This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record.
1. Trial at a Glance
SPLASH is a randomized, parallel, phase 3 oncology trial evaluating [Lu-177]-PNT2002 in metastatic castration-resistant prostate cancer. The registered primary endpoint is radiographic progression-free survival (rPFS), a time-to-event endpoint analyzed using a log-rank test and summarized with a hazard ratio.
| Feature | SPLASH |
|---|---|
| Trial | SPLASH |
| NCT ID | NCT04647526 |
| Phase | Phase 3 |
| Condition | Metastatic Castration-Resistant Prostate Cancer |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | None |
| Primary purpose | Treatment |
| Enrollment | 455 |
| Primary endpoint | Randomization Phase: Radiographic Progression-Free Survival (rPFS) |
| Primary endpoint type | Time-to-event |
| Primary analysis | Log-rank test |
| Effect measure | Hazard ratio |
| Hypothesis type | Superiority |
| Results posted | Yes |
| Statistical analyses posted | 1 |
2. Clinical Question
The central statistical question is whether randomized treatment with [Lu-177]-PNT2002 produces a different time to radiographic progression or death compared with the randomized comparator of abiraterone or enzalutamide in patients with metastatic castration-resistant prostate cancer.
Population
Participants with metastatic castration-resistant prostate cancer enrolled in the phase 3 SPLASH trial.
Intervention
[Lu-177]-PNT2002.
Comparator
Abiraterone or enzalutamide in the Randomization Phase.
Primary question
Does [Lu-177]-PNT2002 improve radiographic progression-free survival relative to abiraterone or enzalutamide?
3. Trial Design
The registry describes SPLASH as a randomized, parallel, unmasked phase 3 treatment study. Enrollment was 455 participants, with four arms recorded in the ClinicalTrials.gov record. The interventions listed in the registry are [Lu-177]-PNT2002, abiraterone, and enzalutamide.
[Lu-177]-PNT2002
- Drug intervention: [Lu-177]-PNT2002
- Primary rPFS comparison includes Arm A
- 114 participants were censored in the reported ITT analysis
Abiraterone or Enzalutamide
- Comparator intervention: abiraterone or enzalutamide
- Primary rPFS comparison includes Arm B
- 40 participants were censored in the reported ITT analysis
4. Trial Timing and Status
Trial start
The registry lists February 25, 2021 as the study start date.
Primary completion
The registry lists November 1, 2023 as the primary completion date.
Active, not recruiting
The ClinicalTrials.gov record identifies the trial status as ACTIVE_NOT_RECRUITING.
5. Primary Endpoint
| Endpoint | Registry definition and time frame | Analysis |
|---|---|---|
| Randomization Phase: Radiographic Progression-Free Survival (rPFS) | From the randomization date to the first documented progressive disease or death from any cause (up to 23 months). rPFS, as assessed by blinded independent central review (BICR), is the time from the randomization date to progression on soft tissue per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) or confirmed progression on bone lesions by Prostate Cancer Working Group 3 (PCWG3) criteria, or death from any cause. | Log-rank test; hazard ratio; superiority hypothesis |
This endpoint combines two clinically important event types into one time-to-event outcome: documented radiographic progression and death from any cause. A participant who experiences either event reaches the endpoint. Participants who have not experienced an event by the relevant observation point can contribute censored follow-up to the analysis.
6. Statistical Methodology
Intention-to-treat analysis
The reported primary analysis used all participants from the ITT analysis set. ITT analysis preserves the randomized comparison by analyzing participants according to their assigned treatment group rather than redefining the primary efficacy population according to subsequent treatment exposure.
The registry-reported analysis reports 114 participants censored in [Lu-177]-PNT2002 (Arm A) and 40 participants censored in Abiraterone or Enzalutamide (Arm B).
Kaplan-Meier framework
Radiographic progression-free survival is a time-to-event endpoint, so the natural descriptive framework is Kaplan-Meier estimation. Kaplan-Meier methods allow participants with incomplete event follow-up to contribute information up to their censoring time rather than requiring every participant to have experienced progression or death.
Here, di represents events at time ti, while ni represents participants at risk immediately before that time.
Log-rank test
The registry identifies the log-rank test as the primary statistical method. The log-rank test compares the observed and expected numbers of events between randomized groups across follow-up, making it appropriate for a time-to-event comparison such as rPFS.
Hazard ratio
The reported effect measure is a hazard ratio. Unlike a simple proportion or risk ratio at one fixed time point, a hazard ratio summarizes the relative instantaneous event rate between treatment groups over the analyzed follow-up under the time-to-event modeling framework.
A hazard ratio below 1 does not mean that the same percentage of every individual patient's risk was reduced, nor does it directly give an absolute difference in progression-free survival.
