CE / CME
Physician Assistants/Physician Associates: 0.50 AAPA Category 1 CME credit
Nurses: 0.50 Nursing contact hour
Pharmacists: 0.50 contact hour (0.05 CEUs)
Physicians: maximum of 0.50 AMA PRA Category 1 Credit™
Released: May 07, 2024
Expiration: May 06, 2025
Case 1: 40-Year-Old Woman With HR-Positive/HER2-Negative EBC and Germline BRCA1 Mutation
We begin with a case to help focus our review of germline BRCA mutation testing and targeting in the setting of HER2-negative EBC.
A 40-year-old woman was diagnosed with clinical stage T2N1M0 disease that is grade 3, estrogen receptor positive at 80%, progesterone receptor positive at 70%, and HER2 negative with an IHC score of 0. Breast imaging demonstrates a 4-cm tumor with a singular suspicious lymph node. Biopsy of the breast and lymph node both demonstrate invasive ductal carcinoma. Despite not having any family history of breast cancer, she is found to have a germline BRCA1 mutation.
She undergoes bilateral mastectomies and axillary surgery that demonstrates a 3.8-cm tumor with 3 out of 8 lymph nodes involved. This was more lymph node involvement than had been anticipated based on her initial imaging.
Following surgery, the patient receives adjuvant chemotherapy with dose-dense AC-T followed by radiation therapy. She is started on endocrine therapy with an aromatase inhibitor and ovarian suppression.
Case 1: Individualizing Adjuvant Treatment
Should we consider the addition of any other therapies to this patient’s adjuvant endocrine therapy?
In my practice, I would discuss adding the PARP inhibitor olaparib. As we will review later, adjuvant olaparib is indicated for patients with high-risk HER2-negative EBC harboring a germline BRCA1/2 mutation. This patient does not fully meet the high-risk criteria for enrollment on the registrational OlympiA trial, which required that patients with HR-positive/HER2-negative disease who had upfront surgery and adjuvant therapy needed to have ≥4 lymph nodes involved. However, she still has high-risk disease given that 3 lymph nodes are involved, and her younger age may be associated with more aggressive disease biology.1
Even though this patient is eligible for adjuvant abemaciclib, I would prefer olaparib. Phase III data show that adjuvant olaparib significantly prolongs OS, whereas the OS data are still immature for the phase III monarchE trial of abemaciclib.2,3
There are some instances where oncologists might consider sequencing olaparib followed by abemaciclib. I would only consider that approach for patients with very high–risk disease after a thorough discussion on the lack of data for sequential therapy.
Prevalence of BRCA Mutations in EBC
How often do we encounter patients with a germline BRCA1 or BRCA2 mutation? These mutations are the most common genetic variants in breast cancer and are associated with aggressive clinical and biologic features. Germline BRCA1/2 mutations are identified in 6% to 7% of all patients with EBC.4,5
Among patients with HR-positive/HER2-negative EBC, BRCA mutations occur at a rate of approximately 3.7%.4 These mutations are more common in patients diagnosed with early TNBC, where the mutation prevalence ranges from 11% to 19%.6-8 The prevalence of BRCA mutations also differs by ethnicity, race, and age.9,10 For example, a retrospective analysis of 450 patients with TNBC referred for genetic counseling found the highest BRCA mutation prevalence in those with Ashkenazi Jewish heritage (50%), followed by White (33.3%), Asian (28.5%), Black (20.4%), and Hispanic (20%). Regarding age, a prospective registry study in 207 unselected patients diagnosed with TNBC found markedly higher mutation prevalence in those diagnosed at 50 years of age or younger vs those diagnosed at 61 years of age or older (27.6% vs 4.9%, respectively).
PARP Inhibition for BRCA-Mutated Cancer
Why would a PARP inhibitor have activity against BRCA-mutated EBC?
Cells with BRCA1/2 mutations are deficient in homologous recombination repair (HRR)—an important pathway that repairs double-strand DNA breaks with high fidelity.11-13 Double-strand DNA breaks also can be repaired through a separate, error-prone pathway.
