reason why Kaplan-Meier methods and log-rank tests are commonly used for endpoints such as rPFS and OS.
Superiority testing
The registry classifies all six reported analyses under a superiority hypothesis type. This is distinct from a non-inferiority design: the statistical objective is to evaluate evidence for a difference favoring the treatment comparison rather than to demonstrate that treatment is no worse than control within a prespecified margin.
9. Statistical Methods Explained
Why is a log-rank test appropriate for these endpoints?
rPFS, OS, time to initiation of cytotoxic chemotherapy, time to pain progression, time to chronic opioid use, and time to skeletal-related event are all time-to-event outcomes in the posted analyses. The log-rank test compares the event-time distributions between randomized groups while incorporating censored observations rather than treating them as if they had experienced no event.
What does an HR of 0.484 mean?
An HR of 0.484 means that the estimated instantaneous rate of the rPFS event in the apalutamide-plus-ADT group was 48.4% of the corresponding rate in the placebo-plus-ADT group under the reported analysis. The complementary 51.6% figure is a relative hazard reduction, not a percentage of participants who benefited.
Why does the confidence interval matter?
A point estimate alone does not communicate how precisely the treatment effect has been estimated. For rPFS, the 95% CI is 0.391–0.600; for OS, it is 0.534–0.793. The width of these intervals gives information about statistical precision, while their location describes the range of hazard-ratio values compatible with the stated confidence framework.
Why doesn't the P-value measure effect size?
A P-value describes how compatible the observed data are with a specified null hypothesis under the statistical model and testing procedure. It does not measure the magnitude of the treatment effect. Two studies can produce different P-values despite similar effect estimates because sample size, event information, variability, and other design characteristics differ.
Why is ITT analysis important?
ITT analysis retains participants in their randomized groups regardless of the treatment actually received. This protects the original randomized comparison and avoids redefining treatment groups after randomization based on post-randomization events. The TITAN registry analyses explicitly identify the ITT population for all six posted endpoints.
Why are rPFS and OS not interchangeable?
rPFS counts radiographic progression or death as the first event, whereas OS counts death from any cause. Consequently, the endpoints answer different clinical questions and can have different hazard ratios, follow-up periods, censoring patterns, and statistical behavior. The TITAN results illustrate this directly: the reported HR is 0.484 for rPFS and 0.651 for OS.
10. Reading the Primary Results Together
The two primary analyses tell a related but distinct statistical story. The rPFS analysis reports an HR of 0.484, while the OS analysis reports an HR of 0.651. Both confidence intervals are entirely below 1, and both reported P-values are <0.0001.
Relative effect
The hazard ratios summarize the relative event rates between randomized groups. They are useful for comparing treatment effects on the time-to-event scale.
Precision
The confidence intervals quantify uncertainty around the two hazard-ratio estimates and show that the estimates are not exact measurements.
Statistical evidence
Both primary P-values are reported as <0.0001 under superiority analyses. The P-values address statistical evidence, not effect magnitude.
Different estimands
rPFS and OS involve different events. Their numerical hazard ratios should therefore not be expected to be identical.
A useful discipline when interpreting clinical-trial statistics is to keep these four ideas separate: what happened, how large the estimated difference was, how precisely it was estimated, and how the hypothesis test evaluated the null hypothesis. A hazard ratio addresses the second question, its confidence interval addresses the third, and the P-value addresses the fourth.
11. Secondary Results: What the Pattern Shows Statistically
The four secondary analyses are informative because they demonstrate why a collection of hazard ratios should not be summarized simply by counting estimates below 1.
| Endpoint | HR | 95% CI includes 1? | P-value | Statistical reading |
|---|---|---|---|---|
| Time to Initiation of Cytotoxic Chemotherapy | 0.469 | No | <.0001 | Reported estimate and interval are below 1. |
| Time to Pain Progression | 0.868 | Yes | 0.1966 | Point estimate below 1, but interval includes 1. |
| Time to Chronic Opioid Use | 0.794 | Yes | 0.1563 | Point estimate below 1, but interval includes 1. |
| Time to Skeletal-related Event (SRE) | 0.857 | Yes | 0.3608 | Point estimate below 1, but interval includes 1. |
The distinction is important. An HR below 1 is a point estimate; it does not by itself establish statistical evidence of superiority. The confidence interval and hypothesis test provide complementary information about uncertainty and compatibility with the null value of 1.
