OLAParib COmbinations: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for OLAParib COmbinations (NCT02576444), a non-randomized phase 2 study. The primary outcome is Overall Response Rate.

2. Clinical Question

3. Trial Design

This was a phase II, parallel-group study with nonrandomized allocation and no masking. The registry lists enrollment of 67 and identifies the study as terminated. It gives a start date of 2015-11 and a primary completion date of 2019-11-18. The reason for termination is not reported in the registry record.

The study was designed around molecularly selected groups rather than random assignment. Group 1 was to receive olaparib, including patients with cholangiocarcinoma harboring IDH 1/2 tumors and patients with tumors harboring mutations in HDR genes. Group 2 was to receive AZD5363 plus olaparib for tumors with specified alterations involving PTEN, PIK3CA, AKT, or ARID1A, or other molecular aberrations leading to PI3K/AKT pathway dysregulation. Group 3 was to receive AZD1775 plus olaparib for tumors with TP53 or KRAS mutations, subject to the stated TP53 eligibility condition. Group 4 was to receive AZD6738 plus olaparib for tumors with HDR gene mutations, including ATM, CHK2, APOBEC, and the MRE11 complex.

The registry states that the AZD1775 plus olaparib arm was never initiated. The posted safety groups include olaparib alone, olaparib with capivasertib, and olaparib with ceralasertib. The registry lists the sponsor as Joseph Paul Eder. It does not report the full operational details of treatment assignment, dose schedules, or reasons for treatment discontinuation.

Because allocation was nonrandomized and treatment groups were selected by molecular and tumor characteristics, observed outcomes across groups would not by themselves establish a treatment difference. The registry also states that no formal comparison between arms was planned. Any interpretation therefore needs to focus on the response information within the stated study context, while recognizing that response results are not reported in the registry record.

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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: 2 patients not included due to death: 1 from Olaparib AZD2881, 1 from Olaparib \& Capivasertib AZD5363. The Olaparib \& Adavosertib AZD1775 arm was never initiated. One participant in Olaparib \& Ceralasertib AZD6738 arm not included because taken off study by physician decision and 2 subjects withdrew.

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: Arm 4 (Olaparib \& Adavosertib AZD1775) was never activated following the study pause due to COVID.

6. Primary Endpoint

The registry lists the primary outcome as Overall Response Rate, measured over Change from baseline to 16 weeks.

The primary endpoint was overall response rate in participants with measurable disease, assessed using RECIST. The registry describes assessment from baseline to 16 weeks and defines complete response as disappearance of all target lesions. Partial response requires at least a 30% decrease in the sum of target-lesion diameters. Stable disease means that neither sufficient shrinkage for partial response nor sufficient increase for progressive disease has occurred. These definitions make the endpoint a classification of tumor status at the stated assessment, rather than a measure of how long response lasts.

Response rate is used in oncology studies to describe the proportion of participants whose tumors meet response criteria under a specified assessment framework. It can summarize tumor change at a particular time point, but does not by itself describe symptom change, survival, duration of response, or effects in people outside the defined study population. The registry additionally defines clinical benefit as the sum of complete response, partial response, or stable disease at 16 weeks. That measure includes stable disease as well as tumor shrinkage meeting response criteria.

The primary endpoint is described as counts of participants, but the registry record does not report the response counts, response rate estimates, or an efficacy analysis. It also says there would be no formal comparison between arms. Consequently, the endpoint definition explains what was intended to be measured, but the posted record does not establish what response outcomes occurred.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The planned primary outcome was a participant-level tumor response assessment at 16 weeks, using RECIST. The registry characterizes the outcome as a count of participants. It describes the comparison as response before versus after treatment within each arm and says that there would be no formal comparison between arms. The record does not report the statistical analysis used to turn the individual response classifications into posted estimates.

What does a binary response outcome represent?

General statistical explanation: a binary outcome places each participant into one of two categories for a particular analysis, such as meeting a specified response definition or not meeting it. The underlying RECIST categories in this study are more detailed: complete response, partial response, stable disease, and progressive disease are described in the endpoint definition. A response-rate analysis would ordinarily require a clear rule for which categories count as response and a defined denominator. The registry describes the categories but does not post the response counts or the analyzed denominator.

The registry separately defines clinical benefit as complete response, partial response, or stable disease at 16 weeks. This is not identical to an outcome that counts tumor shrinkage alone, because stable disease is included. The distinction matters when reading any response-based result: the endpoint definition determines which participant classifications contribute to the outcome. No clinical-benefit count is reported in the registry record.

How should the assessment time point be understood?

The stated timeframe is change from baseline to 16 weeks. General explanation: a fixed assessment time point describes status at a defined moment, and does not by itself show the course of disease between assessments or how long a response persists. The registry does not report additional assessment schedules, handling of assessments that did not occur at the intended time, or duration-of-response results. Those details are not reported in the registry record.

The RECIST definitions give operational criteria for categorizing tumor changes. Complete response is defined as disappearance of all target lesions. Partial response requires at least a 30% decrease in the sum of target-lesion diameters. Stable disease is defined by neither enough shrinkage to qualify as partial response nor enough increase to qualify as progressive disease. The record does not give the progressive-disease definition, details of independent review, or the procedures used to resolve uncertain assessments.

