To Assess Safety and Effect of Olaparib on the Pharmacokinetics of Anastrozole, Letrozole & Tamoxifen, and Their Effect on Olaparib, in Patients With Advanced Solid Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for To Assess Safety and Effect of Olaparib on the Pharmacokinetics of Anastrozole, Letrozole & Tamoxifen, and Their Effect on Olaparib, in Patients With Advanced Solid Cancer (NCT02093351), a non-randomized phase 1 study. The primary outcome is Effect of Olaparib on Exposure to Tamoxifen - Cmax ss.

2. Clinical Question

The central question is about pharmacokinetic interaction, not comparative tumour response. The primary outcome is titled “Effect of Olaparib on Exposure to Tamoxifen - Cmax ss”. Its description also identifies maximum concentrations of tamoxifen, N-desmethyl tamoxifen and endoxifen in the presence and absence of co-administered olaparib, together with associated treatment ratios. The study description also states that it assessed effects in the reverse direction: the effect of the anti-hormonal agents on olaparib.

The three cohorts were organised by the anti-hormonal agent: tamoxifen, anastrozole or letrozole. Each cohort description includes steady-state pharmacokinetic assessments for olaparib alone, the cohort’s anti-hormonal agent alone, and the combined drugs. The registry record does not report numeric primary-outcome estimates here, so the magnitude or precision of any interaction cannot be assessed from the endpoint information.

The question is therefore whether exposure measurements differed across the specified treatment conditions, and how precisely such differences were estimated—not whether one regimen improved clinical outcomes relative to another. The study was open-label and non-randomised, and the arms are not a like-for-like control comparison. Its design and posted endpoint information should be read as a pharmacokinetic investigation in this study population.

3. Trial Design

This was a Phase I, open-label, non-randomised, parallel-group, multicentre study in patients with advanced solid cancer. The registry record lists 79 participants enrolled and the status as completed. It records a start date of 2014-09-01 and a primary completion date of 2015-04-30. AstraZeneca is listed as the sponsor.

The study had two parts. Part A was mandatory and assessed the pharmacokinetics of olaparib and the anti-hormonal agents when given alone and together. Part B allowed eligible patients to continue olaparib after the pharmacokinetic phase and was intended to provide additional safety data. The registry record does not report the eligibility criteria for Part B or how many participants continued.

Part A had three cohorts: tamoxifen, anastrozole and letrozole. Each cohort description lists olaparib-alone steady-state pharmacokinetics, anti-hormonal-agent-alone steady-state pharmacokinetics, and combined steady-state pharmacokinetics. This within-cohort structure supports assessing exposure under different drug conditions. It does not make the cohorts randomised treatment groups, and it does not establish that participants in different cohorts were comparable.

The study was unmasked, so participants and investigators were not blinded to treatment. That feature is less central to laboratory concentration measurements than it would be to a subjective outcome, but it remains relevant to the overall conduct and interpretation of an open-label study. The registry record does not report the sequence of treatment conditions, washout procedures, or the exact timing and duration of each treatment period. Those details should not be inferred from the cohort descriptions.

The posted record identifies pharmacokinetic sampling as a procedure and gives the primary endpoint sampling schedule. It does not report a conventional placebo or untreated control group. Because allocation was non-randomised, the cohort arms should not be read as a like-for-like control comparison. The study’s stated focus is drug exposure and safety, rather than a randomised estimate of clinical benefit.

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: 79 patients were assigned to study treatment and received at least 1 dose of olaparib in Part A; 18 patients did not fulfil eligibility criteria. Part A of the study consisted of 3 treatment periods preceded by a screening period. There was a 4-day washout between the first two treatment periods.

Part A

Reasons for not completing this period:

Part B

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The PK Analysis set included all patients who received a study drug dose and provided evaluable PK profiles for at least 1 treatment period in Part A.

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: All patients enrolled in Part A of the study and who received at least 1 dose of olaparib were included in the baseline analysis.

6. Primary Endpoint

The registry lists the primary outcome as Effect of Olaparib on Exposure to Tamoxifen - Cmax ss, measured over Pre-dose and at 1, 2, 4, 5, 6, 8, 12 and 24 hours post-dose on Day 26 and Day 31.

The primary endpoint is maximum steady-state concentration, written in the endpoint title as “Cmax ss”, for tamoxifen exposure with and without co-administered olaparib. The description also names N-desmethyl tamoxifen and endoxifen, and associated treatment ratios. The unit listed for the endpoint is mcg/mL. Measurements were scheduled before dosing and at 1, 2, 4, 5, 6, 8, 12 and 24 hours post-dose on Day 26 and Day 31.