That being said, PARP inhibitors do not directly target the HRR pathway. These agents inhibit the base excision repair pathway, which is involved in repairing single-strand DNA breaks. Inhibiting PARP1, therefore, leads to accumulation of single-strand breaks. Inhibitors also “trap” PARP on the DNA during cell replication, which leads to conversion of single-strand breaks to double-strand breaks. This means that cells exposed to PARP inhibitors rely on the HRR pathway to accurately repair double-strand breaks.
In a cell with HRR deficiency, PARP inhibition leads to unrepaired single-strand breaks that are converted into double-strand breaks. These double-strand breaks cannot be repaired by the deficient HRR pathway, forcing cells to instead use the other error-prone pathway. The accumulating DNA damage ultimately leads to cell death.
This phenomenon is known as “synthetic lethality,” in which loss of function of both the HRR pathway through BRCA1/2 mutation along with PARP inhibition results in cell death, but loss of function of either alone does not.
Two PARP inhibitors—olaparib and talazoparib—are approved for treatment of HER2-negative metastatic breast cancer harboring a germline BRCA mutation.14-16 Olaparib also has an indication for the adjuvant setting, as we will now discuss.
OlympiA: Adjuvant Olaparib vs Placebo for BRCA1/2-Mutated, High-Risk HER2-Negative EBC
The OlympiA study compared adjuvant olaparib vs placebo for patients with BRCA1/2-mutated, high-risk HER2-negative EBC.2,17 This was an international, randomized, double-blind phase III trial.
All eligible patients had high-risk primary breast cancer and had received previous definitive local therapy plus ≥6 cycles of neoadjuvant or adjuvant chemotherapy containing an anthracycline and/or a taxane. All patients had to have a germline mutation in BRCA1 and/or BRCA2.
Those with TNBC were eligible if they had received neoadjuvant therapy and did not achieve a pathologic complete response. Patients with TNBC could also be eligible if they had undergone surgery upfront, received adjuvant chemotherapy, and were either axillary node positive (≥pN1, any tumor size) or axillary node negative with an invasive primary tumor pathologic size >2 cm (≥pT2).
Patients with HR-positive/HER2-negative disease were eligible if they had received neoadjuvant therapy, did not have a pathologic complete response, and had a CPS + EG score ≥3. The CPS + EG score is a prognostic tool that incorporates the pretreatment clinical stage and posttreatment pathologic stage—the “CPS” part of the score—as well as estrogen receptor status and tumor grade.18 Scores range from 0-6, with higher scores having a worse prognosis. Among cohorts treated with neoadjuvant chemotherapy for EBC, a CPS + EG score of 3 was associated with a 5-year disease-specific survival rate of 72% to 74%.
Patients with HR-positive/HER2-negative disease could also be eligible if they had undergone upfront surgery, received adjuvant chemotherapy, and had ≥4 lymph nodes pathologically confirmed as positive.
Participants were randomly assigned to receive olaparib at 300 mg twice daily for 1 year vs matched placebo. The primary endpoint was invasive disease–free survival (iDFS). Secondary endpoints included DFS, OS, and safety.
OlympiA: Baseline Patient Characteristics
In this study, the most common mutation was in BRCA1, which was present in 71% of the olaparib arm and 73% of the placebo arm.2 Approximately 82% of participants in each arm had TNBC.
OlympiA: iDFS in ITT Population at Median Follow-up of 3.5 Years
Shown here are the results for the primary endpoint of iDFS in the intention-to-treat (ITT) population.2 In the second interim analysis performed after a median follow-up of 3.5 years, the 4-year iDFS rate was 82.7% with adjuvant olaparib vs 75.4% with placebo, corresponding to an absolute difference of 7.3% in favor of olaparib.
Olaparib was consistently favored across subgroups defined by chemotherapy setting, prior platinum exposure, HR status, and BRCA mutation. In the large subgroup of patients with TNBC, the 4-year iDFS rate was 83.1% with olaparib vs 75.2% with placebo. Among those with HR-positive/HER2-negative disease, the rates were 80.1% vs 76.6%, respectively.
