N Engl J Med 2021 Jun 03
Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer
Abstract
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.).
Related Questions
In early-stage ER‑positive, HER2‑negative breast cancer with germline BRCA1 mutation and high genomic risk, how should the choice between neoadjuvant and adjuvant chemotherapy be approached?
I typically do not use the BRCA1 mutation as the determining factor for a neo-adjuvant or adjuvant chemotherapy approach in patients with hormone receptor-positive, HER2-negative non-metastatic breast cancer. However, if the patient's characteristics and their disease would fit the eligibility crite...
How would you treat a patient with end-stage renal disease, a germline BRCA1 mutation, and pT1c pN0 TNBC s/p mastectomy?
To better address this question, I have consulted our phenomenal specialty pharmacist at our breast cancer program, Dr. Michael Berger. Based on the information he provided, doxorubicin and paclitaxel can be given at full doses in patients with end-stage renal disease (ESRD) as these agents are meta...
Is there data supporting the extension of adjuvant olaparib beyond one year in patients with early-stage HER2-negative breast cancer and germline BRCA1/2 mutations?
The current practice of the addition of 1 year of adjuvant olaparib in high-risk HER2-negative early breast cancer in those patients with germline pathogenic or likely pathogenic variants in BRCA1 or BRCA2 is based on the superior DFS and OS benefit reported in the Phase III OlympiA trial. Fortunate...
Would you offer adjuvant olaparib to a male patient with HR+, HER2- T2N0 breast cancer with a BRCA2 germline mutation following mastectomy who is not a candidate for adjuvant chemotherapy?
Will offer brief thoughts but welcome others as well. First, I think it would be helpful to know what risk stratification has been done to decide the patient should be offered chemotherapy and not just endocrine therapy. Also, it would be useful to know why they are not a candidate for chemotherapy ...
When would you use adjuvant abemaciclib in patients with clinically high-risk ER+, HER2-negative breast cancer, but pCR following neoadjuvant chemotherapy?
This patient would not have qualified for the monarchE adjuvant abemaciclib protocol, which used pathologic staging for lymph node status (although baseline imaging was allowed for tumor size determination in patients who received adjuvant chemotherapy) (1). This is in contrast, for example, to the ...
In the neoadjuvant setting, how would you treat a premenopausal woman with a 3 cm ER+, PR weakly positive, Her-2 negative, grade 3 breast cancer with clinical N1 node which shows basal type on Mammaprint?
This patient has high risk features and would likely benefit from chemotherapy. Given positive hormone expression (even if basal molecular type by Mammaprint), she would not be eligible for KEYNOTE-522 study. Hence, I would not recommend pembrolizumab. If there are no significant risks for complicat...
Do you prefer using an anthracycline or non-anthracycline adjuvant regimen in BRCA+ premenopausal patients with localized HR+ breast cancer?
My choice of chemotherapy for localized BRCA+ breast cancer is guided by the patient's risk factors such as tumor grade, tumor size, presence or absence of lymphovascular invasion, number of lymph nodes involved, Oncotype dx result, and the patient's age. For small, node negative, HR+, HER2- breast ...
What is your preferred adjuvant therapy for a patient with triple negative breast cancer and has a BRCA germline mutation who had minimal to no response to neoadjuvant chemotherapy?
The vast majority of OlympiA patients had both anthracycline and taxane therapy. Very few had less than 6 cycles of chemo or only one of the two agents. For this case, I would try to do 4 cycles of dose dense anthracycline treatments then adjuvant olaparib for 1 year.
Would you recommend olaparib for a patient with germline BRCA1 mutation and HER2+ metastatic breast cancer who has progressed through multiple lines of HER2-directed therapy including trastuzumab deruxtecan?
Although OlympiAD (Robson et al., PMID 28578601) and EMBRACA (Litton et al., PMID 30110579) studied olaparib and talazoparib in HER2negative gBRCA mutant metastatic breast cancer, the activity is based on the mechanism of synthetic lethality in BRCA deficient tumors. Thus, it is reasonable to think ...
Given recent OS data from the OlympiA trial, would you offer adjuvant olaparib to a BRCA+ patient with pT1bN0 TNBC?
