Adjuvant Olaparib Significantly Improves OS in BRCA+, High-Risk Early Breast Cancer

At a median follow-up of 3.5 years, adjuvant olaparib (Lynparza) significantly improved overall survival (OS) vs placebo in patients with germline BRCA-mutated, HER2-negative, high-risk early breast cancer who received prior chemotherapy before or after surgery, according to data from the second planned interim analysis of the phase 3 OlympiA trial (NCT02032823).¹

The data, which were shared as part of the March 2022 ESMO Virtual Plenary, showed that the OS benefit derived with olaparib met the significance threshold in the overall population (stratified hazard ratio [HR], 0.68; 98.5% CI, 0.47-0.97; P = .009).

These findings compared favorably with what had been reported at a median follow-up of 2.5 years. At that time point, a numerical improvement in OS was observed with olaparib vs placebo, but the benefit was not determined to be of statistical significance (HR, 0.68; 99% CI, 0.44-1.05; P = .024). The P value needed for significance was 0.010. The 3-year OS rate difference was 3.8% (95% CI, 0.9%-6.6%) in favor of olaparib, and the 4-year difference was 3.4% (95% CI, -0.1 to 6.8).

“At a median follow-up of 3.5 years, effect sizes and absolute differences remain consistent with the previous primary analysis, with tightening 95% CIs across invasive disease-free survival [iDFS], distant disease-free survival [DDFS], and OS end points,” Andrew Tutt, MD, PhD, director of the Breast Cancer Now Research Unit at King’s College London, and honorary consultant clinical oncologist of the Breast Unit at Guy’s Hospital, GSTT, said in a presentation on the data. “Olaparib after local treatment and (neo)adjuvant chemotherapy significantly improves IDFS, DDFS, and OS with limited, manageable toxicity and without new safety signals.”

The multicenter, placebo-controlled trial enrolled patients with HER2-negative breast cancer harboring a germline BRCA mutation. Patients had to be at high risk for disease recurrence, have received treatment for stage II or III breast cancer, and have completed surgery and chemotherapy, with or without radiotherapy. Patients could not have previously received treatment with a PARP inhibitor.

A total of 1836 study participants were randomized 1:1 to receive either olaparib at a twice-daily dose of 300 mg (n = 921) or placebo twice daily (n = 915) for 1 year.

The primary end point of the trial was iDFS, and key secondary end points included DDFS, OS, health-related quality of life, and safety. Patients were stratified by whether they had hormone receptor–positive disease vs triple-negative disease, received neoadjuvant vs adjuvant treatment, or whether they received prior platinum-based chemotherapy or not.

Patients had an average of 42 years (range, 36-49) in the olaparib arm vs 43 years (range, 36-50) in the placebo arm. Additionally, 71.3% of those in the investigative arm and 73.2% of those in the control arm had tumors that harbored BRCA1 germline mutations; 28.3% and 26.1% of patients, respectively had BRCA2 mutations. The most performed primary breast cancer surgery was mastectomy, and this was done in 75.8% of those on the olaparib arm vs 73.6% of those on the placebo arm. Moreover, 81.5% of those on the investigative arm and 82.8% of those on the control arm had triple-negative disease.

At the time of the updated analysis, 14.5% of patients on the olaparib arm and 22.6% of those on the placebo arm had experienced their first iDFS event. Distant recurrence was observed in 9.6% of those on the investigative arm vs 14.9% of those on the control arm; regional recurrence was observed in 1.0% and 2.0% of patients, respectively; local (ipsilateral) recurrence occurred in 1.0% and 1.3% of patients, respectively; and contralateral invasive breast cancer was seen in 1.6% and 2.0% of patients, respectively.

Additionally, second primary non-breast malignancies were reported in 1.2% of those who received olaparib and 2.5% of those who were given placebo. In the investigative arm, 1 patient developed ovarian cancer, 1 patient developed fallopian tube cancer, and 9 patients had a malignancy that was not specified. Two patients in the olaparib arm died without an iDFS event vs no patients in the placebo arm.

Overall, 75 patients on the olaparib arm died vs 109 patients on the placebo arm. In the investigative arm the primary cause of death was disease recurrence for 93.3% of patients, an adverse effect (AE) for 2.7% of patients, or another reason not specified in 4.0% of patients. In the control arm, 94.5% died from breast cancer recurrence, 3.7% died from a toxicity, and 1.8% died from another unspecified reason.

“Treatment effect [with olaparib] was consistent, without evidence of significant heterogeneity, across major subgroups including the BRCA1, BRCA2, hormone receptor–positive, and triple-negative subsets,” Tutt, who is also head of the Division of Breast Cancer Research and director of Breast Cancer at Toby Robins Research Centre, Institute of Cancer Research, added.

Updated data showed that olaparib continued to improve iDFS over placebo in the intent-to-treat population (stratified HR, 0.63; 95% CI, 0.50-0.78); these data were consistent with what has previously been reported (HR, 0.58; 95% CI, 0.41-0.82). At 3 years, the iDFS rate difference was 8.8% (95% CI, 5.0%-12.6%) in favor of olaparib; this was also true at 4 years, where the rate difference was 7.3% (95% CI, 3.0%-11.5%).

Olaparib also continued to improve DDFS over placebo (stratified HR, 0.61; 95% CI, 0.48-0.77); the HR for DDFS at a median follow-up of 2.5 years had been 0.57 (99.5% CI, 0.39-0.83). With longer follow-up, the 3-year DDFS rate difference was 7.0% (95% CI, 3.5%-10.6%) in favor of olaparib, and the 4-year rate difference was 7.4% (95% CI, 3.6%-11.3%).

No changes in toxicity profile were observed since the prior analysis. Any-grade AEs were reported in 91.8% of those who received olaparib vs 83.8% of those who were given placebo; these effects were grade 3 or higher in 24.5% and 11.3% of patients, respectively. Grade 4 toxicities were experienced by 1.9% of those in the investigative arm vs 0.4% of those in the control arm. Serious AEs occurred in 8.7% and 8.6% of patients, respectively.

In the investigative arm, toxicities of special interest included myelodysplastic syndrome/acute myeloid leukemia (0.2%), pneumonitis (1.0%), and a new primary malignancy (2.3%).

Moreover, 10.8% of those in the investigative arm experienced a toxicity that resulted in treatment discontinuation vs 4.6% of those in the control arm. Notably, no additional toxicities leading to death were reported since the previous analysis.

Common toxicities experienced by 10% or more of patients who received olaparib included nausea (57%), fatigue (40%), anemia (24%), vomiting (23%), headache (20%), diarrhea (18%), neutropenia (16%), leukopenia (16%), decreased appetite (13%), dysgeusia (12%), dizziness (11%), and arthralgia (10%).

The most frequent grade 3 or higher toxicities were anemia (9%), neutropenia (5%), leukopenia (3%), and fatigue (2%).

In March 2022, the FDA approved olaparib for the adjuvant treatment of patients with germline BRCA-mutated, HER2-negative, high-risk early breast cancer who received prior chemotherapy either before or after surgery based on earlier data from OlympiA.²

References

1. 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.
2. 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 March 16, 2022. https://bit.ly/3tQePcn