Adjuvant Olaparib for Patients with BRCA1– or BRCA2-Mutated Breast Cancer

BACKGROUND
Poly(adenosine diphosphate–ribose) polymerase inhibitors target cancers with defects in homologous recombination repair by synthetic lethality. New therapies are needed to reduce recurrence in patients with BRCA1 or BRCA2 germline mutation–associated early breast cancer.

METHODS
We conducted a phase 3, double-blind, randomized trial involving patients with human epidermal growth factor receptor 2 (HER2)–negative early breast cancer with BRCA1 or BRCA2 germline pathogenic or likely pathogenic variants and high-risk clinicopathological factors who had received local treatment and neoadjuvant or adjuvant chemotherapy. Patients were randomly assigned (in a 1:1 ratio) to 1 year of oral olaparib or placebo. The primary end point was invasive disease–free survival.

RESULTS
A total of 1836 patients underwent randomization. At a prespecified event-driven interim analysis with a median follow-up of 2.5 years, the 3-year invasive disease–free survival was 85.9% in the olaparib group and 77.1% in the placebo group (difference, 8.8 percentage points; 95% confidence interval [CI], 4.5 to 13.0; hazard ratio for invasive disease or death, 0.58; 99.5% CI, 0.41 to 0.82; P<0.001). The 3-year distant disease–free survival was 87.5% in the olaparib group and 80.4% in the placebo group (difference, 7.1 percentage points; 95% CI, 3.0 to 11.1; hazard ratio for distant disease or death, 0.57; 99.5% CI, 0.39 to 0.83; P<0.001). Olaparib was associated with fewer deaths than placebo (59 and 86, respectively) (hazard ratio, 0.68; 99% CI, 0.44 to 1.05; P=0.02); however, the between-group difference was not significant at an interim-analysis boundary of a P value of less than 0.01. Safety data were consistent with known side effects of olaparib, with no excess serious adverse events or adverse events of special interest.

CONCLUSIONS
Among patients with high-risk, HER2-negative early breast cancer and germline BRCA1 or BRCA2 pathogenic or likely pathogenic variants, adjuvant olaparib after completion of local treatment and neoadjuvant or adjuvant chemotherapy was associated with significantly longer survival free of invasive or distant disease than was placebo. Olaparib had limited effects on global patient-reported quality of life. (Funded by the National Cancer Institute and AstraZeneca; OlympiA ClinicalTrials.gov number, NCT02032823. opens in new tab.)

Andrew N.J. Tutt, M.B., Ch.B., Ph.D., Judy E. Garber, M.D., M.P.H., Bella Kaufman, M.D., Giuseppe Viale, M.D., Debora Fumagalli, M.D., Ph.D., Priya Rastogi, M.D., Richard D. Gelber, Ph.D., Evandro de Azambuja, M.D., Ph.D., Anitra Fielding, M.B., Ch.B., Judith Balmaña, M.D., Ph.D., Susan M. Domchek, M.D., Karen A. Gelmon, M.D., et al., for the OlympiA Clinical Trial Steering Committee and Investigators

This article was published on June 3, 2021, at NEJM.org.22

Breast Cancer

Duration of Adjuvant Aromatase-Inhibitor Therapy in Postmenopausal Breast Cancer

BACKGROUND
For postmenopausal women with hormone-receptor–positive breast cancer, the most effective duration for adjuvant therapy with an aromatase inhibitor remains unclear.

METHODS
In this prospective, phase 3 trial, we randomly assigned postmenopausal women with hormone-receptor–positive breast cancer who had received 5 years of adjuvant endocrine therapy to receive the aromatase inhibitor anastrozole for an additional 2 years (2-year group, receiving a total of 7 years) or an additional 5 years (5-year group, receiving a total of 10 years). The primary end point was disease-free survival. The primary analysis included all the patients who were still participating in the trial and who had no recurrence 2 years after randomization (i.e., when treatment in the 2-year group had ended). Secondary end points were overall survival, contralateral breast cancer, second primary cancer, and clinical bone fracture.

RESULTS
Among the 3484 women who were enrolled in the trial, 3208 remained in the trial without disease progression after the first 2 years of extended anastrozole treatment following randomization. Among these women, disease progression or death occurred in 335 women in each treatment group in the primary-analysis set at 8 years (hazard ratio, 0.99; 95% confidence interval [CI], 0.85 to 1.15; P=0.90). No between-group differences occurred in most secondary end points, and subgroup analyses did not indicate differences in any particular subgroup. The risk of clinical bone fracture was higher in the 5-year group than in the 2-year group (hazard ratio, 1.35; 95% CI, 1.00 to 1.84).

