Adjuvant olaparib extends DFS in high-risk BRCA1/2-mutated HER2-negative early breast cancer

Adjuvant olaparib for 1 year following local treatment and adjuvant/neoadjuvant chemotherapy improved disease-free survival (DFS) in patients with HER2-negative early breast cancer (EBC) with BRCA1 or BRCA2 pathogenic/likely pathogenic variants and high recurrence risk, according to interim results of the multinational, phase III OlympiA study.

“The OlympiA study results, the first reporting the effects of a PARP inhibitor as an adjuvant therapy on survival endpoints, suggest a possible addition to the standard of care for patients with germline BRCA1/2 mutation-associated EBC who have levels of recurrence risk requiring neoadjuvant or adjuvant chemotherapy,” said lead author Professor Andrew Tutt from the Institute of Cancer Research and King’s College London, UK, at ASCO 2021.

“One year of adjuvant olaparib can meaningfully reduce recurrence risk and prevent progression to metastatic disease among [these] patients,” said Tutt and co-authors.

Study participants were 1,836 patients with HER2-negative EBC with BRCA1/2 germline pathogenic/likely pathogenic variants and high-risk clinicopathological factors treated with local therapy and neoadjuvant/adjuvant chemotherapy. They were randomized 1:1 to receive oral olaparib (300 mg BID; median age 42 years) or placebo (median age 43 years) for 1 year.

About 82 percent of patients had triple-negative breast cancer, 72.3 percent had BRCA1 mutations, 27.2 percent BRCA2, and 0.4 percent both. There was an even split of neoadjuvant or adjuvant chemotherapy use, with 93.7 percent receiving an anthracycline- and taxane- containing regimen.

At a median follow-up of 2.5 years (after 284 events), invasive DFS was significantly improved in the olaparib vs placebo group (3-year invasive DFS: 85.9 percent vs 77.1 percent; hazard ratio [HR], 0.58, 99.5 percent confidence interval [CI], 0.41–0.82; p<0.001). [ASCO 2021, abstract LBA1; N Engl J Med 2021;doi:10.1056/NEJMoa2105215]

This benefit with olaparib vs placebo was consistent regardless of germline BRCA mutation, hormone-receptor status, or timing of prior chemotherapy, the authors noted. “[T]here was [also] no evidence that olaparib was less effective in patients treated with platinum-based adjuvant or neoadjuvant chemotherapy,” they said.

Distant DFS was also improved with olaparib vs placebo (3-year distant DFS: 87.5 percent vs 80.4 percent; HR, 0.57, 99.5 percent CI, 0.39–0.83; p<0.001).

Fewer deaths occurred in the olaparib than placebo group (n=59 vs 86), though the between-group difference was not significant at time of interim analysis (HR, 0.68; p=0.02 [interim-analysis boundary, p<0.01]). Breast cancer was the primary cause of death in both the olaparib and placebo groups.

Early treatment discontinuation, including due to recurrence, occurred in 25.9 and 20.7 percent of olaparib and placebo recipients, respectively.

Serious adverse event (AE) incidence was comparable between the olaparib and placebo arms (8.7 percent vs 8.4 percent). Three AEs led to death, one in the olaparib and two in the placebo group.

Common (>1 percent) grade ≥3 AEs among olaparib recipients were anaemia (8.7 percent), decreased neutrophil count (4.8 percent), decreased white-cell count (3.0 percent), fatigue (1.8 percent), and lymphopenia (1.2 percent). Blood transfusion was required in 5.8 and 0.9 percent of olaparib and placebo recipients, respectively.

Dose reductions were more common with olaparib than placebo (25.0 percent vs 5.2 percent), as were AE-related permanent discontinuations (9.9 percent vs 4.2 percent). The most common reasons for olaparib discontinuation were nausea (2.0 percent), anaemia (1.8 percent), fatigue (1.3 percent), and decreased neutrophil count (1.0 percent).

At time of analysis, AEs of special interest were not more frequent with olaparib than placebo (3.3 percent vs 5.1 percent). These included acute myeloid leukaemia or myelodysplastic syndrome (n=2 vs 3), pneumonitis (n=9 vs 11), and new primary cancer (n=19 vs 32).

“Toxicity was limited and manageable without effect on global patient-reported quality of life,” said Tutt.

The results showed that OlympiA participants were at significant risk of recurrence, despite standard therapies, he pointed out. One-year adjuvant treatment with olaparib following local and adjuvant/neoadjuvant chemotherapy improved both invasive and distant DFS, he added.

“[T]he trial [also] provides evidence that germline BRCA1 and BRCA2 sequencing is an important biomarker for the selection of systemic therapy in EBC,” said Tutt and co-authors.