Censoring
The reported ITT analysis includes censored participants: 114 in Arm A and 40 in Arm B. Censoring means that the analysis has follow-up information up to a specified point without observing the endpoint by that point. Correct interpretation of Kaplan-Meier and hazard-ratio analyses depends on how censoring relates to the underlying event process.
7. Primary rPFS Results
ClinicalTrials.gov reports one formal statistical analysis for the primary endpoint. The comparison is between Randomization Phase [Lu-177]-PNT2002 (Arm A) and Randomization Phase Abiraterone or Enzalutamide (Arm B).
Radiographic progression-free survival
95% CI: 0.55–0.92 · P = 0.0088
Analysis: log-rank test · Hypothesis: superiority
| Primary endpoint | [Lu-177]-PNT2002 | Abiraterone or Enzalutamide | Effect estimate | P-value |
|---|---|---|---|---|
| Randomization Phase: Radiographic Progression-Free Survival (rPFS) | Arm A | Arm B | HR 0.71 (95% CI 0.55–0.92) | 0.0088 |
The reported HR of 0.71 means that the estimated instantaneous rate of the rPFS event was 0.71 times that of the comparator group under the reported time-to-event analysis. Expressed as a simple relative-hazard interpretation, this corresponds to an estimated 29% lower hazard in the [Lu-177]-PNT2002 group.
The HR does not mean that 29% of patients avoided progression, that each individual patient had exactly a 29% reduction in risk, or that the absolute probability of progression or death was reduced by 29 percentage points.
The 95% CI of 0.55–0.92 describes uncertainty around the estimated hazard ratio under the analysis framework. It is not a prediction interval for individual patients and does not describe the range of outcomes that individual patients will experience.
The P-value of 0.0088 addresses the statistical evidence against the null hypothesis under the specified testing framework. It does not measure the size or clinical importance of the treatment effect. Effect size and uncertainty are better represented by the HR and its confidence interval.
Because this is a time-to-event analysis, interpretation also depends on censoring and on the extent to which a single hazard ratio appropriately summarizes the treatment difference over follow-up. The ClinicalTrials.gov record does not provide additional diagnostics concerning the proportional-hazards assumption, so no conclusion about that assumption is made here.
What the result says statistically
The reported analysis is consistent with a statistically detectable difference in rPFS between the two randomized groups under the registry's stated superiority hypothesis. The confidence interval is entirely below 1.00, while the point estimate is 0.71.
What the result does not establish by itself
- It does not provide a median rPFS value because none is reported in the ClinicalTrials.gov record.
- It does not provide fixed-time rPFS percentages because none are reported.
- It does not establish the treatment effect for every subgroup because subgroup analyses are not included in the statistical analyses posted on ClinicalTrials.gov.
- It does not by itself quantify absolute benefit because an absolute risk difference or survival probability at a specified time is not provided.
8. Secondary Endpoint Results
the ClinicalTrials.gov record reports 6 outcome measures, but only 1 statistical analysis is posted in the ClinicalTrials.gov record, corresponding to the primary rPFS endpoint.
For a secondary time-to-event endpoint, a typical analysis would use a Kaplan-Meier framework with a between-group comparison such as a log-rank test and an effect measure such as a hazard ratio. However, that describes the standard statistical approach; it does not constitute a reported SPLASH secondary-endpoint result.
9. Safety Results
The ClinicalTrials.gov record reports serious adverse events by phase and arm as affected participants over participants at risk. These counts are reported separately from the primary rPFS analysis.
| Phase / arm | Serious adverse events affected / at risk |
|---|---|
| Dosimetry Phase: [Lu-177]-PNT2002 | 6/27 |
| Randomization Phase: [Lu-177]-PNT2002 (Arm A) | 47/269 |
| Randomization Phase: Abiraterone or Enza | 30/130 |
| Randomization Phase: Abiraterone or Enza | 14/77 |
| PK Extension Phase: [Lu-177]-PNT2002 | 2/15 |
10. Statistical Methods Explained
Why is rPFS a time-to-event endpoint?
rPFS records the amount of time from randomization until the first qualifying event: documented progressive disease or death from any cause. The endpoint therefore incorporates both whether an event occurred and when it occurred. Participants who have not experienced an event by the relevant observation point contribute censored follow-up.
What does an HR of 0.71 mean?
An HR of 0.71 means that the estimated instantaneous rate of the rPFS event in the [Lu-177]-PNT2002 group was 0.71 times the corresponding estimated rate in the comparator group under the reported analysis. The complementary calculation, 1 − 0.71, gives a 29% relative reduction in the estimated hazard. That is not the same as a 29% absolute reduction in the probability of progression or death.