What can a confidence interval add?

General statistical explanation: a confidence interval expresses uncertainty around an estimate, conditional on the statistical method and assumptions. A narrow interval indicates greater precision than a wide interval, while neither interval guarantees that an estimate is free of bias. For a response outcome, the interval is interpreted alongside the response count and analysis denominator. No response estimate or confidence interval is posted for this study, so its precision cannot be evaluated.

The record also does not report p-values or an efficacy analysis. A p-value, in general, measures how compatible observed data are with a specified statistical model or null hypothesis; it is not a measure of clinical importance or a direct probability that a hypothesis is true. Since no formal comparison between arms was intended, a between-arm p-value would not answer the stated primary question. The registry record does not report a within-arm hypothesis test either.

Why does the nonrandomized design matter?

General statistical explanation: random assignment can balance measured and unmeasured prognostic factors across treatment groups on average. Nonrandomized assignment does not provide that protection. In this study, treatment group was linked to molecular characteristics and tumor features, so the groups were assembled for different eligibility profiles. A direct comparison of their outcomes could reflect differences in those profiles as well as treatment exposure. The registry explicitly cautions that the arms are not a like-for-like control comparison and says there would be no formal comparison between them.

The parallel structure means that participants were intended to receive treatment in one of several groups rather than all treatments in sequence. The registry describes the design as parallel, but does not report details about assignment procedures beyond nonrandomized allocation. The record does not report adjustment methods, stratification, or a model for accounting for tumor type or molecular features.

What do the planning illustrations mean?

The registry describes planning illustrations based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It says that the effect to detect is a stated fraction of the observed effect, and that such illustrations are planning calculations rather than observed power. No numerical planning results are reported in the record described for this study. These assumptions should not be read as the trial's own sample-size justification or as evidence that a particular power was achieved. The registry record does not report the study's sample-size justification.

General statistical explanation: sample-size planning estimates how much information a proposed study might need for a specified statistical objective under assumed conditions. It does not describe the information actually obtained, and it cannot replace an outcome analysis. A planned or illustrative sample size is not observed power. In this case, the posted enrollment is 67, but the primary endpoint analysis denominator and response results are not reported.

10. Multiplicity, Missing Data and Analysis Populations

The study planned response assessment in molecularly selected groups and across tumor types, with multiple treatment combinations described. Considering several groups or several outcomes can raise multiplicity questions: when multiple statistical claims are tested, the chance of at least one apparently notable result may increase. General statistical explanation: multiplicity procedures can define how such claims are controlled or prioritized. The registry record does not report a multiplicity adjustment, a hierarchy of hypotheses, or a detailed statistical plan. It does say there would be no formal comparison between arms, and the record lists no analyses.

The response population is not fully described. The registry says two patients were not included due to death: one from the olaparib group and one from the olaparib plus capivasertib group. It also says one participant in the olaparib plus ceralasertib group was not included because the physician took the participant off study. The population description then refers to two subjects but ends before giving a complete reason. The complete exclusion information is not reported in the registry record.

Because of these exclusions, enrollment of 67 does not identify the denominator for the primary response outcome. The registry does not state whether the primary endpoint used an intention-to-treat population, an evaluable population, or another analysis population. It does not report how missing or unevaluable 16-week assessments were handled, whether any data were imputed, or how deaths before assessment were classified in the response analysis. Those methods are not reported in the registry record.

General statistical explanation: missing outcome data can affect an estimate when the availability of an assessment is related to a participant's health or response status. Excluding participants can change the population represented by an analysis. The appropriate interpretation depends on the prespecified estimand and missing-data strategy, neither of which is described in sufficient detail in the registry record. The posted information therefore does not support reconstruction of the endpoint denominator or a sensitivity analysis.

11. 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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: duodenal obstruction (6.2%), nausea (6.2%), rectal pain (6.2%), dyspnea (6.2%), aspiration (6.2%).

The serious adverse event figures are participant counts in the listed safety groups. For olaparib AZD2881, 26 participants were at risk and 10 were affected. For olaparib with capivasertib AZD5363, 16 were at risk and 9 were affected. For olaparib with ceralasertib AZD6738, 25 were at risk and 17 were affected. The record also lists deaths of 1, 1, and 0, respectively, for those groups. These are reported counts, not a comparison adjusted for group differences.

The listed percentages for the serious-event terms are 6.2% for duodenal obstruction, nausea, rectal pain, dyspnea, aspiration, and respiratory, thoracic and mediastinal disorders - Other. The registry record does not state the denominator or event-count details associated with each of these percentages in the information reported. The terms should therefore be read as the listed serious-event categories and percentages, not as a basis for calculating additional quantities.

General statistical explanation: adverse-event counts describe events or affected participants under the registry's reporting definitions; they do not, by themselves, establish that a treatment caused an event. The safety groups are not randomized comparisons, and their sizes and eligibility profiles differ. The AZD1775 combination arm was never initiated, so the listed safety groups do not include that treatment group. These safety figures do not answer the primary tumor-response question.

