Adjuvant olaparib significantly extends DFS in early breast cancer subtype
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One year of adjuvant olaparib significantly extended invasive and distant DFS among patients with high-risk, HER2-negative early-stage breast cancer and germline BRCA1/BRCA2 mutations, according to results of the phase 3 OlympiA study.
The findings, scheduled for presentation during the plenary session of the virtual ASCO Annual Meeting and simultaneously published in The New England Journal of Medicine, also showed acceptable toxicity and may change the standard of care in this setting, according to researchers.
“These results suggest olaparib [Lynparza, AstraZeneca] for 1 year after standard-of-care therapies provides meaningful benefit to germline BRCA1/BRCA2 mutation carriers with high recurrence-risk, early HER2-negative breast cancer,” Andrew Tutt, MB ChB, PhD, FMedSci, head of the division of breast cancer research and director of Breast Cancer Now Toby Robins Research Centre at Institute of Cancer Research in London and Breast Cancer Now Research Unit at Guy’s Hospital King’s College London, said during a press conference.
Five percent of all breast cancers are associated with a germline BRCA1 or BRCA2 mutation.
Olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, targets DNA repair defects in cancers with BRCA mutations and is approved for BRCA-mutated HER2-negative breast cancer that has metastasized.
“Breast and other cancers that develop in patients with germline pathologic variants of BRCA1 or BRCA2 have substantial deficiencies in homologous recombination DNA repair, which makes them very dependent on alternative repair pathways that require activity of PARP,” study author Charles E. Geyer Jr., MD, FACP, Lois E. and Carl A. Davis centennial chair in cancer research and deputy director of the Houston Methodist Cancer Center, told Healio. “Although standard therapies improve outcomes in patients with high-risk early breast cancers that develop in patients with a BRCA pathologic variant, there remained an unacceptable level of risk for recurrence and death even with these aggressive therapies. The OlympiA investigators believed the vulnerability of these cancers to PARP inhibition provided an opportunity to further improve their outcomes and address their unmet medical need.”
Thus, Tutt, Geyer and colleagues sought to evaluate the impact of 1 year of adjuvant olaparib in the early breast cancer setting.
The randomized, double-blind, phase 3 OlympiA study included 1,836 patients with germline BRCA-mutated, HER2-negative, stage II to stage III breast cancer who underwent surgery and standard neoadjuvant (50.1%) or adjuvant (49.9%) chemotherapy with or without radiotherapy; 26.5% had received a platinum agent.
All patients were deemed at high risk for cancer recurrence. Among the 82.2% of patients who had triple-negative disease, all had high-risk disease as defined by pT2 or greater or pN1 or greater disease prior to adjuvant chemotherapy, or lack of pathologic complete response after neoadjuvant chemotherapy. The remaining patients with hormone receptor-positive breast cancer had four or more positive nodes prior to adjuvant chemotherapy or failed to achieve complete response and had a CPS+EG score of 3 or greater after neoadjuvant chemotherapy.
Researchers randomly assigned patients 1:1 to receive 1 year of continuous treatment with 300 mg oral olaparib twice daily (n = 921; median age, 42 years; range, 36-49) or placebo (n = 915; median age, 43 years; range, 36-50).
Invasive DFS — which included local or metastatic recurrence, other new cancers and death of any cause — in the intent-to-treat population served as the study’s primary endpoint. Secondary endpoints included distant DFS, OS and safety.
The study protocol called for an interim analysis after 165 invasive DFS events among the first 900 patients, with superiority boundaries established as P < .005 for invasive and distant DFS and P < .01 for OS.
Results of that analysis, conducted after 2.5 years of median follow-up, showed olaparib significantly extended invasive DFS compared with placebo (HR = 0.58; 99.5% CI, 0.41-0.82), with 3-year invasive DFS rates of 85.9% vs. 77.1% (difference, 8.8 percentage points; 95% CI, 4.5-13).
“Most patients completed the planned year of therapy, and global quality of life did not differ between the group receiving olaparib and the group receiving placebo,” Geyer said. “Reductions in risk of this magnitude obtained with an oral and nonchemotherapy medication with a manageable side effect profile are very meaningful for patients.”