Why use a log-rank test?
The log-rank test is designed for comparing survival-type distributions between groups when participants may be censored. Instead of reducing each patient to a single binary outcome at one fixed time, it uses information from the timing of observed events throughout follow-up.
Why is the confidence interval important?
The point estimate of 0.71 is only one estimate of the treatment effect. The 95% CI of 0.55–0.92 communicates uncertainty around that estimate. A narrower interval would indicate greater statistical precision, while a wider interval would indicate less precision. The interval does not describe individual-level variation in treatment response.
Why does the P-value not measure effect size?
The P-value of 0.0088 quantifies how compatible the observed statistical evidence is with the specified null hypothesis under the testing framework. It does not tell us that the treatment effect is "0.0088" in size. The HR describes relative effect, while the CI communicates uncertainty around the HR.
Why does censoring matter?
Censoring allows a participant to contribute observed follow-up even when the endpoint is not observed during that person's available follow-up. Time-to-event methods rely on assumptions about the relationship between censoring and the underlying event process. The ClinicalTrials.gov record identifies censored participants but do not provide further diagnostics about the censoring mechanism.
Does HR 0.71 prove proportional hazards?
No. A hazard ratio is a relative time-to-event measure, but the ClinicalTrials.gov record does not report a diagnostic assessment of the proportional-hazards assumption. The HR should therefore be interpreted as the reported model-based summary rather than as evidence that hazards were necessarily proportional at every point in time.
11. Randomization and the ITT Principle
Randomization is central to the causal interpretation of a randomized trial because treatment assignment is determined by the study design rather than by investigators or participants choosing the treatment based on prognosis. SPLASH is registered as randomized, and the primary analysis in the ClinicalTrials.gov record uses the ITT analysis set.
Why ITT is useful
Analyzing participants according to randomized assignment preserves the comparison created by randomization and avoids redefining the primary efficacy population solely according to subsequent treatment exposure.
What ITT does not solve
ITT analysis does not eliminate missing follow-up, censoring, treatment discontinuation, or every other source of uncertainty. Those features remain part of the interpretation of the time-to-event analysis.
12. Understanding the Hazard Ratio in Context
The reported HR of 0.71 indicates a lower estimated instantaneous rPFS-event rate for [Lu-177]-PNT2002 relative to abiraterone or enzalutamide in the reported randomized comparison.
The 95% CI of 0.55–0.92 gives the statistical uncertainty around the estimated HR. The interval remains below 1.00, consistent with the direction of the reported superiority analysis.
The reported P = 0.0088 indicates the strength of evidence against the null hypothesis under the specified analysis. It should not be used as a substitute for examining the HR, confidence interval, endpoint definition, and trial design.
The ClinicalTrials.gov record does not report median rPFS or fixed-time rPFS probabilities. Consequently, the HR cannot be converted here into an absolute number of additional months without introducing information outside the ClinicalTrials.gov record.
13. What Is Known — and What Is Not Reported Here
| Question | Information reported |
|---|---|
| Was the trial randomized? | Yes. |
| Was it parallel? | Yes. |
| Was it masked? | No. |
| What was enrollment? | 455. |
| What was the primary endpoint? | Randomization Phase: Radiographic Progression-Free Survival (rPFS). |
| What was the analysis method? | Log-rank test. |
| What was the effect measure? | Hazard ratio. |
| What was the primary estimate? | 0.71. |
| What was the 95% CI? | 0.55–0.92. |
| What was the P-value? | 0.0088. |
| What was the hypothesis type? | Superiority. |
| Are median rPFS values reported? | No. |
| Are fixed-time rPFS rates reported? | No. |
| Are formal secondary statistical analyses reported? | No; one statistical analysis is reported, for the primary endpoint. |
| Are subgroup statistical analyses reported? | No. |
| Are interim-analysis details reported? | No. |
| Is a non-inferiority margin reported? | No; the registered hypothesis type is superiority. |
14. Design Topics Not Supported by the Supplied Data
Several design questions are important in clinical-trial statistical interpretation, but they should not be inferred when the registry data posted on ClinicalTrials.gov for a particular analysis do not contain the relevant information.
Non-inferiority margin
The registered hypothesis type is superiority. No non-inferiority margin is reported, so no margin-based interpretation is appropriate.
Interim analysis
The ClinicalTrials.gov record does not describe an interim efficacy analysis, alpha-spending plan, or stopping boundary.
Multiplicity
The ClinicalTrials.gov record does not provide an alpha-allocation or multiplicity-adjustment strategy beyond identifying the primary hypothesis as superiority.
