Study of Ipatasertib or Apitolisib With Abiraterone Acetate Versus Abiraterone Acetate in Participants With Castration-Resistant Prostate Cancer Previously Treated With Docetaxel Chemotherapy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of Ipatasertib or Apitolisib With Abiraterone Acetate Versus Abiraterone Acetate in Participants With Castration-Resistant Prostate Cancer Previously Treated With Docetaxel Chemotherapy (NCT01485861), a randomized phase 1, phase 2 study. The primary outcome is Phase Ib: Percentage of Participants With Dose-Limiting Toxicities (DLTs).

2. Clinical Question

3. Trial Design

The registry describes a multicenter, international Phase Ib/II study with three stages. Phase Ib was an open-label dose-finding stage in which recommended Phase II doses were determined for ipatasertib with abiraterone and apitolisib with abiraterone. The record says this stage is no longer active. Its listed primary endpoint is the percentage of participants with dose-limiting toxicities during the first 28 days of Cycle 1.

Phase II was a randomized, double-blind, parallel-group comparison with three arms: ipatasertib 400 mg plus abiraterone, ipatasertib 200 mg plus abiraterone, and placebo plus abiraterone. Prednisone or prednisolone was also part of the described regimens. Treatment was described in continuous 28-day cycles until disease progression or intolerable toxicity. The registry lists overall survival and PSA progression among the Phase II outcomes.

A safety cohort was open-label and single-arm. Its description concerns ipatasertib 400 mg daily alone or with prednisone or prednisolone, or with prednisone or prednisolone plus abiraterone. The detailed schedule in the record is incomplete, so further regimen details are not reported in the registry record.

The record lists enrollment as 298 and study status as completed. The listed study start is 2012-01-11 and the primary completion date is 2015-09-01. The record does not establish that the results discussed for every endpoint use the same analysis population: the overall-survival and PSA-progression endpoints are labelled ITT, while the Phase Ib safety endpoint uses the Safety Population.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: The study consisted of 3 stages: Phase Ib determined recommended Phase II doses (RP2D) for ipatasertib and apitolisib in combination with abiraterone and prednisone/prednisolone. Phase II stage compared ipatasertib (400 mg or 200 mg daily) versus placebo each combined with abiraterone and prednisone/prednisolone. The third stage included the safety cohort.

Phase Ib

Reasons for not completing this period:

Phase II

Reasons for not completing this period:

Safety Phase

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Safety Population was defined as all participants who had received ipatasertib, apitolisib, placebo, or abiraterone treatment on Day 1 of Cycle 1.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Population: Intent-To-Treat (ITT) Population included all participants allocated to the treatment arm according to randomization.

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Phase Ib: Percentage of Participants With Dose-Limiting Toxicities (DLTs), measured over Days 1 to 28 of Cycle 1 (Cycle length = 28 days).

The primary endpoint is the percentage of participants with dose-limiting toxicities during Days 1 to 28 of Cycle 1. The registry defines a dose-limiting toxicity as a specified serious toxicity considered at least possibly related to ipatasertib or apitolisib. The listed criteria include severe non-hematologic toxicity, febrile neutropenia, prolonged severe neutropenia, severe platelet or anemia events, specified high blood-glucose events, and specified liver-test elevations. Adverse events were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events v 4.0.

This early-cycle endpoint is used in dose-finding to characterize short-term tolerability at the tested doses and to inform dose selection for later study. It is distinct from the Phase II endpoints of overall survival and PSA progression. The defined Safety Population consists of participants who received ipatasertib, apitolisib, placebo, or abiraterone treatment on Day 1 of Cycle 1.

The posted Phase Ib values are 0.0 for the ipatasertib 400 mg group and 0.0 for the apitolisib 30 mg group, with group sizes of 14.0 and 6.0, respectively. The registry record does not report an estimable two-arm comparison for this binary endpoint. The observed zero values describe the recorded sample; they do not establish that the underlying risk is zero or characterize later-cycle safety.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Different statistical summaries answer different questions. The Phase Ib primary endpoint is a percentage: it describes the fraction of the defined Safety Population with a qualifying event in the stated observation window. The Phase II PSA endpoint is also a percentage, but its timeframe extends from screening to PSA progression. A percentage is a sample description; its precision depends on both the observed proportion and the amount of information in the group. The registry record does not post a confidence interval for the Phase Ib primary endpoint.

