Analysis of Olaparib Response in Patients With BRCA1 and/or 2 Promoter Methylation Diagnosed of Advanced Breast Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Analysis of Olaparib Response in Patients With BRCA1 and/or 2 Promoter Methylation Diagnosed of Advanced Breast Cancer (NCT03205761), a na phase 2 study. The primary outcome is Overall Response Rate (ORR).

2. Clinical Question

3. Trial Design

The registry identifies NCT03205761 as the COMETA-Breast Study, a phase II clinical trial sponsored by the Spanish Breast Cancer Research Group. It is described as multicenter, single-arm, and open-label, with no masking. The study enrolled 11 participants and is listed as completed. Its start date is 2017-10-23 and its primary completion date is 2022-12-15.

All participants in the study arm were assigned to receive olaparib; the registry does not describe a separate comparison arm. The intended population was narrowly defined: patients with advanced triple-negative breast cancer and BRCA1 and/or BRCA2 promoter methylation assessed in DNA from metastatic lesions, without BRCA1 and BRCA2 germline mutations. The arm description further refers to positive methylation status in at least one gene and the absence of known deleterious or suspected deleterious mutations in both genes.

The primary outcome was overall response rate, assessed through study treatment, with an average timeframe of 8 weeks stated in the registry. Secondary outcomes listed include clinical benefit rate, response duration, progression-free survival, overall survival, adverse events related to study treatment, and correlations between methylation status for each gene and efficacy outcomes. Although these outcomes are named, their numerical results are not reported in the registry record. The registry record also does not report a detailed protocol for treatment duration, assessment scheduling beyond the primary outcome wording, or the rationale for the enrollment target.

Because the design has one treatment group, outcomes can be described for the enrolled participants, but there is no internal control group against which to distinguish treatment-associated change from other explanations. The registry record does not report random allocation or a masking procedure; masking is listed as none and allocation as not applicable.

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:

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.

6. Primary Endpoint

The registry lists the primary outcome as Overall Response Rate (ORR), measured over Through study treatment, and average of 8 weeks.

Overall response rate (ORR) is the primary endpoint. The registry defines it as the percentage of patients in the efficacy population who have a complete response or a partial response. Under the stated RECIST 1.1 definitions, complete response means disappearance of all target lesions, while partial response means a >=30% decrease in the sum of the longest diameters of target lesions. Tumor response was to be assessed using Response Evaluation Criteria In Solid Tumors Criteria, version 1.1.

As a general statistical concept, a response-rate endpoint reduces a set of tumor assessments to a binary classification: each person is counted as having or not having a qualifying response. It is useful for summarizing the proportion meeting a defined response threshold, but it does not by itself describe how long a response lasts or what happens after treatment. Those are distinct questions, reflected in the listed secondary outcomes for response duration, progression-free survival, and overall survival.

The registry defines the efficacy population as a subset of the intention-to-treat population: participants who received at least one dose and had at least one tumor response assessment, unless progression, death, or unacceptable toxicity occurred before the first assessment. The primary result itself—the response count and efficacy-population denominator—is not reported in the registry record, so the ORR cannot be interpreted from the posted primary outcome entry.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is a binary response outcome. Each participant in the defined efficacy population is classified according to whether their tumor assessment met the registry’s complete-response or partial-response criteria. The ORR is the proportion classified as having either response. This is the endpoint definition in the record; the observed count and proportion are not reported in the registry record.

What does the response definition capture?

RECIST 1.1 provides standardized criteria for classifying changes in target lesions. In this record, complete response is defined as disappearance of all target lesions, and partial response as a >=30% decrease in the sum of the longest diameters of target lesions. These thresholds turn tumor measurements into categories that can be summarized across participants. As a general statistical point, a categorical endpoint is easier to summarize than a collection of lesion measurements, but it can conceal variation within each category. It also does not indicate how durable a response was; the registry lists response duration separately as a secondary outcome.

Who is included in the endpoint denominator?

The registry describes an efficacy population that is a subset of the intention-to-treat population. To enter the efficacy population, a participant must have received at least one dose and completed at least one tumor response assessment, unless progression, death, or unacceptable toxicity occurred before the first assessment. This exception is part of the stated definition. The record does not report the size of either population or how many participants met each condition, so the actual ORR denominator cannot be reconstructed from the registry entry.

As a general statistical concept, a proportion is most interpretable when its numerator and denominator are both clear. A response count without the population used to calculate the rate, or a rate without the count and denominator, offers less information about the amount of data behind the estimate. Confidence intervals are commonly used to describe uncertainty around a proportion. A confidence interval gives a range of values compatible with the data under the stated method; it does not remove design limitations or turn a single-group result into a comparison. No ORR confidence interval is reported in the registry record.