I would not, as those patients were not included in OlympiA.
What is your process for assessing the "high risk" clinical features in gBRCA+ breast cancer in order to offer olaparib, given varying definitions of risk and recent changes in staging guidelines?
I follow the criteria used in the eligibility for the OlympiA trial to determine who I will offer olaparib to in the adjuvant setting, which is consistent with the ASCO Hereditary Breast Cancer Guideline Rapid Recommendation Update.In patients with gBRCA+ breast cancer who received at least 6 cycles...
Do you plan to offer adjuvant olaparib to all gBRCA+ breast cancer whether TNBC or HR+?
I offer adjuvant olaparib to germline BRCA mutated breast cancer patients (TNBC or hormone receptor positive and Her-2 negative) only if they meet the inclusion criteria that was used in the OlympiA study, which is as follows:1) Patients with triple-negative breast cancer who were treated with adjuv...
If you have a high risk HR+, BRCA+ breast cancer patient who qualifies for adjuvant olaparib and abemaciclib, which one would you give and why?
The results of the recent OympiA trial published in the New England Journal of Medicine by Tutt et al. for women with high risk BRCA positive breast cancer, together with the MonarchE trial for high-risk ER positive breast cancer, has created somewhat of a dilemma as to which therapy to add to patie...
Would you recommend adjuvant olaparib in a premenopausal BRCA1+ woman with stage IA pT1bN0 ER/PR+ HER2- breast cancer and a high OncoType score?
This is a data-free zone. Although this patient appears to have a high recurrence risk based on her Oncotype RS, she does not seem eligible for adjuvant olaparib based on her clinical-pathological characteristics. The Oncotype RS was not taken into consideration as part of the eligibility criteria i...
Would you consider adding pembrolizumab to adjuvant chemotherapy in a patient with stage 3 TNBC who did not receive neoadjuvant treatment?
It seems that we might be missing some key clinical information here. However, I assume that this was high risk enough - given the ki-67, potentially LN positive, and larger size tumor to make the treating physician concerned. As a first point, while the ctDNA reflects (based on accumulating data) p...
Would you consider adjuvant olaparib in a patient with HER2+, high-risk, early stage breast cancer with germline BRCA mutation?
We do not yet know whether HER2 amplified cancers in women with BRCA mutations are in fact driven by HER2. However, given the remarkable efficacy of anti-HER2 therapy, I would be loath to discard the accepted strategies for managing HER2-positive disease. There is also a pragmatic challenge which is...
In patients who receive neoadjuvant pembrolizumab and chemotherapy for TNBC, how will you manage adjuvant treatment if they have a germline BRCA mutation?
For patients with clinically high risk early TNBC and germline PV in BRCA 1 or 2 undergoing neoadjuvant chemotherapy along with pembrolizumab, the course of adjuvant therapy will depend on pathologic response at surgery.For those with pCR - I would continue adjuvant pembrolizumab for patients who ar...
How do you sequence capecitabine and olaparib, if at all, in patients with BRCA+ TNBC and residual disease after neoadjuvant chemotherapy?
Patients with germline PV in BRCA 1/2 and residual disease following NAC in early TNBC have two options that likely represent standard of care in the adjuvant setting, a) adjuvant capecitabine (CREATE-X, EA1131) and/or b) adjuvant olaparib (NSABP B55). B55 did not allow for any further adjuvant chem...
Should we start performing universal germline mutation testing for all newly diagnosed breast cancer?
The OlympiA study resulted in a statistically significant iDFS and DDFS benefit with adjuvant olaparib vs placebo in high-risk, HER2-negative patients with gBRCA mutation. Given the notable improvement in outcomes, it is imperative that every potentially eligible patient be considered for adjuvant o...
Will you offer adjuvant olaparib to patients with somatic BRCA mutated breast cancer given that OlympiA only enrolled germline BRCA+?
I agree that the 3-year DFS benefit is quite compelling for considering adjuvant olaparib in patients meeting the eligibility criteria in NSABP B55 (Tutt et al., PMID 34081848). This also raises the possibility of clinical benefit in other scenarios, particularly those where PARPi have shown meaning...