OlympiA: OS in ITT Population at Median Follow-up of 3.5 Years
At the second interim analysis of OS, olaparib significantly improved the 4-year OS rate at 89.8% vs 86.4% with placebo, yielding an absolute difference of 3.4%.2 The hazard ratio for death was 0.68 (98.5% CI: 0.47-0.97; P = .009).
Once again, the subgroup analysis of OS consistently favored olaparib. Among patients with TNBC, the 4-year OS rate was 90.1% with olaparib vs 86.3% with placebo. Among patients with HR-positive/HER2-negative disease, the 4-year OS rate was 88.1% vs 86.3%, respectively.
Recall that our case patient had high-risk HR-positive/HER2-negative EBC with a germline BRCA1 mutation. Altogether, these data demonstrate that adjuvant olaparib would benefit such patients by significantly reducing their risk of invasive disease as well as death.
OlympiA: Safety
This is a summary of the key safety data from the OlympiA trial.2 Nausea was the most common AE, occurring at any grade in 57.1% of patients treated with olaparib, with most events being low grade. Fatigue was the second most common AE at 40.3%, also mostly grade 1/2. Cytopenias are an important part of the safety profile for PARP inhibitors, and we see any-grade anemia in 23.6% and a decreased neutrophil count in 16.1%.
Dose modifications were common with olaparib, with 25.0% of patients requiring a dose reduction vs 5.2% with placebo. Dose holds lasting ≥3 days occurred in 44.5% vs 30.9% of patients, respectively. Permanent discontinuations were more common in the olaparib arm, occurring in 10.8% vs 4.6% of patients on the placebo arm. The most common AEs leading to discontinuation of olaparib were nausea (2.2%), anemia (1.8%), fatigue (1.6%), and a decreased neutrophil count (1%).
AEs of special interest that occurred with olaparib were pneumonitis (1.0% vs 1.3% with placebo), myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) (0.2% vs 0.3%), and new primary malignancy (2.3% vs 4.0%).
MDS/AML is a particularly important consideration for patients with early-stage disease who can expect to live for many years after diagnosis. Later, we will review how to discuss these risks vs benefits of adjuvant olaparib with patients.
Adjuvant Olaparib for EBC With BRCA1/2 Mutations: FDA Approval
Based on the OlympiA data, olaparib received FDA approval for adjuvant treatment of patients with deleterious or suspected deleterious germline BRCA mutations who have high-risk HER2-negative EBC, and who have received neoadjuvant or adjuvant chemotherapy.15 Patients should be selected based on an FDA-approved companion diagnostic, and we will shortly review current guidance on testing for BRCA1/2 mutations.
Deciding Between Adjuvant Olaparib vs Abemaciclib in Eligible Patients
How should we decide between adjuvant olaparib and abemaciclib for a patient with high-risk, node-positive HR-positive/HER2-negative EBC harboring a germline BRCA mutation?
I favor olaparib in patients eligible for both of these agents. OlympiA demonstrated that adjuvant olaparib significantly improves OS. By contrast, the OS data from monarchE for adjuvant abemaciclib are not yet mature.2,3
Should we concurrently administer these agents? I would not coadminister olaparib and abemaciclib because we lack both efficacy and safety data, and I would be concerned about cytopenias, which are a risk with both agents.
Healthcare professionals could potentially consider administering these agents sequentially in select patients at very high risk of recurrence. Olaparib is then given first for 1 year followed by abemaciclib, which can be initiated up to 16 months after surgery, per monarchE. However, we will need more data to know whether sequential administration helps reduce the overall risk of recurrence.
NCCN Guidelines on Testing for BRCA1/2 Mutations
Shown here are current National Comprehensive Cancer Network guidelines on testing for germline BRCA1/2 mutations.19 In brief, we should always test for germline BRCA1/2 mutations in patients with any TNBC and those with HER2-negative EBC who would be a candidate for olaparib based on their high-risk status. Other eligibility criteria for testing are outlined here, which generally include a significant personal and/or family history of certain cancers.
