Talazoparib For Neoadjuvant Treatment Of Germline BRCA1/2 Mutation Patients With Early Human Epidermal Growth Factor Receptor 2 Negative Breast Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Talazoparib For Neoadjuvant Treatment Of Germline BRCA1/2 Mutation Patients With Early Human Epidermal Growth Factor Receptor 2 Negative Breast Cancer (NCT03499353), a non-randomized phase 2 study. The primary outcome is Percentage of Participants Achieving Pathological Complete Response (pCR) as Per Independent Central Review (ICR) in Evaluable Analysis Set as Per ICR With 80% Confidence Interval (CI).

2. Clinical Question

3. Trial Design

The registry identifies this as a Phase 2, multicenter, open-label, non-randomized, single-group study of talazoparib. Enrollment was 61. The listed condition was early breast cancer, and the study focused on participants with germline BRCA1/2 mutations and HER2-negative disease. Because there was one treatment group and no random allocation, the design does not provide a concurrent control group for estimating a treatment contrast.

The intervention was talazoparib, described in the arm as 1 mg once daily. The primary endpoint description states that talazoparib was given for 24 weeks before surgery. For participants with baseline moderate renal impairment, the stated starting dose was 0.75 mg/day. The primary response assessment was planned at surgery, with the timeframe described as a maximum of approximately 8 months after baseline and assessment within a maximum of 6 weeks of the last dose.

The registry lists the study start as 2018-08-27 and primary completion as 2020-09-23. Its status is TERMINATED. The reason for termination is not reported in the registry record, so the status alone does not explain why the study ended or whether termination affected the analyses.

Enrollment is not the same as the primary analysis population. The primary endpoint population required receipt of at least 80% of the prescribed dose and breast surgery. The registry record does not report the number of participants meeting those criteria or the number included in the primary endpoint analysis. It also does not report a sample-size justification or a detailed statistical analysis plan.

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: A total of 61 participants were enrolled and treated with talazoparib.

Treatment

Reasons for not completing this period:

Safety Follow-up

Long-Term Follow-up

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The analysis population included all participants enrolled who received at least 80% of the dose of talazoparib prescribed at treatment start (1 mg/day, with the exception of participants with baseline moderate renal impairment who received a starting dose of 0.75 mg/day) and underwent breast surgery and pCR assessment by ICR, as well as participants who progressed or died before pCR could be assessed by ICR (these participants were considered as non-responders).

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: Baseline analysis population included all participants who received any amount of talazoparib.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants Achieving Pathological Complete Response (pCR) as Per Independent Central Review (ICR) in Evaluable Analysis Set as Per ICR With 80% Confidence Interval (CI), measured over Date of surgery (maximum of approximately 8 months post-baseline) (assessed within a maximum of 6 weeks of last dose of talazoparib).

The primary endpoint was the percentage of participants in the evaluable analysis set who achieved pathological complete response (pCR), as assessed by independent central review. The registry defines pCR as no residual invasive cancer in the breast and axillary lymph nodes on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes after neoadjuvant systemic therapy. The stated staging definition is ypT0/Tis ypN0 in the current American Joint Committee on Cancer staging system.

A response endpoint assessed at surgery captures whether invasive cancer remains in the specified tissues after preoperative treatment. It is a binary outcome for each participant: pCR is either achieved or not achieved according to the stated definition. The overall percentage describes the frequency of that outcome in the analysis population; it does not measure the size of a response or establish what would have happened under a different treatment.

The endpoint was assessed after talazoparib treatment for 24 weeks followed by surgery. Its numerator is the number of evaluable participants meeting the pCR definition, and its denominator is the evaluable population described in the registry. The planned uncertainty measure was an 80% confidence interval calculated using Blaker’s method. The primary percentage and interval are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a binary response measure. Each participant in the defined evaluable population either met the pCR definition or did not. The reported percentage would be the proportion of that analysis population meeting the definition. A proportion summarizes the observed frequency in the analyzed group; it does not by itself indicate a causal effect, particularly in a single-arm study without a concurrent comparator.

What does the confidence interval describe?

In general, a confidence interval expresses uncertainty around an estimate. For a response proportion, its width depends on the observed proportion and the amount of information in the analysis population. A narrower interval indicates greater statistical precision under the method used; a wider interval indicates more uncertainty. An interval is not a guarantee that the true value lies within its endpoints, nor does it account for every possible source of bias or measurement error.

The primary endpoint specified an 80% confidence interval. The registry also lists secondary pCR outcomes with 80% and 95% confidence intervals for one intention-to-treat outcome. These interval levels are different conventions for expressing uncertainty; they do not change the underlying observed response count or definition. The primary interval was to use Blaker’s method, an exact method for binomial proportions. The registry record does not report the interval endpoints, so the precision of the primary estimate cannot be judged.

Why specify an analysis population?

