Significantly prolonged invasive disease-free survival with adjuvant olaparib in HER-2 negative high-risk early breast cancer with BRCA1/2 mutations

Results of the phase III OlympiA trial, evaluating 1 year of adjuvant olaparib in patients with high risk, HER2-negative early breast cancer harbouring a germline BRCA mutation who received prior (neo)adjuvant chemotherapy, indicate that this treatment strategy results in a significant improvement in the invasive and distant disease free survival compared to placebo. Moreover, the olaparib treatment was well-tolerated and did not have an effect on the quality of life of patients.

The PARP inhibitor olaparib (OL) is currently licensed in an advanced or metastatic setting of various BRCA1/2-associated cancers, including HER2-negative breast cancer (BC) with a germline BRCA mutation (gBRCAm). For patients with stage II/III BRCA1/2-associated BC, however, (neo)adjuvant chemotherapy ([N]ACT) is currently the standard of care, a treatment that is associated with a substantial risk of recurrence. To improve on this, the  phase III OlympiA trial investigates the potential of adjuvant olaparib in this setting.

Study design

In OlympiA, a total of 1,836 HER2-negative early BC patients, who were either hormone receptor-positive (HR+) or triple negative (TNBC), were randomised (1:1) to receive either oral OL (300mg twice daily) or placebo (PL) continuously for 1 year. Different staging criteria were used, according to receptor subtype, in order to design a cohort with a similar recurrence risk. Patients who had received prior NACT were required to have a non-pathological complete response (non-pCR) if they had TNBC, or a non-pCR and a CPS+EG score of ≥3 if they were HR+. Patients who had received ACT were required to have ≥pT2 or ≥pN1 TNBC, or HR+ disease with ≥4 positive lymph nodes. Endocrine therapy and bisphosphonates were allowed, per local protocol. The primary endpoint of this study was invasive disease free survival (IDFS), with secondary end points of distant disease free survival (DDFS), overall survival (OS), quality of life (QoL) and safety.  

Adjuvant olaparib improves the invasive and distant disease-free survival

Baseline demographics and tumour characteristics were well balanced between arms. The most common stage of disease was IIA (OL: 57.3%, PL: 54.9%). Approximately half of the patients (49.9%) received ACT, while the other half (50.1%) received NACT. Approximately 82.2% had TNBC and about 70% of patients harboured a mutation in BRCA1 (OL: 71.3%, PL: 73.2%;  BRCA2 mutations: OL: 28.3%, PL: 26.1%). Furthermore, 75.8% and 73.6% of patients in the olaparib and placebo groups, respectively, had received prior mastectomy.

At 36 months, the IDFS in the intention-to-treat (ITT) population was reported at 85.9% and 77.1% with OL and PL, respectively (HR[95%-CI]: 0.58[0.41-0.82], p<0.0001). All IDFS events were lower in the OL arm, with 106 and 178 events occurring in each arm respectively. The majority of these events were distant recurrences (7.8% vs. 13.1%). At a longer follow-up of 3.5 years, IDFS results supported the findings observed in the ITT population, with a 3-year IDFS difference of 8.6% between OL and PL, with distinct and early curve separation (HR[99.5%-CI]: 0.61[0.39-0.95]). Similar results were obtained in terms of DDFS at 36 months (87.5% vs. 80.4%) (HR[99.5%-CI]: 0.57[0.39-0.83], p<0.0001). Although OL did extend OS numerically compared to PL, this difference was not statistically significant (92.0% vs. 88.3%) (HR[99%-CI]: 0.68[0.44-1.05], p=0.024).

Occurring in ≥10% of patients, the most common adverse events (AEs) with OL were nausea (57%), fatigue (40%) and anaemia (23%), although the majority of cases were grade 1 or 2. The most common grade ≥3 AEs with OL were fatigue (2%), anaemia (9%), neutropenia (5%) and leukopenia (3%). AEs leading to treatment discontinuation occurred in 9.9% and 4.2% of OL and PL patients, respectively. Serious AEs were comparable between both arms (OL: 8.7%, PL: 8.4%) and AEs of special interest occurred less in patients who received OL (3.3% vs. 5.1%). Assessed by EORTC QLQ-C30, OL also did not negatively impact QoL in patients who received NACT or ACT.

Conclusion

When treated with OL for 1 year, high risk HER2-negative early breast cancer patients with a germline BRCA mutation, who had received prior (N)ACT had significantly improved IDFS and DDFS rates. Although fewer deaths were reported with OL, the OS benefit obtained with OL was not significant. Furthermore, toxicity was limited and manageable, with no negative impact to global QoL observed in patients who received OL.

Reference

Tutt A et al., OlympiA: A phase III, multicenter, randomized, placebo-controlled trial of adjuvant olaparib after (neo)adjuvant chemotherapy in patients with germline BRCA1/2 mutations and high risk HER2-negative early breast cancer. Presented at ASCO 2021; Abstract LBA1.