Researchers also observed a significant benefit with olaparib in terms of distant DFS (3-year, 87.5% vs. 80.4%; difference, 7.1 percentage points; 95% CI, 3-11.1; HR = 0.57; 99.5% CI, 0.39-0.83). These data indicated patients who received adjuvant olaparib had a 43% reduction in risk for metastatic breast cancer, new cancer and death of any cause.
The interim analysis showed a trend toward an OS benefit with olaparib, but this did not reach statistical significance as the data were not yet mature (HR = 0.68; 99% CI, 0.44-1.05). Rates of 3-year OS were 92% with olaparib and 88.3% with placebo (difference, 3.7 percentage points; 95% CI, 0.3-7.1).
Tutt noted that the safety profile of olaparib appeared consistent with previous reports.
Grade 3 or greater adverse events that occurred among 1% or more of patients assigned olaparib included anemia (8.7%), neutropenia (4.8%), leukopenia (3%), fatigue (1.8%) and lymphocytopenia (1.2%).
Researchers observed comparable incidence between olaparib- and placebo-treated patients of serious adverse events (8.7% vs. 8.4%) and adverse events of special interest, which included myelodysplastic syndrome/acute myeloid leukemia, new primary malignancy and pneumonitis (2.6% vs. 4.6%).
“The OlympiA study is the first to report the benefits of a PARP inhibitor as an adjuvant treatment for early forms of germline BRCA1/BRCA2 mutation-associated cancer,” Tutt said. “Patients who received olaparib after surgery and chemotherapy were more likely to be alive without cancer and avoid metastasis than the patients who received placebo.
“Germline testing for BRCA1/BRCA2 mutations provides important information that can influence systemic therapy in early breast cancer,” he added.
Researchers plan to continue following patients to better understand the magnitude of the recurrence risk reduction over time, and to understand the impact of the therapy on long-term OS, Geyer told Healio.
“We also will carefully monitor for possible late side effects of the therapy and the potential of the therapy to reduce risk for new cancers, which represent an important problem for cancer survivors with BRCA pathologic variants,” he added. “Studies to understand why some patients still develop cancer recurrence after receipt of olaparib also will be important.”
References:
- Tutt ANJ, et al. Abstract LBA1. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
- Tutt ANJ, et, al. N Engl J Med. 2021;doi:10.1056/NEJMoa2105215.
Perspective
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These findings are tremendously exciting. We have known for some time that PARP inhibitors — which are biologic or targeted agents specifically for patients with BRCA mutations — have activity in patients with metastatic breast cancer, but this is the first time we have seen efficacy in the early-stage setting. This study showed a substantial reduction in the risk for recurrence in this population and, therefore, the potential to cure more patients with BRCA-associated early breast cancer.
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Lori J. Pierce, MD, FASTRO, FASCO
These results are so important, because about 5% of all breast cancers are associated with a BRCA1/BRCA2 mutation and some of these cancers are indeed aggressive. This study demonstrates a significant reduction in invasive recurrences thanks to 1 year of oral olaparib, and a significant reduction in distant disease. This further highlights the importance of genetic testing in appropriate patients so that we know which will benefit from this therapy. It may even open the door to additional trials of adjuvant PARP inhibition for other BRCA1/BRCA2-associated cancers.
Michigan Medicine
Perspective
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This trial is practice changing. Olaparib already is approved for use in metastatic BRCA1/BRCA2-mutated breast cancer. If fast-tracked for FDA approval, olaparib will become the new standard of care in the adjuvant setting for germline BRCA1/BRCA2 mutation carriers who are HER2-negative and who receive adjuvant or neoadjuvant chemotherapy as part of their treatment for early-stage disease.
One of the next possible steps is to test olaparib for women with germline BRCA mutations in the prevention setting. Finally, it behooves us to expand our genetic testing so that every appropriate woman — and man — receives genetic testing.
Icahn School of Medicine at Mount Sinai
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Tutt A, et al. Abstract LBA1. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
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