What does the single-group design mean for analysis?

The study has one olaparib group and no concurrent control group. General statistical interpretation of this design focuses on describing observed outcomes in the participants studied. It cannot estimate a treatment-versus-control contrast within the trial. In a randomized comparison, allocation helps create groups suitable for estimating such a contrast; this study is not described as randomized and does not include a like-for-like control arm. The record does not report an alternative comparative analysis.

The sample-size assumptions associated with the page are planning illustrations rather than the trial’s own design justification. They use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect stated as a fraction of the observed effect. For time-to-event outcomes, the stated illustrations concern total events; for other outcomes, they concern participants per arm. These are not descriptions of the single-group design, and they must not be read as observed power. The registry record does not report the trial’s sample-size justification or protocol assumptions. The posted primary response result is also absent, so no observed response effect can be read from this record.

Why can outcome structure affect the analysis?

ORR is a count-based binary outcome, whereas progression-free survival, response duration, and overall survival are time-to-event outcomes. General methods for time-to-event data account for both the timing of an event and participants whose event time is not observed during follow-up. The registry lists these outcomes but does not report their results, analysis methods, follow-up details, or censoring rules. Those details cannot be inferred from the endpoint names alone.

Likewise, the registry lists clinical benefit rate and gene-specific correlations as secondary outcomes, but does not state the analytic procedures or numerical findings for them in the posted entry. The registry shows no analysis entries. It does not report a statistical analysis plan, a prespecified model for the binary outcome, adjustments for covariates, or a method for handling multiple secondary comparisons. Any such choices would affect how estimates and uncertainty should be interpreted, so they should not be assumed.

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("Olaparib")
n      <- c(11)
events <- c(1)
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  Olaparib  11  1  9.1  0.2  41.3  1.6  37.7  2.1  38.5

11. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary outcome and several secondary outcomes: clinical benefit rate, response duration, progression-free survival, overall survival, adverse events related to study treatment, and correlations of BRCA1 and BRCA2 methylation status with efficacy outcomes. The record does not report a multiplicity strategy, such as whether secondary outcomes were treated as exploratory, whether any adjustment was planned, or how the primary endpoint would be protected from the effects of multiple testing. The registry also shows no analysis entries, and a statistical analysis plan is not reported in the registry record.

As a general statistical concept, testing or estimating many outcomes can make isolated findings harder to interpret. A prespecified hierarchy or adjustment can help clarify which results are confirmatory and which are exploratory. Without a reported plan, readers cannot determine how the investigators intended to address that issue. This is especially relevant to the listed gene-specific correlations, which involve more than one methylation measure and efficacy outcomes.

The efficacy-population definition is described, including the exception for progression, death, or unacceptable toxicity before the first tumor response assessment. However, the registry does not report the actual sizes of the intention-to-treat and efficacy populations, missing assessment counts, reasons for missing data, or a missing-data method. It also does not report how a participant without an evaluable response assessment was handled in the primary analysis beyond the stated population definition. Consequently, the impact of incomplete assessments on the posted response estimate cannot be assessed, and the response result itself is not reported in the registry record.

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: progression disease (36.4%).

The adverse-event listing identifies 11 participants at risk in the Olaparib group. It lists 4 participants with serious adverse events and 8 participants with other adverse events, and records 8 deaths. These are participant counts, not a basis for assuming the number of distinct events. The categories may overlap, and the registry entry does not explain their overlap or the timing of events.

The most frequent serious term shown is “Progression Disease,” listed as 36.4%. The registry record does not give the denominator or additional context for that percentage in the displayed listing, so it should be quoted as reported rather than used to infer a count. The listed safety outcome also refers to adverse events related to study treatment, but the entry does not supply event-by-event descriptions or a detailed account of attribution.

As a general statistical point, counts describe how many participants were recorded in a category, while fuller safety interpretation also depends on definitions, observation time, severity, timing, and relatedness assessment. The registry figures should therefore be read as a compact description of recorded events, not as a complete safety profile or a comparison with another group. The record does not provide a concurrent control group.

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

This record describes a phase II, multicenter, single-arm study of olaparib in a selected population with advanced triple-negative breast cancer and BRCA1 and/or BRCA2 promoter methylation. It states that 11 participants enrolled, identifies overall response rate as the primary endpoint, and gives the RECIST 1.1 criteria used to define complete and partial responses. These details explain what the trial was designed to assess.