Missing-data imputation
No specific imputation method is reported. The primary endpoint is a time-to-event outcome with reported censoring rather than a simple continuous endpoint requiring a conventional imputation rule.
15. Why the Primary Analysis Is a Survival Analysis
A conventional two-arm comparison of means would discard much of the information contained in the timing of progression or death. rPFS instead records a time from randomization to an event, while allowing some participants to remain event-free at the time their available follow-up ends.
| Statistical feature | Role in SPLASH |
|---|---|
| Randomization | Creates the treatment-group comparison. |
| ITT analysis | Defines the reported primary efficacy population. |
| Time-to-event endpoint | Uses both event occurrence and event timing. |
| Censoring | Allows participants without an observed endpoint to contribute available follow-up. |
| Log-rank test | Provides the reported between-group survival comparison. |
| Hazard ratio | Provides the reported relative effect measure. |
| Confidence interval | Communicates uncertainty around the HR. |
| P-value | Communicates statistical evidence under the stated hypothesis test. |
16. Limitations
- Limited reported statistical detail: the ClinicalTrials.gov record contains one formal statistical analysis, so the page cannot reconstruct a broader efficacy-results program without introducing information outside the permitted data.
- No median rPFS: the ClinicalTrials.gov record reports the hazard ratio, confidence interval, and P-value but do not report median rPFS.
- No fixed-time survival probabilities: no rPFS probabilities at specific time points are reported.
- No subgroup analyses: the ClinicalTrials.gov record does not include subgroup-specific hazard ratios or interaction tests.
- No proportional-hazards diagnostic: the registry data do not report whether the proportional-hazards assumption was assessed.
- Censoring: the reported ITT analysis includes 114 censored participants in Arm A and 40 in Arm B, so the analysis necessarily incorporates incomplete event observation.
- Four-arm design with a single registry-reported primary comparison: the ClinicalTrials.gov record records four arms, while the registry-reported formal analysis compares the two Randomization Phase groups specified as Arm A and Arm B.
- Safety denominators vary by phase: serious-adverse-event counts are posted on ClinicalTrials.gov for different phases and risk sets and should not be pooled without additional registry definitions.
- No treatment-effect heterogeneity analysis: the ClinicalTrials.gov record does not provide an interaction analysis or other formal test of whether the treatment effect differs across patient subgroups.
17. Why This Trial Matters Statistically
SPLASH is a useful teaching case because its primary endpoint illustrates the core structure of modern randomized time-to-event analysis: randomized treatment assignment, an ITT efficacy population, an event defined using radiographic progression or death, censoring, a log-rank comparison, a hazard ratio, a confidence interval, and a superiority hypothesis.
| Concept | How it appears in SPLASH |
|---|---|
| Randomization | The trial is registered as randomized. |
| Parallel design | The registered design model is parallel. |
| Intention-to-treat analysis | The primary rPFS analysis uses all participants from the ITT analysis set. |
| Time-to-event endpoint | rPFS is measured from randomization to progression or death. |
| Kaplan-Meier framework | Appropriate for describing a time-to-event endpoint with censoring. |
| Log-rank test | The registry-reported primary statistical method. |
| Hazard ratio | The registry-reported effect measure. |
| Confidence interval | 95% CI of 0.55–0.92 around the HR of 0.71. |
| P-value | 0.0088 for the reported superiority comparison. |
| Censoring | 114 participants in Arm A and 40 in Arm B were censored in the reported analysis. |
18. Related Tutorials
Learn more about the methods used in this trial:
19. Related Calculators
20. Sources
- ClinicalTrials.gov: SPLASH, NCT04647526.
- Linked PubMed record: PMID 39839782.
- Linked PubMed record: PMID 36735603.
Continue learning from the SPLASH statistical framework
Explore the broader Clinical Biostats collection of biostatistics tutorials, statistical calculators, and clinical-trial statistical analyses.
21. Record Summary
SPLASH provides a clear example of a randomized phase 3 time-to-event analysis. The registry identifies radiographic progression-free survival as the primary endpoint, defines it from randomization to documented progressive disease or death, and reports an ITT comparison between [Lu-177]-PNT2002 and abiraterone or enzalutamide using a log-rank test. The reported hazard ratio was 0.71, with a 95% CI of 0.55–0.92 and P = 0.0088 under a superiority hypothesis.
The most informative statistical reading of that result combines the relative effect estimate with its confidence interval and P-value while recognizing what those quantities do not provide. The HR does not give an absolute treatment benefit, the P-value does not measure effect size, and the confidence interval does not describe individual patient outcomes. The ClinicalTrials.gov record also establish important boundaries: only one formal statistical analysis is provided, secondary endpoint analyses are not included, and the reported analysis contains censored participants in both randomized groups.