Maximum concentration is a pharmacokinetic summary: it describes the highest measured concentration over the specified sampling profile. At steady state, repeated dosing has reached a stable exposure pattern as defined by the study’s pharmacokinetic framework. Comparing maximum concentrations under drug-alone and co-administration conditions can help describe whether the measured peak exposure differs when the drugs are taken together. Treatment ratios express the comparison between conditions, although the registry record does not report the numeric ratios or their uncertainty.

This endpoint is used to characterise exposure, not to establish a clinical outcome. It does not by itself show whether a participant’s cancer changed, nor does it establish the clinical consequences of any concentration difference. Interpretation depends on the observed values, the treatment-ratio estimates and their precision. Those numerical results are not reported in the registry record. The listed endpoint timeframe describes sampling occasions; it should not be mistaken for a follow-up period for clinical outcomes.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The study’s methods are best understood by separating its pharmacokinetic objective from a conventional randomised treatment comparison. The cohorts were non-randomised and open-label. Within each cohort, the descriptions identify pharmacokinetic assessments for olaparib alone, the relevant anti-hormonal agent alone, and the combination. This arrangement makes the drug conditions the focus of the exposure question. It does not create a randomised control group, and comparisons between the three cohorts should not be treated as if allocation to anti-hormonal agent had been randomised.

What does Cmax ss describe?

Cmax is the maximum concentration measured over a sampling profile. The “ss” notation in the endpoint title indicates that the stated maximum is assessed at steady state. Steady-state measurements are used to describe exposure after repeated dosing has reached a stable pattern under the study’s conditions. The primary endpoint lists mcg/mL as its unit and describes measurements for tamoxifen and its named metabolites in the presence and absence of olaparib. The endpoint timeframe lists pre-dose and post-dose sampling at 1, 2, 4, 5, 6, 8, 12 and 24 hours on Day 26 and Day 31.

Sampling across a concentration-time profile helps characterise exposure rather than relying on a single isolated measurement. The scheduled measurements provide the basis for summarising the maximum concentration. The registry record does not report the exact calculation rules used to select or derive each maximum, the handling of concentrations below assay limits, or the laboratory assay details. Those features should not be assumed.

Why report geometric means and variability?

The primary outcome specifies a geometric mean and a geometric coefficient of variation as its summary measures. In general statistical terms, a geometric mean summarises positive measurements on a multiplicative scale and can be useful when concentrations are right-skewed. A geometric coefficient of variation describes relative variability on that scale. These summaries differ from an arithmetic mean and standard deviation, so their interpretation should match the scale on which the data are presented.

For a treatment-ratio question, the ratio compares exposure under one condition with exposure under another. A ratio near the equality point would indicate similar estimated exposure on that scale; a ratio on either side would indicate a directional difference. This is general interpretation, not a claim about this study’s result. The registry record does not report the numerical treatment ratios or their uncertainty in the endpoint information. It also does not identify the exact statistical model or transformation used to estimate them.

What does a confidence interval add?

In general, a confidence interval presents a range of values compatible with the observed data under the chosen statistical method. It communicates precision as well as the direction and magnitude of an estimate. A narrow interval indicates greater precision than a wide interval, while an interval that spans substantively different possibilities leaves more uncertainty. For a ratio, interval interpretation is on the ratio scale, not as a difference in concentration. The registry record does not report confidence intervals for the primary result in the information, so precision cannot be judged from the endpoint title alone.

Why does over-dispersion matter?

Over-dispersion is a general issue that arises when observed variability is greater than a statistical model expects. If a model underestimates variability, standard errors may be too small and intervals may be too narrow. This concept is not a reported finding in this trial: the record does not identify over-dispersion as a concern or state that a model requiring an over-dispersion adjustment was used. It is relevant only as a general reminder that model assumptions should match the data and outcome distribution.

The record lists 12 outcome measures and 12 analyses. Those counts describe the breadth of posted outcomes and analyses; they do not identify the methods used for each result. The record does not report a detailed statistical analysis plan, the estimation method for treatment ratios, the confidence level for intervals, or any adjustment for multiple comparisons. None of these methods should be inferred simply from the fact that treatment ratios are mentioned.

The sample-size illustrations elsewhere on the page use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect expressed as a stated fraction of the observed effect. Those are planning illustrations, not a description of the trial’s own design justification. For time-to-event tables, the illustration uses total events; other illustrations give participants per arm. The record does not report the trial’s own sample-size justification. Such illustrations are not observed power and should not be presented as evidence that the study had a particular probability of detecting an effect.

