Javelin BRCA/ATM: Avelumab Plus Talazoparib in Patients With BRCA or ATM Mutant Solid Tumors: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Javelin BRCA/ATM: Avelumab Plus Talazoparib in Patients With BRCA or ATM Mutant Solid Tumors (NCT03565991), a na phase 2 study. The primary outcome is Percentage of Participants With Confirmed Objective Response (OR) as Assessed by Blinded Independent Central Review (BICR).

2. Clinical Question

3. Trial Design

This was a Phase 2 study of avelumab plus talazoparib in locally advanced or metastatic solid tumors with a BRCA or ATM defect. The registry lists a single-group model, no masking, and an open-label combination arm. It does not describe a randomized control group. Cohort assignment distinguished participants with a BRCA 1/2 defect from those with an ATM defect.

The registry enrollment is 202. The study start date is 2018-06-18, and the primary completion date is 2022-03-28. 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 that decision was related to efficacy, safety, recruitment, or another consideration.

The primary endpoint was the percentage of participants with confirmed objective response, assessed by blinded independent central review. The registry describes the analysis population as enrolled participants who received at least 1 dose of study treatment, classified according to the cohort assigned at enrollment. The primary endpoint timeframe extended from the first dose until documented disease progression or death, whichever came first, with assessment up to approximately 24 months.

Secondary outcomes included treatment-emergent adverse events, changes in hematology and chemistry laboratory results, drug concentrations for both treatments, and avelumab anti-drug antibody categories. The record lists 25 outcome measures, but does not report the individual response results in the registry record for this account. It also lists no analysis records. Details such as the reason for termination, planned sample-size justification, and a full statistical analysis plan 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.

Before assignment: A total of 270 participants were screened for this study, 202 participants were enrolled and assigned to study treatment but 2 participants never started the treatment. In total 200 participants were treated (159 in Cohort 1 and 41 in Cohort 2).

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The analysis set included all enrolled participants who received at least 1 dose of study treatment. Participants were classified according to the cohort assigned at enrollment.

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 enrolled participants who received at least 1 dose of study treatment.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Confirmed Objective Response (OR) as Assessed by Blinded Independent Central Review (BICR), measured over From the first dose of study treatment until the date of first documented disease progression or date of death from any cause, whichever came first, assessed up to approximately 24 months.

The primary endpoint is the percentage of participants with a confirmed objective response, assessed by blinded independent central review. It summarizes the proportion of the defined analysis population who met response criteria, rather than measuring how long response lasted or how long participants lived without progression. The response estimate and its 95% confidence interval are not reported in the registry record.

For solid tumors other than metastatic castration-resistant prostate cancer, response required a complete response or partial response under RECIST version 1.1. A response had to be confirmed by repeat assessment no less than 4 weeks after the criteria were first met. A complete response meant disappearance of target and non-target lesions, with an exception for nodal disease. A partial response required at least 30% decrease from baseline in the sum of diameters of target measurable lesions. Non-target lesions could not show progressive disease.

For metastatic castration-resistant prostate cancer, the endpoint used the best overall soft-tissue response of complete or partial response under RECIST version 1.1, together with no confirmed bone disease progression under PCWG3 criteria. These rules specify how the registry classified response across the tumor types included. Independent central review can provide a consistent assessment process, while confirmation reduces reliance on a single assessment. These are general reasons for using such endpoint procedures; the registry does not report a rationale specific to this study.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The endpoint is a percentage, meaning that the clinical quantity of interest is the share of the defined analysis population classified as having confirmed objective response. In general, a proportion is estimated by counting participants who meet the endpoint definition and relating that count to an eligible denominator. The registry describes the analysis set as enrolled participants who received at least 1 dose and says they were classified by cohort assigned at enrollment. It does not report the response count or the endpoint denominator, so no response proportion can be interpreted from the registry entries.

What does the confidence interval convey?

The primary endpoint specifies a 95% confidence interval. In general, a confidence interval communicates the uncertainty around an estimated quantity under the method used to construct it. A narrower interval indicates greater precision than a wider interval, while the estimate itself describes the observed response proportion. The interval does not give the probability that a particular treatment effect is true, and it does not remove limitations arising from study design or missing data. Neither the interval limits nor the underlying estimate are reported in the registry record.

The study has a single-group design. In general, that design can estimate outcomes observed among participants receiving the study regimen, but without a concurrent randomized control group it cannot isolate the regimen's effect from other explanations for those outcomes. The registry lists allocation as not applicable and masking as none. It also specifies blinded independent central review for the primary endpoint. These refer to different aspects of the study: treatment masking is listed as absent, whereas the endpoint assessment is described as centrally reviewed and blinded. The registry does not give additional operational details about that review.

Why does confirmation matter?

For solid tumors other than metastatic castration-resistant prostate cancer, a response had to be confirmed by repeat assessment no less than 4 weeks after the response criteria were first met. Generally, confirmation helps distinguish a sustained classification from a one-time measurement that may not persist on reassessment. The endpoint used RECIST version 1.1 definitions: complete response involved disappearance of target and non-target lesions except nodal disease, while partial response required at least 30% decrease from baseline in the sum of target lesion diameters. Non-target lesions had to be non-progressive. For metastatic castration-resistant prostate cancer, the endpoint combined best overall soft-tissue complete or partial response with no confirmed bone disease progression under PCWG3 criteria.