How to read a confidence interval

A confidence interval expresses uncertainty around an estimate under the statistical method used. A wider interval indicates less precision than a narrower interval. For a hazard ratio, 1 is the reference value corresponding to equal instantaneous event rates under the model's comparison. For a risk difference, 0 is the reference value corresponding to equal proportions. When an interval includes its reference value, the posted data do not rule out that reference value at the corresponding confidence level. An interval is not a guarantee that the true effect lies within its endpoints, and it does not describe the probability that a particular treatment effect is true.

The reported overall-survival comparisons use hazard ratios from log-rank analyses. A hazard ratio compares event rates over follow-up rather than comparing the percentages of participants who have died at a single time. A hazard ratio below 1 is in the direction of a lower event rate in the ipatasertib group relative to placebo, while a value above 1 is in the opposite direction. Interpretation also depends on the interval, follow-up, censoring, and analysis assumptions. The registry record does not provide enough detail to assess all those assumptions.

Median survival and hazard ratios

The posted median overall-survival estimates describe the time by which half the participants in the relevant analysis group have experienced the event, subject to the survival-analysis method and censoring. The medians are not substitutes for the hazard ratios: medians summarize one point on the survival distribution, while the hazard ratio summarizes a relative event-rate contrast over time. For the ITT population, median survival is 18.27 months for ipatasertib 400 mg, 17.31 months for ipatasertib 200 mg, and 18.37 months for placebo. The corresponding 95% confidence intervals are broad enough that the medians should not be treated as exact or directly decisive comparisons.

The registry reports a 95% confidence interval and p-value for each hazard-ratio comparison. The p-value measures how unusual data at least as discrepant as those observed would be under the null hypothesis and the test assumptions. It is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of an effect. A p-value should be read alongside the estimate, confidence interval, study design, and multiplicity context.

Risk differences for PSA progression

The posted unadjusted risk difference compares the event proportion in an ipatasertib group with the proportion in the placebo group. Negative values indicate a lower observed proportion in the ipatasertib group under the subtraction order used in the calculation. For 400 mg, the interval is below zero but close to the reference boundary; for 200 mg, it spans zero. These estimates are recalculated from posted summary statistics and are not the sponsor's reported inferential analyses. The registry does not list a reported analysis for the PSA-progression endpoint, so the recalculated p-values should be interpreted as unadjusted and exploratory rather than as a replacement for a prespecified sponsor analysis.

Planning illustrations are not observed power

The sample-size illustrations are based on the observed effect, with assumptions of a two-sided significance level of 0.05, equal allocation, and a normal approximation. For time-to-event outcomes, the entries are total events; for other outcomes, they are participants per arm. Rows for 100% of the observed effect, 75% of the observed effect, and 50% of the observed effect illustrate how planning requirements change if a future study aims to detect a fraction of the observed estimate. These are planning scenarios, not the study's original design justification, not evidence of the trial's achieved power, and not a forecast of what a future trial would observe. The original sample-size justification and the statistical plan are not reported in the registry record.

For survival comparisons, the number of events rather than enrollment alone governs much of the information available to estimate a hazard ratio. A small observed effect can imply a large event requirement in a planning exercise. That arithmetic does not make the posted treatment effect more or less credible; it reflects the information needed to distinguish effects under the stated assumptions.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Phase Ib: Ipatasertib 400 mg", "Phase Ib: Apitolisib 30 mg")
n      <- c(14, 6)
events <- c(0, 0)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Phase Ib: Ipatasertib 400 mg  14  0  0.0  0.0  23.2  0.0  21.5  0.2  21.8
ARM  Phase Ib: Apitolisib 30 mg  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists many outcome measures and analyses, but does not report a multiplicity adjustment or a hierarchical testing strategy for the results discussed. When several endpoints, doses, or subgroups are examined, interpreting each nominal p-value as if it were the only test can overstate the strength of evidence. Whether and how the original study controlled this issue is not reported in the registry record.