Finally, the pharmacokinetic analysis set is defined in the record: it included patients who received a study drug dose and provided evaluable pharmacokinetic profiles for at least one Part A treatment period. This is an analysis-population definition, not a complete account of missing-data handling. The record does not specify how incomplete profiles, missing samples, protocol deviations, or exclusions were handled in the analyses. Those details matter because pharmacokinetic estimates depend on the availability and evaluability of measurements under the relevant conditions.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists 12 outcome measures and 12 analyses. Having multiple outcomes or analyses creates a multiplicity question: when many statistical comparisons are considered, the chance of at least one apparently notable result can increase. A prespecified hierarchy or adjustment can help define how results should be interpreted. The record does not report a multiplicity strategy, a hierarchy among the outcomes, or whether any adjustment was used. It is therefore not possible to say from this record whether the reported analyses were treated as confirmatory, exploratory, or both.

The primary endpoint is identified as the effect of olaparib on tamoxifen maximum steady-state concentration, with a description that also names metabolites and associated treatment ratios. The broader study evaluates three anti-hormonal agents and the reverse effect on olaparib. This range of pharmacokinetic questions makes clarity about which comparisons were prespecified especially useful. The registry record does not provide enough detail to reconstruct that plan or determine how the multiple comparisons were handled.

The pharmacokinetic analysis set included patients who received a study drug dose and had evaluable profiles for at least one Part A treatment period. This definition makes clear that the analysis did not necessarily require an evaluable profile for every treatment condition. The record does not report how many participants were included in each endpoint analysis, how many profiles were incomplete, or how missing samples and unevaluable profiles were handled. It also does not state whether any imputation was performed.

These omissions limit assessment of the potential effects of missingness and selection into the analysis set. If participants with incomplete profiles differ from those with evaluable profiles, the analysed data may not represent all enrolled participants in the same way. This is a general methodological concern, not evidence that such a difference occurred. The record does not report a sensitivity analysis addressing missing pharmacokinetic data.

The registry record also does not report an analysis plan detailing model choice, interval estimation, or treatment of deviations from the planned sampling schedule. The available analysis-set definition and endpoint description are useful, but they do not replace those methodological details. Interpretation should remain limited to the methods and results actually posted.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: anaemia (7.2%), ascites (3.3%), vomiting (3.3%), device occlusion (2.9%), urinary tract infection (2.9%).

The safety figures are descriptive counts of participants affected within the groups named in the record. Serious adverse events were reported for 2 of 30 participants in Cohort 1 - Tamoxifen, 0 of 23 in Cohort 2 - Anastrozole, and 0 of 26 in Cohort 3 - Letrozole. For Olaparib (Part B), serious adverse events were reported for 22 of 69 participants. The record lists one death in each of the four groups.

Other adverse events were reported for 27 of 30 participants in the tamoxifen cohort, 20 of 23 in the anastrozole cohort, 20 of 26 in the letrozole cohort, and 66 of 69 in the Part B olaparib group. The record separately lists serious-event terms and percentages, including Anaemia (7.2%), Ascites (3.3%), Vomiting (3.3%), Device Occlusion (2.9%), Urinary Tract Infection (2.9%) and Urosepsis (2.9%). These entries describe reported events; they do not show whether an event was caused by a study drug.

The groups should not be compared as though they were randomised arms. Part B involved eligible patients who could continue olaparib after the pharmacokinetic phase, and its group is not a like-for-like control for the Part A cohorts. The record does not provide the timing, duration, severity details beyond the serious-event classification, or individual clinical context needed for fuller interpretation. Counts alone do not establish comparative risk or causality.

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

This trial’s stated purpose was to assess pharmacokinetics and safety when olaparib and the anti-hormonal agents tamoxifen, anastrozole and letrozole were administered alone and in combination. The primary endpoint focuses on tamoxifen maximum steady-state concentration, while the description includes tamoxifen metabolites and treatment ratios. These are exposure measures. They can describe how measured drug concentrations compare across treatment conditions, but they are not direct measures of cancer response or patient benefit.

The posted endpoint information does not include numeric estimates for the primary outcome, treatment ratios, or confidence intervals. As a result, it does not establish the size, direction, or precision of a pharmacokinetic difference. The registry record’s description of what was measured should not be mistaken for a reported result. The endpoint tables and plots elsewhere on the page are the appropriate places to inspect any posted estimates; where a result is not reported in the registry record, it cannot be inferred from the design.

The safety information shows that serious adverse events and deaths were recorded in the listed groups. The counts are descriptive. The study was non-randomised, and Part B was an eligibility-dependent continuation group, so the groups are not a basis for straightforward comparative safety claims. The record does not establish that a particular event was caused by olaparib or an anti-hormonal agent.