These definitions make the endpoint dependent on imaging and assessment rules, not simply on a clinician's general impression of improvement. A blinded independent central review is a structured way to assess response separately from open-label treatment delivery. In general, independent review may reduce the influence of expectations on outcome classification, but the registry entries do not establish how much any such influence affected this study.

What can be concluded without a comparator?

A response proportion in a single-group study describes the observed outcome in the treated analysis set. General statistical reasoning does not permit that proportion alone to establish what would have happened to the same participants under a different treatment. A randomized comparison can help estimate a relative treatment effect by creating comparable groups, but no such comparison is described. The BRCA 1/2 defect and ATM defect cohorts represent different mutation categories, not randomized control conditions in the registry description.

Precision and causal interpretation are separate issues. A confidence interval can quantify sampling uncertainty around a single-group proportion, but even a precise estimate would not resolve the absence of a concurrent control. Conversely, the lack of a reported estimate means that even the precision of this endpoint cannot be assessed from the registry record. The enrollment listing of 202 is not, on its own, a response denominator or an indication of endpoint completeness.

What statistical details remain unavailable?

The registry entries specify a 95% confidence interval for the primary endpoint but do not report its construction method, response estimate, interval limits, missing-assessment rules, or analysis records. They also do not report whether any interim analyses were performed, how the study's sample size was justified, or what statistical decision thresholds were planned. Those details are not reported in the registry record and should not be inferred from the Phase 2 designation or the study's termination status.

In general, missing outcome assessments can affect a proportion if participants without an assessment are handled differently from those with known outcomes. A complete interpretation therefore depends on the denominator, the number of missing or unevaluable assessments, and the analysis rule for those participants. None of those response-specific details is available in the registry entries. The stated analysis-set definition identifies who could be included, but does not establish how many actually entered that set or how every participant's response status was determined.

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("Cohort 1 (BRCA 1/2 Defect)", "Cohort 2 (ATM Defect)")
n      <- c(159, 41)
events <- c(44, 3)
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  Cohort 1 (BRCA 1/2 Defect)  159  44  27.7  20.9  35.3  21.3  35.1  21.3  35.1
ARM  Cohort 2 (ATM Defect)  41  3  7.3  1.5  19.9  2.5  19.4  2.7  19.5

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 25 outcome measures, including the primary response endpoint, safety outcomes, laboratory changes, pharmacokinetic measures, and anti-drug antibody categories. Testing or estimating many outcomes can raise a multiplicity issue: in general, the chance of at least one apparently notable result can increase when many hypotheses are examined. A statistical plan may specify which endpoint is primary, how secondary analyses are interpreted, and whether any adjustment is used. Such details, including any multiplicity strategy, are not reported in the registry record.

The primary analysis population is described as enrolled participants who received at least 1 dose, classified according to the cohort assigned at enrollment. The registry enrollment is 202, but the number meeting the analysis-set definition and the response denominator are not reported in the registry entries. The record does not give the response counts or explain how participants with missing, incomplete, or unevaluable response assessments were handled. Those missing-data rules are not reported in the registry record.

In general, missing outcome data can change a proportion's interpretation when the chance of missingness is related to prognosis or treatment experience. Sensitivity analyses can explore whether conclusions depend on assumptions about unobserved outcomes. Whether such analyses were planned or conducted is not reported in the registry record. The registry entries also do not describe an intention-to-treat analysis, per-protocol analysis, or other analysis population beyond the stated primary analysis-set definition.

The record lists no analysis records. It does not report interim analyses, stopping rules, or statistical monitoring arrangements. Their absence from the registry entries should be read as unavailable information, not proof that a particular procedure was or was not used.

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: disease progression (5.0%), anaemia (4.9%), alanine aminotransferase increased (4.9%), aspartate aminotransferase increased (4.9%), pneumonia (2.5%).

The registry reports adverse-event counts separately for the BRCA 1/2 defect and ATM defect cohorts. For Cohort 1, it lists 159 participants at risk for serious adverse events and 50 affected; for Cohort 2, it lists 41 at risk and 7 affected. For other adverse events, the corresponding figures are 159 at risk and 153 affected in Cohort 1, and 41 at risk and 40 affected in Cohort 2. The registry also lists 15 deaths in Cohort 1 and 3 in Cohort 2.

These are descriptive safety counts, not a randomized comparison. The cohort sizes and participant characteristics may differ, and the registry does not identify the cohorts as control groups. The counts do not establish that an event or death was caused by the study treatment. The relationship of the listed deaths to treatment is not reported in the registry record.