The secondary endpoint results also demonstrate why statistical interpretation should not be reduced to a single threshold. For example, the HR of 0.794 for time to chronic opioid use is numerically lower than 1, but the 95% CI extends to 1.094 and the P-value is 0.1563. The same principle applies to time to pain progression and time to skeletal-related event.
12. Safety Results
The ClinicalTrials.gov record reports serious adverse events by arm as affected participants over participants at risk. The safety data include the two principal treatment groups and a separately identified group described as placebo + ADT to apalutamide + ADT.
| Safety group | Serious adverse events affected / at risk | Observed proportion |
|---|---|---|
| Placebo + ADT | 115 / 527 | 115/527 |
| Placebo + ADT to Apalutamide + ADT | 29 / 208 | 29/208 |
| Apalutamide + ADT | 153 / 524 | 153/524 |
The registry's safety field reports affected / at-risk counts, rather than a formal comparative effect measure. These counts should therefore be kept separate from the efficacy hazard ratios. A serious adverse-event count does not answer the same statistical question as a time-to-event efficacy analysis.
13. Randomization and the ITT Principle
Randomization is the mechanism that creates the basis for a causal treatment comparison. Before outcomes are observed, participants are assigned to treatment groups according to the trial's randomization process. The ITT analysis then keeps participants associated with their original randomized assignments.
The TITAN registry explicitly states that the ITT population includes all randomized participants and classifies them according to assigned treatment regardless of actual treatment received. This makes the efficacy analysis answer a randomized-treatment question rather than a question based only on participants who remained on their assigned treatment.
This distinction becomes particularly important when treatment exposure changes after randomization. An analysis that excludes or reassigns participants after randomization can answer a different question and may lose some of the protection against post-randomization selection that randomization provides.
14. Crossover and Treatment Switching
The ClinicalTrials.gov record contains a separately named group, “Placebo + ADT to Apalutamide + ADT”, with serious adverse events reported as 29/208. This terminology indicates that the registry distinguishes participants associated with a transition from placebo plus ADT to apalutamide plus ADT in the posted safety data.
For statistical interpretation, however, the presence of a treatment-transition category should not be used to infer an unreported crossover rate, timing, or crossover-adjusted survival estimate. The ClinicalTrials.gov record does not provide those quantities.
15. Multiplicity and Multiple Endpoints
TITAN has two registered primary endpoints and four posted secondary analyses. That structure creates a fundamental statistical issue: multiple hypotheses are being examined.
| Endpoint role | Number reported | Statistical method | Hypothesis type |
|---|---|---|---|
| Primary | 2 | Log-rank test | Superiority |
| Secondary | 4 | Log-rank test | Superiority |
When multiple hypotheses are tested, the interpretation of individual P-values can depend on the prespecified multiplicity strategy. A trial may control familywise type I error through hierarchical testing, alpha allocation, adjusted thresholds, or another procedure. The registry-reported TITAN data do not identify such a procedure.
Accordingly, the most precise description here is to report each registry P-value exactly as posted and avoid assigning an unreported multiplicity-adjusted interpretation. The two primary endpoints should also be distinguished from the four secondary endpoints rather than treating all six analyses as one undifferentiated set.
16. Interim Analysis and Alpha Spending
Interim-analysis details are not provided in the registry-reported TITAN trial data. The registry information identifies the formal statistical analyses, their endpoints, populations, methods, effect measures, confidence intervals, and P-values, but it does not specify an interim-analysis schedule, alpha-spending method, stopping boundary, or information fraction.
