Olaparib is an oral poly(adenosine diphosphate–ribose) polymerase inhibitor that has promising antitumor activity in patients with metastatic breast cancer and a germline BRCA mutation. We conducted a randomized, open-label, phase 3 trial in which olaparib monotherapy was compared with standard therapy in patients with a germline BRCA mutation and human epidermal growth factor receptor type 2 (HER2)–negative metastatic breast cancer who had received no more than two previous chemotherapy regimens for metastatic disease. Patients were randomly assigned, in a 2:1 ratio, to receive olaparib tablets (300 mg twice daily) or standard therapy with single-agent chemotherapy of the physician’s choice (capecitabine, eribulin, or vinorelbine in 21-day cycles). The primary end point was progression-free survival, which was assessed by blinded independent central review and was analyzed on an intention-to-treat basis. Of the 302 patients who underwent randomization, 205 were assigned to receive olaparib and 97 were assigned to receive standard therapy. Median progression-free survival was significantly longer in the olaparib group than in the standard-therapy group (7.0 months vs. 4.2 months; hazard ratio for disease progression or death, 0.58; 95% confidence interval, 0.43 to 0.80; P<0.001). The response rate was 59.9% in the olaparib group and 28.8% in the standard-therapy group. The rate of grade 3 or higher adverse events was 36.6% in the olaparib group and 50.5% in the standard-therapy group, and the rate of treatment discontinuation due to toxic effects was 4.9% and 7.7%, respectively. Among patients with HER2-negative metastatic breast cancer and a germline BRCA mutation, olaparib monotherapy provided a significant benefit over standard therapy; median progression-free survival was 2.8 months longer and the risk of disease progression or death was 42% lower with olaparib monotherapy than with standard therapy. (Funded by AstraZeneca; OlympiAD ClinicalTrials.gov number, NCT02000622.)

In 2012, the estimated age-adjusted annual incidence of breast cancer in 40 European countries was 94.2/100 000 and the mortality 23.1/100 000 [1]. The incidence increased after the introduction of mammography screening, and continues to grow with the ageing of the population. The most important risk factors include: genetic predisposition, exposure to oestrogens (endogenous and exogenous), ionising radiation, low parity and a history of atypical hyperplasia. The Western-style diet, obesity and the consumption of alcohol also contribute to the rising incidence of breast cancer [2]. There is a steep age gradient, with about a quarter of breast cancers occurring before age 50, and <5% before age 35. The estimated 5-year prevalence of breast cancer in Europe in 2012 was 1 814 572 cases [1]. Prevalence is increasing, as a consequence of increased incidence and due to improvements in treatment outcomes. In most Western countries, the mortality rate has decreased in recent years, especially in younger age groups, because of improved treatment and earlier detection [3, 4]. However, breast cancer is still the leading cause of cancer-related deaths in European women.

Advanced Breast Cancer (ABC) comprises both locally advanced breast cancer (LABC) and metastatic breast cancer (MBC) [1]. Although treatable, MBC remains virtually an incurable disease with a median overall survival (OS) of ∼3 years and a 5-year survival of only ∼25% [2, 3]. The MBC Decade Report [2] shows that progress has been slow in terms of improved outcomes, quality of life (QoL), awareness and information regarding ABC. More recently, some studies seem to indicate an improvement in OS, mostly due to advances in human epidermal growth factor receptor 2 (HER2)-positive ABC [4–6]. The better survival is seen in an environment with access to the best available care and particularly in de novo ABC, while recurrent ABC seems to become harder to manage [7, 8].

In the OlympiAD study, olaparib was shown to improve progression-free survival compared with chemotherapy treatment of physician’s choice (TPC) in patients with a germline BRCA1 and/or BRCA2 mutation (BRCAm) and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (mBC). We now report the planned final overall survival (OS) results, and describe the most common adverse events (AEs) to better understand olaparib tolerability in this population. OlympiAD, a Phase III, randomized, controlled, open-label study (NCT02000622), enrolled patients with a germline BRCAm and HER2-negative mBC who had received ≤2 lines of chemotherapy for mBC. Patients were randomized to olaparib tablets (300 mg bid) or predeclared TPC (capecitabine, vinorelbine, or eribulin). OS and safety were secondary end points. A total of 205 patients were randomized to olaparib and 97 to TPC. At 64% data maturity, median OS was 19.3 months with olaparib versus 17.1 months with TPC (HR 0.90, 95% CI 0.66–1.23; P = 0.513); median follow-up was 25.3 and 26.3 months, respectively. HR for OS with olaparib versus TPC in prespecified subgroups were: prior chemotherapy for mBC [no (first-line setting): 0.51, 95% CI 0.29–0.90; yes (second/third-line): 1.13, 0.79–1.64]; receptor status (triple negative: 0.93, 0.62–1.43; hormone receptor positive: 0.86, 0.55–1.36); prior platinum (yes: 0.83, 0.49–1.45; no: 0.91, 0.64–1.33). Adverse events during olaparib treatment were generally low grade and manageable by supportive treatment or dose modification. There was a low rate of treatment discontinuation (4.9%), and the risk of developing anemia did not increase with extended olaparib exposure. While there was no statistically significant improvement in OS with olaparib compared to TPC, there was the possibility of meaningful OS benefit among patients who had not received chemotherapy for metastatic disease. Olaparib was generally well-tolerated, with no evidence of cumulative toxicity during extended exposure. Please see the article online for additional video content.

In 2008, the estimated age-adjusted annual incidence of breast cancer in Europe (40 countries) was 88.4/100 000 and the mortality 24.3/100 000. The incidence increased after the introduction of mammography screening and continues to do so with the aging of the population. The most important risk factors include genetic predisposition, exposure to estrogens (endogenous and exogenous) and ionising radiation, low parity and history of atypical hyperplasia. The Western-style diet, obesity and consumption of alcohol also contribute to the rising incidence of breast cancer [2]. There is a steep age gradient, with about a quarter of breast cancers occurring before age 50, and <5% before age 35. The estimated prevalence of breast cancer in Europe in 2010 was 3 763 070 cases [3] and is increasing, both as a consequence of increased incidence and of improvements in treatment outcomes. In most Western countries, the mortality rate has decreased in recent years, especially in younger age groups because of improved treatment and earlier detection [4]. However, breast cancer is still the leading cause of cancer-related deaths in European women.