The registry's listed serious-event terms include disease progression at 5.0%, anaemia at 4.9%, alanine aminotransferase increased at 4.9%, aspartate aminotransferase increased at 4.9%, pneumonia at 2.5%, and neutropenia at 2.4%. The denominator and cohort-specific breakdown for these term percentages are not reported in the registry entries. Event categories may overlap, so their percentages should not be added. The listed terms do not replace a complete clinical assessment of severity, timing, or causality.

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

The study asked whether confirmed objective responses occurred among participants receiving avelumab plus talazoparib for locally advanced or metastatic solid tumors with a BRCA or ATM defect. The registry specifies how response was defined and assessed, including central review and confirmation for most solid tumors. However, the response estimate and 95% confidence interval are not reported in the registry record. The central efficacy result therefore cannot be characterized numerically from these registry entries.

Even if a response proportion were available, the single-group design would describe outcomes among treated participants rather than provide a randomized estimate of comparative benefit. There was no control arm in the registry description. The BRCA 1/2 defect and ATM defect cohorts are mutation-defined groups, not treatment and control groups. Differences between them could not be attributed to a treatment contrast without further design and analysis information.

The registry's adverse-event figures describe reported participant counts in the two cohorts and include a list of serious-event terms with percentages. They do not, by themselves, establish that the combination caused an event or death. Context about event timing, duration, severity, attribution, and participant-level overlap is not fully reported in the registry record. The serious-event counts should therefore be understood as registry safety summaries, not standalone causal evidence.

The terminated status is a study-record status, not an efficacy conclusion. The reason for termination is not reported in the registry record. It is not possible to infer from that status alone whether results were favorable, unfavorable, inconclusive, or affected by operational considerations. Nor does the Phase 2 label reveal a sample-size rationale or decision rule; those details are not reported.

Overall, the record describes the study question, design, response criteria, and selected safety counts, but it does not report the primary response result or enough analysis detail to assess its precision. Statistical interpretation should remain limited to those documented details.

14. Why This Trial Matters Statistically

This study illustrates an important distinction between defining an endpoint and reporting its result. The registry gives detailed criteria for confirmed objective response, including RECIST version 1.1 and PCWG3 elements, and specifies a 95% confidence interval. Yet the response estimate and interval are not reported in the registry entries. A clearly defined endpoint cannot substitute for the numerical result needed to assess the observed response proportion and its precision.

It also highlights the limits of a single-group design. A single-group study can characterize outcomes among treated participants, but it does not supply a randomized control comparison. The mutation-defined cohorts may be clinically and statistically useful for organizing outcomes, but they are not a substitute for an assigned control group. This matters when readers distinguish description from causal comparison.

The open-label treatment design and blinded independent central review also demonstrate that masking can differ across study activities. The registry lists no masking while describing blinded review for the primary endpoint. Careful interpretation should retain both details rather than treating the endpoint review as proof that participants or treating staff were masked.

Finally, the record lists multiple outcomes and adverse-event summaries but no analysis records. Without endpoint results, response denominators, missing-data handling, and a reported statistical plan, the scope for evaluating precision, multiplicity, and robustness is limited. These are not technical details separate from interpretation: they determine what conclusions the available data can support.

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 most consequential limitation for interpreting efficacy is that the primary response estimate and its 95% confidence interval are not reported in the registry record. The response count, response denominator, and number of participants with unevaluable assessments are also not reported. As a result, neither the observed response frequency nor its precision can be described from the registry entries.

The single-group, open-label design has no randomized comparator. It therefore cannot provide a direct treatment-versus-control contrast. Blinded independent central review is specified for the primary endpoint, but the record does not report further details of review procedures or how disagreements and missing assessments were addressed.

The registry status is terminated, but the reason is not reported. The record does not supply a statistical analysis plan, sample-size justification, interim-analysis information, multiplicity approach, or missing-data methods. It lists 25 outcome measures and no analysis records, which limits assessment of how planned analyses relate to reported outcomes.

Safety interpretation is also constrained. Although cohort-level adverse-event counts and selected serious-event term percentages are reported, the registry entries do not provide the denominator for those term percentages, the event-term cohort breakdown, or the treatment attribution of deaths. The listed categories should not be treated as mutually exclusive or causal. These limitations are specific to the details available in the registry record; they do not establish that additional analyses or documentation do not exist elsewhere.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Javelin BRCA/ATM: Avelumab Plus Talazoparib in Patients With BRCA or ATM Mutant Solid Tumors — NCT03565991.
• Registry record last updated 2023-09-25; status last verified 2023-08.
• Results first posted 2023-08-07.
• 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

NCT03565991 is a Phase 2, single-group, open-label study of avelumab plus talazoparib in locally advanced or metastatic solid tumors with BRCA or ATM defects. The registry lists enrollment as 202, a study start date of 2018-06-18, a primary completion date of 2022-03-28, and a terminated status.

The primary endpoint was the percentage of participants with confirmed objective response by blinded independent central review. The record defines response criteria but does not report the response estimate or confidence interval. It lists safety, laboratory, pharmacokinetic, and immunogenicity outcomes, along with selected cohort-specific adverse-event counts. The reason for termination, detailed statistical plan, response denominator, and missing-data handling are not reported in the registry record.