CONCLUSIONS
In postmenopausal women with hormone-receptor–positive breast cancer who had received 5 years of adjuvant endocrine therapy, extending hormone therapy by 5 years provided no benefit over a 2-year extension but was associated with a greater risk of bone fracture. (Funded by AstraZeneca and the Austrian Breast and Colorectal Cancer Study Group; ABCSG-16/SALSA ClinicalTrials.gov number, NCT00295620. opens in new tab.)

Michael Gnant, M.D., Florian Fitzal, M.D., Gabriel Rinnerthaler, M.D., Guenther G. Steger, M.D., Sigrun Greil-Ressler, M.D., Marija Balic, M.D., Dietmar Heck, M.D., Raimund Jakesz, M.D., Josef Thaler, M.D., Daniel Egle, M.D., Diether Manfreda, M.D., Vesna Bjelic-Radisic, M.D., et al., for the Austrian Breast and Colorectal Cancer Study Group

This article was updated on July 29, 2021, at NEJM.org.

Breast Cancer

21-Gene Assay to Inform Chemotherapy Benefit in Node-Positive Breast Cancer

BACKGROUND
The recurrence score based on the 21-gene breast-cancer assay has been clinically useful in predicting a chemotherapy benefit in hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative, axillary lymph-node–negative breast cancer. In women with positive lymph-node disease, the role of the recurrence score with respect to predicting a benefit of adjuvant chemotherapy is unclear.

METHODS
In a prospective trial, we randomly assigned women with hormone-receptor–positive, HER2-negative breast cancer, one to three positive axillary lymph nodes, and a recurrence score of 25 or lower (scores range from 0 to 100, with higher scores indicating a worse prognosis) to endocrine therapy only or to chemotherapy plus endocrine (chemoendocrine) therapy. The primary objective was to determine the effect of chemotherapy on invasive disease–free survival and whether the effect was influenced by the recurrence score. Secondary end points included distant relapse–free survival.

RESULTS
A total of 5083 women (33.2% premenopausal and 66.8% postmenopausal) underwent randomization, and 5018 participated in the trial. At the prespecified third interim analysis, the chemotherapy benefit with respect to increasing invasive disease–free survival differed according to menopausal status (P=0.008 for the comparison of chemotherapy benefit in premenopausal and postmenopausal participants), and separate prespecified analyses were conducted. Among postmenopausal women, invasive disease–free survival at 5 years was 91.9% in the endocrine-only group and 91.3% in the chemoendocrine group, with no chemotherapy benefit (hazard ratio for invasive disease recurrence, new primary cancer [breast cancer or another type], or death, 1.02; 95% confidence interval [CI], 0.82 to 1.26; P=0.89). Among premenopausal women, invasive disease–free survival at 5 years was 89.0% with endocrine-only therapy and 93.9% with chemoendocrine therapy (hazard ratio, 0.60; 95% CI, 0.43 to 0.83; P=0.002), with a similar increase in distant relapse–free survival (hazard ratio, 0.58; 95% CI, 0.39 to 0.87; P=0.009). The relative chemotherapy benefit did not increase as the recurrence score increased.

CONCLUSIONS
Among premenopausal women with one to three positive lymph nodes and a recurrence score of 25 or lower, those who received chemoendocrine therapy had longer invasive disease–free survival and distant relapse–free survival than those who received endocrine-only therapy, whereas postmenopausal women with similar characteristics did not benefit from adjuvant chemotherapy. (Funded by the National Cancer Institute and others; RxPONDER ClinicalTrials.gov number, NCT01272037. opens in new tab.)

Kevin Kalinsky, M.D., William E. Barlow, Ph.D., Julie R. Gralow, M.D., Funda Meric-Bernstam, M.D., Kathy S. Albain, M.D., Daniel F. Hayes, M.D., Nancy U. Lin, M.D., Edith A. Perez, M.D., Lori J. Goldstein, M.D., Stephen K.L. Chia, M.D., Sukhbinder Dhesy-Thind, M.D., Priya Rastogi, M.D., et al.

This article was published on December 1, 2021, at NEJM.org.

Breast Cancer