The primary population was defined by receipt of at least 80% of the prescribed starting dose and undergoing breast surgery. This is an evaluable population rather than simply all enrolled participants. Restricting analysis to participants meeting post-enrollment criteria can make the endpoint population differ from the enrolled population. The number meeting the criteria and the number with an assessable pCR result are not reported in the registry record.

The registry also names intention-to-treat outcomes. In general, an intention-to-treat analysis aims to retain participants in their assigned group, regardless of treatment received, when group assignment exists. This trial was single-arm, and the registry record does not give the detailed operational rules used for its intention-to-treat outcome analyses. It is therefore important to distinguish the named populations rather than assume that the primary evaluable analysis included every enrolled participant.

What does the study design allow?

A single-arm study estimates outcomes in the treated group. Without randomized allocation to a comparator, the study cannot isolate a treatment effect from other explanations for the observed outcome. General factors such as participant selection, disease characteristics, other care, and the timing or completeness of outcome assessment can affect the response proportion. This does not make a single-arm estimate meaningless; it defines what that estimate can describe and what it cannot establish.

The primary endpoint was assessed by independent central review, while some secondary outcomes were assessed by the investigator. Central review and investigator assessment are distinct ascertainment approaches. Different reviewers may classify cases differently, so results tied to one reviewer type should be interpreted according to that definition. The registry record does not report a comparison of agreement between reviewers.

What can planning calculations say?

General sample-size calculations illustrate how many participants might be needed under specified assumptions to detect an effect at a chosen significance level and power. They are planning illustrations, not observed power and not evidence that an effect was found. The described illustrations use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect expressed as a stated fraction of the observed effect. For non-time-to-event outcomes, the figures are participants per arm; time-to-event calculations refer to total events.

Those assumptions do not describe the actual single-arm design, which has no two-arm allocation. The registry record does not report the trial’s own sample-size justification. The observed primary effect is also not reported, so no conclusion about the study’s planned or achieved ability to estimate pCR can be drawn from these registry entries. Any planning illustration should be read as a hypothetical design calculation, not as a description of participants observed in this study.

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("Talazoparib 1 mg QD")
n      <- c(48)
events <- c(22)
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  Talazoparib 1 mg QD  48  22  45.8  31.4  60.8  32.6  59.7  32.5  59.8

11. Multiplicity, Missing Data and Analysis Populations

The registry lists several related pCR outcomes: assessment by independent central review or by the investigator, analysis in evaluable or intention-to-treat populations, and response in the breast only. These outcomes differ in reviewer, population, or anatomical definition. They are not interchangeable estimates of one identical quantity, and selecting among them can affect how results are interpreted.

When many outcomes or analyses are considered, multiplicity is a general concern: the chance of highlighting an apparently notable finding can increase if many comparisons are examined. The registry record does not report a multiplicity adjustment, a hierarchy for secondary endpoints, or a statistical plan explaining how multiple outcomes would be interpreted. The record lists 60 outcome measures and 0 analyses, but does not provide their results or establish which were emphasized.

Missing-data handling is also not reported in the registry record. In general, missing endpoint assessments can affect a response proportion, depending on how many outcomes are unavailable and how those cases are handled. The primary analysis population required breast surgery and receipt of at least 80% of the prescribed dose, but the record does not state how participants without an assessable surgery result were treated in analyses. It also does not give the number excluded, the reasons for exclusion, or any imputation or sensitivity-analysis methods.

The evaluable primary population and the named intention-to-treat secondary population answer different analysis questions. The registry does not report the number included in either population or the analysis rules in sufficient detail to reconcile them. The primary pCR estimate and its interval are not reported in the registry record. The record also does not report interim analyses, stopping criteria, or a complete statistical analysis plan.

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: anaemia (14.8%), neutropenia (1.6%), intestinal obstruction (1.6%), influenza like illness (1.6%).

The registry safety summary lists 61 participants at risk for serious adverse events and 11 affected by at least one serious adverse event. For other adverse events, it lists 61 at risk and 60 affected. These are participant counts in the registry summary; they do not describe event duration, severity beyond the serious-event classification, or the number of separate events experienced by each participant. Deaths are listed as 2.

The most frequently listed serious adverse event terms are Anaemia at 14.8%, Neutropenia at 1.6%, Intestinal obstruction at 1.6%, and Influenza like illness at 1.6%. These registry percentages are safety summaries, not measures of comparative risk. The record does not state that the events were caused by talazoparib, and a single-arm study cannot provide a randomized comparison of safety outcomes against another treatment.

Terms may describe events experienced by the same participant, so listed categories should not be added together to infer a total number of affected people. The registry record does not report further details such as event timing, duration, resolution, or participant-level overlap. Safety figures should be read as descriptive counts and percentages for the listed treatment group, not as proof of causation or a treatment comparison.