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

The registry record establishes the intended question and the structure of the study: response was to be assessed using RECIST at 16 weeks in molecularly selected participants, within each treatment group. It also establishes that the study used nonrandomized allocation, had no masking, was terminated, and enrolled 67 participants. The record does not report the response counts, response rates, clinical-benefit results, or an efficacy analysis. As a result, the primary endpoint cannot be interpreted as evidence for or against a particular response outcome from this record.

The study's molecularly directed treatment groups also limit what can be inferred from any cross-group contrast. Participants were assigned to groups according to tumor and molecular features, and the registry states that no formal between-arm comparison was planned. Even if group-specific response estimates were available, those estimates would be descriptive unless supported by an appropriate comparative analysis and assumptions. The registry does not report such an analysis.

The response definitions explain what would count as complete response, partial response, or stable disease. The additional clinical-benefit definition includes those three categories at the stated assessment. These definitions do not establish that an outcome occurred, and the posted record does not contain counts needed to calculate either response or clinical benefit.

The safety findings provide a separate account of affected participants and serious-event terms in the groups with reported safety data. They should not be interpreted as efficacy findings or as proof of causation. The AZD1775 combination group was never initiated, and the registry does not report safety data for that planned group.

In general, a registry record can document intended methods and selected results without providing a complete trial report. The absence of efficacy results in this record is not itself evidence that the treatment did or did not produce tumor responses. It means that the response magnitude and its precision are not reported in the registry record. No medical conclusion about treatment should be drawn from the missing endpoint results.

13. Why This Trial Matters Statistically

This trial is statistically notable for the way its treatment groups were defined. The study did not randomize participants among therapies; molecular and tumor characteristics determined which treatment group was relevant. This design can be appropriate for studying biomarker-selected populations, but it changes the interpretation of comparisons. Groups that differ in eligibility features are not automatically valid controls for one another, a point made explicitly in the registry record.

The endpoint also illustrates the distinction between an outcome definition and an outcome result. RECIST criteria specify how tumor status is categorized, and the 16-week timeframe specifies when the primary assessment was intended. Yet without response counts, analysis denominators, or an efficacy analysis, a clearly defined endpoint does not yield an interpretable estimate of response. Statistical reporting needs both the measurement rules and the observed data.

The clinical-benefit definition provides a further example of how endpoint construction affects interpretation. It includes stable disease as well as complete and partial response. That composite answers a broader classification question than response based only on tumor shrinkage. The record states the definition but does not report the corresponding count.

Finally, the record shows why analysis populations and missing assessments matter. Deaths and a physician decision are mentioned among exclusions, while the remaining population description is incomplete. Without a complete denominator and rules for missing assessments, readers cannot determine which participants contributed to the primary endpoint. These limitations are central to judging the scope and precision of a result, and the registry does not supply the information needed to resolve them.

14. 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.

The most consequential limitation for interpretation is that the registry record does not report the primary response results. There are no response counts, response-rate estimates, clinical-benefit counts, confidence intervals, or efficacy analyses. The endpoint is defined, but its observed outcome cannot be assessed from the posted information.

The full primary analysis population is also unclear. The registry mentions two exclusions due to death and one participant taken off study by physician decision, then gives an incomplete statement about two further subjects. It does not report the final denominator, the endpoint-specific analysis population, or how missing assessments were handled. Enrollment of 67 cannot resolve these omissions.

The study used nonrandomized, biomarker-directed treatment groups, and no formal comparison between arms was planned. The AZD1775 plus olaparib arm was never initiated. Thus, the study does not provide a randomized comparison among all planned regimens, and the record does not report a comparative efficacy analysis for the groups with posted safety data.

The registry does not report the reason for termination, the sample-size justification, a detailed statistical plan, multiplicity handling, or analysis methods for tumor types and molecular subgroups. It also does not provide further details about response assessment procedures or the handling of assessments that were not available at 16 weeks. These limitations are specific to what the registry record documents; their absence should not be replaced with assumptions about the protocol or the conduct of analyses.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: OLAParib COmbinations — NCT02576444.
• Registry record last updated 2022-12-28; status last verified 2022-11.
• Results first posted 2022-12-28.
• 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.

18. Record Summary

NCT02576444, titled OLAParib COmbinations, was a phase II, parallel, nonrandomized study with no masking. It enrolled 67 participants and is listed as terminated. The study evaluated olaparib alone or in combination with AZD5363, AZD1775, or AZD6738 in molecularly selected patients with advanced solid tumors. The AZD1775 combination arm was never initiated.

The primary endpoint was tumor overall response rate using RECIST, assessed from baseline to 16 weeks. The registry defines complete response, partial response, stable disease, and clinical benefit, and states that no formal comparison between arms would be made. The record does not report primary response results or an efficacy analysis. It lists safety counts for olaparib alone, olaparib with capivasertib, and olaparib with ceralasertib, but these do not supply the missing efficacy outcomes.

The registry gives a start date of 2015-11 and a primary completion date of 2019-11-18. It does not report the reason for termination or enough information to identify the final primary endpoint denominator.