The record also does not report whether the PTEN-loss subgroup was prespecified, how its membership was determined for analysis, or whether a treatment-by-PTEN interaction test was performed. A within-subgroup comparison asks whether treatment groups differ among participants meeting the subgroup definition. An interaction test asks whether the treatment contrast differs between subgroup levels. Those are distinct questions; the former alone cannot establish the latter.

Analysis populations vary by endpoint. The overall-survival and PSA-progression outcomes are labelled ITT, whereas the Phase Ib primary endpoint uses a Safety Population defined by treatment received on Day 1 of Cycle 1. The record does not report detailed handling of protocol deviations, missing measurements, withdrawals, or participants without an event assessment. For survival outcomes, censoring rules and the extent of missing follow-up are not reported in the registry record. For PSA progression, the handling of missing or unevaluable PSA assessments is also not reported.

These gaps affect how fully the estimates can be independently assessed. They do not demonstrate that the analyses were inappropriate; rather, the public registry information does not document the details needed to evaluate those choices. No interim-analysis plan, stopping rule, or complete statistical analysis plan is reported in the registry record. Consequently, the posted results should be interpreted with attention to the stated populations and methods, without assuming unreported safeguards or procedures.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: hyperglycaemia (33.3%), rash maculo-papular (33.3%), pneumonia (16.7%), prostate cancer (16.7%), hypotension (16.7%).

The adverse-event figures describe the safety groups listed for Phase Ib, Phase II, and the safety cohort. In the Phase II groups, serious adverse events were recorded for 43 of 84 participants receiving ipatasertib 400 mg plus abiraterone, 42 of 88 receiving ipatasertib 200 mg plus abiraterone, and 18 of 81 receiving placebo plus abiraterone. The registry also lists other adverse events, deaths, and serious-event terms by group. These summaries are descriptive and should be read with the group definitions and follow-up context.

A serious adverse event is not the same as a dose-limiting toxicity. The primary endpoint applies specified toxicity criteria during Days 1 to 28 of Cycle 1; the serious-event summaries cover a different safety concept and do not have the same stated window. The registry record does not provide a comparative statistical analysis for these safety figures, nor does it give exposure-adjusted rates in the information summarized.

Differences in raw counts can reflect group size, duration of observation, and exposure as well as underlying event patterns. The listed serious-event terms include events from different categories, and the record does not establish that each term represents a distinct participant. These data describe reported safety events; they do not by themselves estimate causal effects or establish comparative safety.

13. What the Result Does, and Does Not, Mean

The results mean that the registry contains a descriptive Phase Ib report of zero recorded dose-limiting toxicity percentage values in the two listed groups, alongside Phase II estimates for survival and PSA progression. The estimates vary in direction, precision, and analysis status. The ITT overall-survival comparisons do not show a statistically clear departure from the null in their reported confidence intervals and p-values. The PTEN-loss subgroup and PSA-progression estimates require additional caution because of subgroup uncertainty, unadjusted recalculation, and unreported multiplicity handling.

They do not mean that a treatment effect is absent simply because an interval includes its null value. Such an interval indicates uncertainty that includes both the null and other possible effects. Nor does a nominally notable p-value in one subgroup establish a dependable effect across the full study population or prove that subgroup status modifies the treatment contrast. These are distinct claims and require appropriate analyses and context.

The posted estimates also do not establish equivalence, guarantee an outcome for an individual, or demonstrate a causal safety difference from the descriptive event counts alone. The Phase Ib endpoint concerns an early treatment window; it cannot characterize all later adverse events. The Phase II results concern specified study populations and follow-up, and the registry record does not report all analysis details needed to evaluate missing data, censoring, or the full multiplicity strategy.

The appropriate interpretation is therefore limited to the outcomes and groups as recorded: a small Phase Ib dose-finding result, Phase II time-to-event estimates with reported uncertainty, a subgroup analysis with unresolved multiplicity context, and PSA comparisons recalculated without reported sponsor analyses. Any stronger conclusion would go beyond what the registry record documents.