Nor does the study design support a randomised comparison of clinical efficacy. The registry record identifies a Phase I pharmacokinetic and safety investigation, not a trial designed as a randomised test of tumour outcomes. Any claim that a regimen works or does not work would go beyond the posted information. The appropriate interpretation is narrower: the study asked how exposure measurements behaved under specified drug conditions and recorded adverse events in the listed cohorts. Numerical conclusions require the corresponding posted estimates and their uncertainty, together with appropriate caution about the non-randomised design and analysis details not reported in the registry record.

13. Why This Trial Matters Statistically

Drug-interaction studies ask a distinct statistical question from trials that compare clinical outcomes. Here, the central interest is whether exposure to olaparib and the anti-hormonal agents differed when the drugs were given alone versus together. The cohort descriptions make that structure visible: each names olaparib alone, the relevant anti-hormonal agent alone, and the combination. Careful separation of exposure outcomes from clinical outcomes helps readers avoid interpreting a concentration comparison as evidence about tumour response.

The record also illustrates why an endpoint definition is not a result. It specifies Cmax ss, geometric means, geometric coefficients of variation, a unit, and a sampling schedule. Those details tell readers what kind of measurement was intended and when it was collected. Without the numerical estimates and their precision, however, they do not answer whether exposure changed or how uncertain that conclusion would be.

Design labels matter too. The study was non-randomised and open-label, with separate cohorts for the three anti-hormonal agents and an eligibility-dependent Part B. These features shape which comparisons are defensible. Within-cohort pharmacokinetic conditions address the stated exposure question; differences between cohorts are not equivalent to randomised comparisons. Part B safety counts also need to be read separately from the Part A cohort counts.

Finally, this record highlights the value of transparent reporting around multiple analyses, analysis populations and missing samples. It lists 12 outcome measures and 12 analyses and defines the pharmacokinetic analysis set, but does not report a multiplicity strategy or detailed missing-data methods. Those details help readers understand how estimates were selected and how complete the underlying profiles were. The statistical importance of the study lies in its focused exposure question and in the need to distinguish measured pharmacokinetics, descriptive safety counts and conclusions that the posted record cannot support.

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 main limitation for interpreting the pharmacokinetic question from this record is that numeric primary endpoint results and treatment ratios are not reported in the endpoint information. Without estimates and measures of uncertainty, neither the magnitude nor precision of a difference can be assessed. The endpoint title and sampling schedule alone do not show what the observed concentrations were.

The non-randomised design limits comparisons across the tamoxifen, anastrozole and letrozole cohorts. The record itself cautions that the arms are not a like-for-like control comparison. Open-label conduct also means treatment was not masked, although the endpoint is based on pharmacokinetic measurements. The record does not report the treatment sequence, washout procedures, assay details, or full dosing schedule, so those aspects of the design cannot be evaluated.

The analysis set includes participants with evaluable pharmacokinetic profiles for at least one Part A treatment period, but the record does not report the number included in each endpoint analysis or the handling of missing samples and incomplete profiles. It also does not report detailed statistical methods, a multiplicity plan, or the trial’s sample-size justification. These gaps limit assessment of the robustness and precision of any estimates.

Safety counts should be interpreted cautiously because the groups were not randomised comparators and Part B consisted of eligible patients who could continue olaparib. The posted record does not give the event timing or context needed to assess causality, and the listed counts do not establish treatment-related risk. These limitations constrain interpretation of the record; they do not by themselves show that the study’s measurements were invalid.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: To Assess Safety and Effect of Olaparib on the Pharmacokinetics of Anastrozole, Letrozole & Tamoxifen, and Their Effect on Olaparib, in Patients With Advanced Solid Cancer — NCT02093351.
• Registry record last updated 2019-10-02; status last verified 2019-09.
• Results first posted 2016-06-01.
• 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

This completed Phase I study enrolled 79 patients with advanced solid cancer. It was open-label, non-randomised and parallel-group, with cohorts for tamoxifen, anastrozole and letrozole. Part A assessed pharmacokinetics for olaparib and each anti-hormonal agent alone and in combination; eligible patients could continue olaparib in Part B for additional safety data.

The primary endpoint concerned tamoxifen maximum steady-state concentration, with the description also naming N-desmethyl tamoxifen, endoxifen and treatment ratios. The posted record specifies geometric-mean summaries and a sampling schedule, but the numerical primary results and their precision are not reported in the endpoint information. The record lists 12 outcome measures and 12 analyses.

Safety counts are descriptive and should not be treated as randomised comparisons. The cohort arms are not like-for-like controls, and Part B is a continuation group. The record does not report a multiplicity strategy, detailed missing-data methods, or the trial’s sample-size justification.