What can be established
The registry reports six formal analyses, all using log-rank testing and hazard ratios, with superiority as the hypothesis type.
What cannot be established here
The ClinicalTrials.gov record does not specify whether the reported analyses were subject to an interim-monitoring or alpha-spending scheme.
This distinction matters because repeatedly examining accumulating trial data can affect type I error unless the monitoring strategy is incorporated into the statistical design. Without the relevant protocol or statistical-analysis-plan details, no specific alpha-spending conclusion should be attached to the posted TITAN results.
17. Missing Data, Censoring, and Model Assumptions
Time-to-event analyses naturally involve censoring. A participant can remain alive or event-free at the end of available follow-up and therefore contribute information without contributing an observed event. The ClinicalTrials.gov record does not provide the detailed censoring rules or missing-data/imputation strategy.
Censoring
Survival methods can incorporate participants whose event time is not observed during their available follow-up.
Missing data
No specific imputation method is reported in the ClinicalTrials.gov record, so none is assumed for this analysis.
Proportional hazards
A hazard ratio is most naturally interpreted as a relative hazard under the model's assumptions. The ClinicalTrials.gov record does not report diagnostics for proportional hazards.
Endpoint assessment
For rPFS, the registry explicitly identifies investigator assessment in its endpoint definition.
These limitations do not invalidate the reported analyses. They define what can and cannot be concluded from the registry-level ClinicalTrials.gov record. A rigorous statistical review should distinguish reported methods from methods that would need to be confirmed from a protocol or statistical-analysis plan.
18. Understanding the Hazard Ratios Across TITAN
The visualization highlights an important statistical lesson: the six estimates are not all equally informative merely because they are below 1. The primary rPFS and OS intervals are entirely below 1, as is the interval for time to initiation of cytotoxic chemotherapy. The other three secondary confidence intervals extend across 1.
The graph also should not be read as a ranking of clinical importance. Each endpoint represents a different event, and the registry provides different time frames and uncertainty intervals for each. A hazard ratio is most useful when interpreted in the context of its endpoint definition, confidence interval, P-value, analysis population, and prespecified role in the trial.
19. What the Hazard Ratio Does — and Does Not — Mean
An HR below 1 indicates a lower estimated instantaneous event rate in the apalutamide-plus-ADT group than in the placebo-plus-ADT group under the reported analysis. For example, the rPFS HR of 0.484 corresponds to an estimated hazard approximately 51.6% lower than the comparison hazard.
A hazard ratio does not tell an individual participant their probability of avoiding an event. It also does not mean that a fixed percentage of participants experienced the same relative reduction. The measure describes a relative comparison of event hazards across time.
The 95% confidence interval describes uncertainty around the estimated hazard ratio. For OS, the interval is 0.534–0.793. It is not a prediction interval for individual survival times and should not be interpreted as saying that individual participants' effects fall within those limits.
The P-value evaluates the evidence against a specified null hypothesis under the statistical testing framework. A smaller P-value does not automatically imply a larger treatment effect. Effect magnitude and statistical evidence are separate concepts.
20. Clinical Interpretation vs Statistical Interpretation
Statistical interpretation
The registry reports hazard ratios below 1 for both primary endpoints, with 95% confidence intervals entirely below 1 and P-values <0.0001. The primary analyses were performed in the ITT population using log-rank tests and superiority hypotheses.
Clinical interpretation
The trial evaluates whether adding apalutamide to ADT changes clinically relevant time-to-event outcomes in participants with mHSPC. The registry reports distinct effects across progression, survival, chemotherapy initiation, pain progression, chronic opioid use, and skeletal-related events.
Keeping these interpretations separate prevents a common statistical error: treating statistical significance as synonymous with clinical magnitude. The TITAN registry results provide quantitative estimates, confidence intervals, and hypothesis-test results; the clinical meaning of each endpoint depends on what event it measures and how that event relates to patient outcomes.
21. Limitations
- Registry-level information: This page is limited to the ClinicalTrials.gov record. It does not reconstruct information absent from that dataset.