What the record does not show is the primary response result. The number of responders, efficacy-population denominator, ORR estimate, and uncertainty interval are not reported in the registry record. Accordingly, this page cannot establish how often response occurred in the study group or how precisely that proportion was estimated. The existence of a defined endpoint is not itself evidence of a particular result.

Even if an outcome estimate were available, the single-group design would describe outcomes among participants receiving olaparib without a concurrent control comparison. As a general statistical principle, observed outcomes in one group do not by themselves isolate the effect of treatment from other influences. Nor would a response-rate result answer the separate questions of response duration, progression-free survival, overall survival, or safety. Those outcomes are separately listed, but their numerical results are not reported in the registry entry.

The study’s eligibility description also defines the scope of its question. The record concerns participants with specified disease and molecular features, not all people with advanced breast cancer. The registry does not provide enough outcome information to assess the response measure, and the trial design does not supply a randomized comparison. The responsible interpretation is therefore limited to the study’s design and stated measurement framework, rather than a conclusion about treatment benefit or lack of benefit.

14. Why This Trial Matters Statistically

This trial illustrates why a registry description and a result are not interchangeable. The record gives a clear primary endpoint label, a response definition, and an efficacy-population rule. Those features are necessary for understanding what an ORR would mean. But without the numerator, denominator, estimate, and uncertainty, readers cannot evaluate the observed response data. Statistical interpretation depends not only on the choice of endpoint, but also on the actual result and the population from which it was calculated.

The study also highlights the distinction between a single-group estimate and a comparative effect. A response proportion in one arm can describe the experience of that group. It does not, on its own, quantify how outcomes compare with another treatment. The registry identifies no concurrent control arm, so a comparative claim cannot be based on this design as described.

The narrowly specified population is another statistical consideration. The trial question concerns advanced triple-negative breast cancer with BRCA1 and/or BRCA2 promoter methylation assessed in metastatic-lesion DNA and specified germline mutation status. The eligibility criteria define the target population for the study; they also limit how broadly a result could be generalized. Because the primary outcome is not reported, the record cannot show whether the endpoint yielded a precise or imprecise estimate even within that population.

Finally, the listed secondary outcomes span response, time-to-event outcomes, safety, and methylation correlations. These outcomes address different questions and may require different analysis methods. The record does not report those methods or results, nor does it describe a multiplicity plan. This makes the trial a useful example of how design, endpoint definitions, analysis reporting, and result availability all contribute to a sound statistical reading.

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 of the posted record for interpreting efficacy is that the primary response result is not reported. The record supplies neither the response count nor the efficacy-population denominator, and no ORR estimate or confidence interval is shown. The listed endpoint definition alone cannot establish the observed response rate.

The study enrolled 11 participants and used a single-group design. There is no concurrent control group in the registry description, so the study cannot provide a randomized within-trial comparison. The small enrolled group also means that any estimate, if available, would need to be interpreted in light of its precision; the record does not provide an interval with which to judge that precision.

Several details needed for a fuller statistical assessment are not reported in the registry record. These include the sample-size justification, a detailed statistical analysis plan, missing-data procedures, the number of participants in the efficacy population, and the approach to the multiple listed secondary outcomes. The registry does not report the analysis methods or numerical results for the secondary outcomes listed, including time-to-event outcomes and gene-specific correlations.

The primary outcome timeframe is described as “Through study treatment, and average of 8 weeks,” but the record does not provide further detail that would resolve how assessments were scheduled across participants. The safety listing gives counts and a serious-event term, but does not provide event timing, overlap, or further attribution detail. These gaps restrict what can be concluded from the registry entry and should not be filled by assumptions about the protocol or analyses.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Analysis of Olaparib Response in Patients With BRCA1 and/or 2 Promoter Methylation Diagnosed of Advanced Breast Cancer — NCT03205761.
• Registry record last updated 2024-10-18; status last verified 2024-08.
• Results first posted 2024-05-01.
• 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.

19. Record Summary

NCT03205761, the COMETA-Breast Study, is listed as a completed, multicenter phase II single-arm trial sponsored by the Spanish Breast Cancer Research Group. It enrolled 11 participants with advanced triple-negative breast cancer selected for BRCA1 and/or BRCA2 promoter methylation and specified germline mutation status. Participants received olaparib.

The primary endpoint was overall response rate under RECIST 1.1, defined by complete or partial response in the stated efficacy population. The registry record describes the endpoint and population but does not report the response count, denominator, estimate, or confidence interval. Secondary outcomes are listed, but their numerical results and analysis methods are not reported in the registry entry. The record therefore documents the trial’s design and measurement framework without providing the primary result needed to assess observed response.