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

The registry record describes a study designed to estimate the pCR percentage after neoadjuvant talazoparib in a defined population of participants with early HER2-negative breast cancer and germline BRCA1/2 mutations. It gives the endpoint definition, the planned assessment at surgery, and the method intended for its 80% confidence interval. However, the primary pCR result and its interval are not reported in the registry record. The central response finding therefore cannot be quantified or judged for precision from this record.

Even if a response percentage were available, the single-arm design would mean it described the observed outcome in the analyzed group rather than a randomized treatment contrast. Without a comparator, the result would not show what response frequency would have occurred under another treatment or without talazoparib. It would also not by itself separate treatment effects from participant selection, other care, or differences in outcome ascertainment.

The safety summary gives descriptive counts, percentages, and deaths for the treatment group. Those figures do not establish that treatment caused an event, and there is no randomized safety comparison in this design. The listed serious adverse event terms provide additional description, but the registry record does not report the timing or clinical course of those events.

The study status is TERMINATED, but the registry record does not report why. That status cannot be used alone to infer the reason for termination, the completeness of follow-up, or whether the results were affected. The record supports a careful account of the study’s question, design, endpoint, and listed safety figures. It does not support a conclusion about the primary response result because that result is not reported.

14. Why This Trial Matters Statistically

This study illustrates why an endpoint definition and an analysis population matter when interpreting a clinical response percentage. The pCR definition specifies which tissue findings count as a response, and the independent central review identifies who assessed it. The evaluable population adds criteria for treatment exposure and surgery. Each choice shapes the question answered by the resulting proportion.

It also illustrates the distinction between estimating an outcome and estimating a treatment effect. In a single-arm study, a response proportion can describe outcomes among participants receiving the intervention, but a comparator is needed for a direct randomized contrast. This distinction is especially important when considering results alongside studies that may enroll different participants or use different pCR definitions, reviewers, or analysis populations.

Uncertainty is part of the result, not an optional detail. The planned 80% confidence interval was intended to communicate statistical precision around the primary pCR estimate. Because neither the estimate nor its interval is reported in the registry record, the endpoint cannot be evaluated for precision. This makes the difference between a prespecified statistical method and an available statistical result especially clear.

The record also shows why safety counts require context. The number of participants with serious adverse events, other adverse events, and deaths is descriptive; without a comparison group it cannot establish a comparative safety profile or causation. Finally, the TERMINATED status and missing endpoint results underline the importance of transparent reporting of analysis populations, missing-data handling, and reasons for study completion or termination. Those details are not reported in the registry 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.

The main limitation for statistical interpretation is that the registry record does not report the primary pCR percentage, the 80% confidence interval, or the number analyzed. Although enrollment was 61, the primary population required receipt of at least 80% of the prescribed dose and breast surgery. The number satisfying those criteria is not reported, so enrollment cannot be used as the primary endpoint denominator.

The study was non-randomized and single-arm. It therefore does not provide a randomized control comparison, and any response or safety summary would be descriptive for the treated group. The record does not report an external comparator or a method for adjusting comparisons with other populations. The open-label design and the mix of central-review and investigator-assessed secondary outcomes also make the assessment source important when interpreting any outcome results.

The registry record does not report the reason for termination, the trial’s own sample-size justification, interim analyses, missing-data procedures, or a full statistical analysis plan. It does not report the number of participants with unavailable endpoint assessments or the handling of such cases. These omissions prevent assessment of how planned analyses relate to the final enrolled and analyzed populations.

The secondary outcome descriptions cover multiple reviewer types, populations, and pCR definitions, but results and multiplicity procedures are not reported. The available safety summary is limited to participant counts and selected serious adverse event terms; timing, duration, and participant-level overlap are not reported. These limitations restrict interpretation to the design and descriptive registry information rather than a full evaluation of efficacy or comparative safety.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Talazoparib For Neoadjuvant Treatment Of Germline BRCA1/2 Mutation Patients With Early Human Epidermal Growth Factor Receptor 2 Negative Breast Cancer — NCT03499353.
• Registry record last updated 2021-11-09; status last verified 2021-10.
• Results first posted 2021-11-09.
• 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

NCT03499353 is a Phase 2, multicenter, open-label, non-randomized, single-arm study of talazoparib for neoadjuvant treatment of early HER2-negative breast cancer in participants with germline BRCA1/2 mutations. Enrollment was 61. The study status is TERMINATED; the reason is not reported in the registry record.

The primary endpoint was the percentage achieving pCR by independent central review in an evaluable population, with an 80% confidence interval planned using Blaker’s method. The primary endpoint result, interval, and analysis denominator are not reported in the registry record. The safety summary lists 11 participants with serious adverse events among 61 at risk, 60 with other adverse events among 61 at risk, and 2 deaths. These are descriptive figures and do not establish causation or a comparative treatment effect.