- No baseline table: Baseline demographic and disease characteristics are not included in the ClinicalTrials.gov record and therefore are not reproduced here.
- No median event times: The ClinicalTrials.gov record contains hazard ratios, confidence intervals, and P-values but do not provide median rPFS or OS estimates.
- No Kaplan-Meier coordinates: The registry data do not provide event-time or censoring coordinates sufficient to reconstruct Kaplan-Meier curves.
- No subgroup estimates: The statistical analyses posted on ClinicalTrials.gov do not include subgroup-specific hazard ratios or interaction tests.
- No interim-analysis details: The ClinicalTrials.gov record does not specify interim looks, stopping boundaries, or alpha spending.
- No imputation strategy: The ClinicalTrials.gov record does not specify a missing-data or imputation method.
- No proportional-hazards diagnostics: The registry reports hazard ratios but does not provide diagnostics establishing whether proportional hazards held throughout follow-up.
- Multiplicity specification: Six statistical analyses are posted, but the ClinicalTrials.gov record does not identify the multiplicity-control procedure.
- Safety detail: Serious adverse events are reported as affected/at-risk counts, without a formal comparative safety analysis in the ClinicalTrials.gov record.
22. Why This Trial Matters Statistically
TITAN is a useful teaching case because it places several fundamental clinical-trial concepts into one randomized time-to-event framework. The same trial illustrates how an endpoint's definition, analysis population, effect measure, confidence interval, and P-value must be interpreted together.
| Concept | How it appears in TITAN |
|---|---|
| Randomization | The trial is randomized with 2 parallel treatment arms. |
| Blinding | The registry classifies the study as triple-masked. |
| ITT analysis | All six posted analyses use the ITT population. |
| Time-to-event endpoints | Both primary endpoints and all four secondary analyses are time-to-event outcomes. |
| Log-rank test | The reported method for all six statistical analyses. |
| Hazard ratio | The reported effect measure for every posted analysis. |
| Confidence interval | Each statistical analysis includes a two-sided 95% CI. |
| P-values | Each of the six posted analyses includes a reported P-value. |
| Superiority | All posted analyses are classified with a superiority hypothesis type. |
| Multiple endpoints | Two primary and four secondary analyses are posted. |
| Crossover / treatment transition | The safety data separately identify a placebo + ADT to apalutamide + ADT group. |
| Safety analysis | Serious adverse events are reported as affected participants over those at risk. |
The strongest statistical lesson is that an effect estimate is inseparable from its endpoint and analysis framework. An HR of 0.484 for rPFS and an HR of 0.651 for OS cannot be interpreted as competing versions of the same outcome. They quantify different event processes over different reported time frames.
23. Related Tutorials
Learn more about the methods used in this trial:
24. Related Calculators
25. Sources
- ClinicalTrials.gov: TITAN, NCT02489318.
- PubMed: PMID 42728112.
- PubMed: PMID 42616151.
- PubMed: PMID 39163505.
- PubMed: PMID 39058790.
- PubMed: PMID 38940282.
Continue through the Clinical Biostats statistical library
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26. Record Summary
TITAN provides a clear example of randomized clinical-trial analysis centered on time-to-event outcomes. The ClinicalTrials.gov record reports two primary endpoints—radiographic progression-free survival and overall survival—and four secondary time-to-event endpoints. All six analyses use the ITT population, compare placebo plus ADT with apalutamide plus ADT, use the log-rank test, report hazard ratios with two-sided 95% confidence intervals, and are classified as superiority analyses.
The primary rPFS analysis reports an HR of 0.484 (95% CI 0.391–0.600; P <0.0001), while the primary OS analysis reports an HR of 0.651 (95% CI 0.534–0.793; P <0.0001). Among the secondary endpoints, the reported HR is 0.469 for time to initiation of cytotoxic chemotherapy, while the confidence intervals for time to pain progression, time to chronic opioid use, and time to skeletal-related event include 1.