14. Why This Trial Matters Statistically

This study is statistically instructive because it combines distinct development stages and questions within one registry record. Phase Ib addresses dose-limiting toxicity during an early cycle, while the randomized Phase II stage compares two ipatasertib doses with placebo on an abiraterone background. The design therefore produces outcomes with different purposes, populations, and appropriate interpretations; a single result cannot stand in for the whole study.

It also illustrates why point estimates must be read alongside uncertainty. The overall-survival hazard ratios are near the null reference and have confidence intervals that include it. The PTEN-loss subgroup has a different-looking pattern, but subgroup results need context about prespecification, interaction testing, and multiplicity. The PSA endpoint has unadjusted recalculated comparisons, which should not be confused with reported sponsor analyses. A nominal p-value alone cannot resolve these distinctions.

The registry includes planning illustrations based on observed effects. Their role is to show how a future sample-size or event target changes under alternative effect assumptions. They do not describe the trial's original design or its achieved power. Keeping planning scenarios separate from observed outcomes is essential to avoid treating a post hoc calculation as a prospective guarantee.

Finally, the record shows the limits of registry-based interpretation. Some definitions and results are available, but the multiplicity plan, missing-data procedures, detailed censoring rules, and original sample-size justification are not reported. This does not invalidate the posted estimates; it defines the boundary of what can be assessed from the record.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

Several limitations are specific to interpreting this record. The primary endpoint is a Phase Ib dose-limiting toxicity percentage in two small listed groups, and the registry does not post a confidence interval or estimable comparative analysis for it. The zero values are consequently descriptive and provide limited information about precision or risk beyond the recorded observation window.

The Phase II results include comparisons across doses and outcomes, as well as a PTEN-loss subgroup. The record does not report whether the subgroup analysis was prespecified, whether an interaction was tested, or how the full set of analyses was handled for multiplicity. This makes isolated nominal results difficult to distinguish from exploratory findings.

For PSA progression, the posted group percentages are accompanied in the analysis data by unadjusted recalculations, but the registry does not list a reported analysis. The recalculated comparisons are useful for describing the posted summaries, but they are not a substitute for a documented prespecified analysis. The record also does not report details of missing PSA assessments or the criteria used to handle them.

For survival, the registry gives medians, hazard ratios, confidence intervals, and log-rank p-values, but does not report the detailed censoring rules, proportional-hazards assessment, or missing-follow-up procedures in the information summarized. The posted enrollment and group sizes do not resolve those methodological questions. Safety summaries also lack exposure-adjusted comparative analyses in this record, and the serious-event counts span safety groups with different roles in the study.

Finally, the detailed safety-cohort schedule is truncated in the record, and the original sample-size justification and complete statistical analysis plan are not reported. These limitations constrain independent assessment without implying that unreported methods were or were not used.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study of Ipatasertib or Apitolisib With Abiraterone Acetate Versus Abiraterone Acetate in Participants With Castration-Resistant Prostate Cancer Previously Treated With Docetaxel Chemotherapy — NCT01485861.
• Registry record last updated 2023-09-14; status last verified 2023-08.
• Results first posted 2023-09-14.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

The registry record describes NCT01485861, a completed multicenter, international Phase Ib/II study in participants with castration-resistant prostate cancer previously treated with docetaxel-based chemotherapy. It lists enrollment as 298, with an open-label Phase Ib dose-finding stage, a randomized double-blind three-arm Phase II comparison, and an open-label safety cohort.

The listed primary outcome is the Phase Ib percentage of participants with dose-limiting toxicities during Days 1 to 28 of Cycle 1. Phase II outcomes include overall survival in the ITT population, overall survival among participants with ICR IHC PTEN loss, and PSA progression. Overall-survival comparisons use reported log-rank analyses; the PSA comparisons discussed are unadjusted recalculations because no reported analysis is listed for that endpoint.

The record reports group estimates and safety summaries but does not report the multiplicity strategy, detailed missing-data procedures, or original sample-size justification. Those omissions limit the scope of conclusions that can be drawn from the registry record alone.