Adjuvant Olaparib Continues to Improve iDFS in BRCA1/2+, HER2- Breast Cancer

Adjuvant Olaparib (Lynparza) continued to show the clinically meaningful efficacy, compared with placebo, in patients with BRCA1/2 mutation–positive, HER2-negative high-risk breast cancer, according to findings from the third pre-specified analysis of the phase 3 OlympiA trial (NCT02032823), presented at the 2024 San Antonio Breast Cancer Symposium.¹

Adjuvant olaparib continued to show a strong efficacy benefit in patients with BRCA1/2 mutation–positive, HER2-negative high-risk breast.

The analysis occurred at a median follow-up of 6.1 years (max, 9.6 years) and 2.6 years since the previous analysis. The updated data for all first invasive disease-free survival (iDFS) events—the primary end point of the trial—demonstrated that distant (11.5% vs 16.3%), regional (1.2% vs 2.4%), and local recurrences (1.2% vs 1.3%) all continued to be less frequent in the olaparib arm vs the placebo arm. This translated to a 9.4% (95% CI, 5.1%-12.7%) absolute difference in the 6-year iDFS rate favoring olaparib vs placebo, with a hazard ratio of 0.65 (95% CI, 0.53-0.78).

The iDFS benefit was consistent across all prespecified patient subgroups, including hormone receptor–positive patients (HR, 0.68) and triple-negative patients (HR, 0.65). “At this updated analysis, the magnitude of the benefit remains similar with more than 30% reduction in both groups,” said Judy Garber, MD, who is the Susan F. Smith Chair and chief of the Division of Cancer Genetics and Prevention at Dana-Farber Cancer Institute and a Professor of Medicine at Harvard Medical School.

The absolute difference in the 6-year distant disease-free survival (DDFS) rate also favored olaparib at 7.8% (95% CI, 3.8%-11.5%), with an HR of 0.65 (95% CI, 0.53-0.81). The DDFS benefit was consistent across all subgroups.

At the time of the updated analysis, there had been 107 (11.6%) deaths in the olaparib arm and 143 (15.6%) deaths in the placebo arm. The primary cause of death in both arms was breast cancer recurrence (10.2%, olaparib arm; 14.0%, placebo arm). The absolute difference in the 6-year overall survival (OS) rate was 4.4% (95% CI, 0.9%-6.7%) favoring olaparib with an HR of 0.72 (95% CI, 0.56-0.93). As with iDFS and DDFS, the OS benefit was consistent across all subgroups.

“These data continue to support adjuvant olaparib as standard of care for patients with BRCA+ high-risk HER2-negative primary breast cancer and therefore highlight the importance of germline BRCA testing for treatment planning,” said Garber.

The safety population included 911 patients in the olaparib arm and 904 patients in the placebo arm. Adverse events (AEs) of special interest continued to be higher in the placebo arm. AEs of special interest occurring at any time were reported in 6.3% of the olaparib arm vs 9.3% in the placebo arm. There were fewer second primary malignancies in the olaparib group at 4.9% vs 7.5%. “Of note, with further follow-up the incidence of MDS/AML events, in particular, remains low with 4 in the olaparib arm and 6 in the placebo arm,” said Garber.

OlympiA Trial Design and Patient Characteristics

The multicenter OlympiA trial enrolled 1836 patients with HER2-negative breast cancer harboring a germline BRCA1/2 mutation. Patients were randomized 1:1 to receive 300 mg of oral olaparib twice daily for 1 year (n = 921) or placebo (n = 915). Additionally, patients had to have been treated for stage II or III breast cancer, and have completed surgery and chemotherapy, with or without radiotherapy. Inclusion criteria also required that patients have a high risk of disease recurrence. Prior treatment with a PARP inhibitor was not allowed.

Patient characteristics were well balanced between the study arms, with a median age of about 43 years. About 70% of patients in each cohort had a BRCA1 mutation, with about 30% having a BRCA2 mutation. Around 60% of patients in each arm were premenopausal and nearly 75% had received mastectomy. Approximately 80% of patients in each arm were triple-negative. About half of the patients in each cohort received adjuvant chemotherapy and about half received neoadjuvant chemotherapy. About 90% of the hormone receptor­–positive patients in the study groups received concurrent endocrine therapy.

Significant benefits for IDFS and DDFS with olaparib had been previously demonstrated in the first interim analysis of the OlympiA trial,² as well as a significant OS benefit in the second analysis.³

Based on the initial data from the OlympiA trial, the FDA previously approved olaparib for the adjuvant treatment of patients with germline BRCA-mutated, HER2-negative, high-risk early breast cancer who have previously received chemotherapy either before or after surgery.⁴

In her concluding remarks, Garber noted that blinded follow-up for the final planned analysis of the OlympiA trial is continuing until June 2029.

References

1. Garber, J. OlympiA- Phase 3, multicenter, randomized, placebo-controlled trial of adjuvant olaparib after (neo)adjuvant chemotherapy in patients w/ germline BRCA1/BRCA2 pathogenic variants & high risk HER2-negative primary breast cancer; longer term follow.-up Presented at: San Antonio Breast Cancer Conference; December 10-13, 2024; San Antonio, TX. GS1-09
2. Tutt ANJ, Garber JE, Kaufman B, et al. Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer. N Engl J Med. 2021;384(25):2394-2405. doi:10.1056/NEJMoa2105215
3. Tutt ANJ, Garber J, Gelber RD, et al. Pre-specified event driven analysis of overall survival (OS) in the OlympiA phase III trial of adjuvant olaparib (ol) in germline BRCA1/2 mutation (gBRCAm) associated breast cancer. Presented at: March 2022 ESMO Virtual Plenary; March 16-18, 2022; virtual. Accessed March 16, 2022.
4. Lynparza approved in the US as adjuvant treatment for patients with germline BRCA-mutated HER2-negative high-risk early breast cancer. AstraZeneca. News release. March 11, 2022. Accessed December 11, 2024. https://bit.ly/3tQePcn