Patients

Eligible patients were at least 18 years of age and had HER2-negative metastatic breast cancer that was hormone-receptor positive (i.e., estrogen-receptor positive, progesterone-receptor positive, or both) or was triple negative. Patients had a confirmed deleterious or suspected deleterious germline BRCA mutation; the mutation was detected by central testing with BRACAnalysis (Myriad Genetics) in 297 patients and by local testing in 167 patients (with confirmation by central testing with BRACAnalysis in all but 5 of those patients). Patients had received no more than two previous chemotherapy regimens for metastatic disease, and they had received neoadjuvant or adjuvant treatment or treatment for metastatic disease with an anthracycline (unless it was contraindicated) and a taxane. Patients with hormone-receptor–positive breast cancer had received at least one endocrine therapy (adjuvant therapy or therapy for metastatic disease) and had had disease progression during therapy, unless they had disease for which endocrine therapy was considered to be inappropriate. Previous neoadjuvant or adjuvant treatment with platinum was allowed if at least 12 months had elapsed since the last dose. Previous treatment with platinum for metastatic disease was allowed if there was no evidence that disease progression had occurred during treatment. Patients had normal baseline organ and bone marrow function, and they had measurable disease, which was defined as the presence of at least one lesion that was suitable for baseline and subsequent assessments for disease progression according to modified Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Complete eligibility criteria are provided in the trial protocol, which is available with the full text of this article at NEJM.org. The protocol was approved by ethics review committees at the participating institutions. All the patients provided written informed consent.

Trial Design and Treatments

The OlympiAD trial was a randomized, controlled, open-label, multicenter, international, phase 3 trial. Randomization was stratified according to previous use of chemotherapy for metastatic disease (yes vs. no), hormone-receptor status (hormone-receptor positive vs. triple negative), and previous use of platinum-based therapy (yes vs. no); this information was obtained locally at the time of trial registration with the use of an interactive voice or Web response system. All other clinical data and disease characteristics were collected at baseline with the use of a case-report form.

Patients were randomly assigned, in a 2:1 ratio, to receive olaparib tablets (300 mg twice daily) or standard therapy with one of the following three prespecified chemotherapy regimens: capecitabine administered orally at a dose of 2500 mg per square meter of body-surface area daily (divided into two doses) for 14 days, repeated every 21 days; eribulin mesylate administered intravenously at a dose of 1.4 mg per square meter on day 1 and day 8, repeated every 21 days; or vinorelbine administered intravenously at a dose of 30 mg per square meter on day 1 and day 8, repeated every 21 days. The assigned treatment was continued until disease progression or unacceptable toxic effects occurred. After disease progression occurred, treatment was at the discretion of the investigator. Crossover to olaparib was not permitted in this trial.

End Points and Assessments

The primary end point was progression-free survival, which was defined as the time from randomization to objective radiologic disease progression (according to modified RECIST, version 1.1) or death from any cause. The primary analysis was based on blinded independent central review, which was performed by two main reviewers, with adjudication by a third reviewer in cases in which the two main reviewers disagreed. A prespecified sensitivity analysis was based on investigator assessment. At the time of data cutoff for the primary end point (after at least 230 events had occurred), additional data were collected for the following prespecified secondary end points: safety outcomes, overall survival, time from randomization to a second progression event or death after a first progression event (based on investigator assessment), objective response rate (based on blinded independent central review, according to modified RECIST, version 1.1), and scores for health-related quality of life.

Computed tomography or magnetic resonance imaging was performed every 6 weeks until week 24 and then every 12 weeks thereafter. Overall survival and the time to a second progression event or death after a first progression event were assessed every 8 weeks after the first progression event. Adverse events were graded with the use of the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Health-related quality of life was assessed with the use of the 30-item European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30), which was completed by the patient at baseline and then every 6 weeks until disease progression. Scores on the QLQ-C30 range from 0 to 100, with higher scores indicating better quality of life; an increase or decrease of at least 10 points was considered to be a clinically meaningful change.14

Trial Oversight

This trial was performed in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines, and the AstraZeneca policy on bioethics. The trial was designed in collaboration between the principal investigator and AstraZeneca. AstraZeneca was responsible for overseeing the collection, analysis, and interpretation of the data. An external independent data and safety monitoring committee performed two interim reviews of the safety data. The manuscript was written with medical-writing support, which was funded by AstraZeneca, with critical review and input from the authors. The authors had access to the data and made the decision to submit the manuscript for publication. The authors vouch for the accuracy and completeness of the data and analyses and for the fidelity of the trial to the protocol.

Statistical Analysis

We determined that a total of 230 progression-free survival events would give the trial 90% power (at a two-sided significance level of 5%) to show a statistically significant difference in progression-free survival between the olaparib group and the standard-therapy group, with a corresponding hazard ratio for disease progression or death of 0.635. Efficacy data were analyzed on an intention-to-treat basis, and safety was assessed in all patients who received at least one dose of the assigned treatment. The primary analysis of progression-free survival was based on blinded independent central review and was performed with the use of a stratified log-rank test. The Kaplan–Meier method was used to generate time-to-event curves, from which medians were calculated. For the primary end point, a log-rank test (stratified according to hormone-receptor status and previous use of chemotherapy) was used to compare the Kaplan–Meier curves in the two treatment groups, and the P value derived from this comparison was reported. Hazard ratios and confidence intervals were estimated from the log-rank test statistics. Progression-free survival event rates at 12 months were calculated with the use of Kaplan–Meier curves.

Exploratory sensitivity analyses were conducted. The first analysis excluded patients who did not receive the assigned treatment; the second, stratifying analyses were performed with the use of values abstracted from electronic case-report forms for randomization factors. If statistical significance was shown for progression-free survival, time to a second progression event or death after a first progression event was then compared between groups with the use of a stratified log-rank test and a hierarchical multiple-testing strategy. If statistical significance was shown for time to a second progression event or death after a first progression event, overall survival was then compared between groups with the use of a stratified log-rank test. The mean change from baseline in QLQ-C30 score across all time points was analyzed with the use of a mixed model for repeated measures. Kaplan–Meier curves were used to compare time to a clinically meaningful decrease in QLQ-C30 score between the two treatment groups, and the P value derived from this comparison was reported.