Performing BRCA1/2 Testing
Once we have identified an eligible patient, how should we perform germline testing for BRCA1/2 mutations?
If treatment decisions are urgent, healthcare professionals can consider counseling patients and ordering the testing themselves.19-21 However, it is useful to involve genetic counselors, particularly when performing multigene panel testing or when interpreting results indicating non-BRCA alterations and/or variants of uncertain significance.
Typically, testing is performed on a blood or saliva sample, with a turnaround time of 3-4 weeks. Most insurance plans will cover testing if patients meet criteria, and testing labs may offer special financial programs to help allay costs.
Adjuvant Olaparib for Patients With Somatic BRCA or Non-BRCA Mutations
We have focused so far on identifying and treating patients harboring germline BRCA1/2 mutations. Should we consider adjuvant olaparib for patients with somatic (tumor) mutations in BRCA1/2?
Currently, I do not recommend adjuvant olaparib for patients with somatic mutations in BRCA1/2. We usually would not be aware of somatic mutations in patients being treated in the curative setting. Outside of a clinical trial, we generally do not perform next-generation sequencing or somatic mutation testing in EBC, whereas we routinely perform that testing in the metastatic setting. We also lack data to support or guide the use of adjuvant olaparib for patients with somatic BRCA mutations.
Would I recommend adjuvant olaparib for patients with non-BRCA mutations in the HRR pathway? This is an excellent question, and some healthcare professionals may consider adjuvant olaparib in select patients with these mutations. A phase II trial in the metastatic setting reported olaparib activity in patients with somatic BRCA1/2 mutations or germline PALB2 mutations.22
These questions are under clinical investigation. For example, the biomarker-guided phase II COGNITION-GUIDE trial in Germany is evaluating olaparib in a cohort with EBC who have somatic or germline BRCA1/2 mutations or germline PALB2 mutations (NCT05332561).
That being said, I currently reserve adjuvant olaparib for those with germline BRCA mutations.2
Dosing Considerations for Adjuvant Olaparib in EBC
We will now discuss dosing considerations and management of AEs associated with adjuvant olaparib.
Per the OlympiA study, the standard starting dose for adjuvant olaparib is 300 mg twice daily, taken with or without food.15,17,23 OlympiA required participants to start olaparib after having completed all local therapy 2-12 weeks prior to study entry; participants must also have completed ≥6 cycles of chemotherapy in either the neoadjuvant or adjuvant setting. Adjuvant olaparib is then given for 1 year.
As we will discuss shortly, dose holds and dose reductions are key to managing olaparib-related AEs. The first dose level reduction is to 250 mg twice daily and the second dose level reduction is to 200 mg twice daily.15,17 Permanent discontinuation of olaparib is reserved for recurrent or high-grade AEs.
Practical Management Strategies: Olaparib AEs
Cytopenias
As we discussed earlier when reviewing the OlympiA safety results, cytopenias are a common and troublesome AE of olaparib, requiring dose holds and reductions.15,24
Anemia is characteristic of the safety profiles for PARP inhibitors. Guidelines recommend close monitoring of patients whose hemoglobin levels drop to <8 g/dL and/or who require transfusion for symptomatic relief. If this is a recurrent issue, patients should have their dose reduced to avoid multiple transfusions.
Neutropenia is also common. If the ANC is <500/mm3 (grade ≥3) for ≥5 days or is associated with a fever, guidelines recommend holding olaparib until ANC recovery to grade ≤2. Olaparib then should be resumed at a reduced dose.
MDS/AML
Secondary MDS/AML is a rare but very serious complication, occurring in approximately 1% of patients treated with PARP inhibitors.15,25 If patients have prolonged hematologic toxicity that is unexplained and they have had previous exposure to olaparib, the possibility of secondary MDS/AML should be considered and a hematologist should be consulted. A bone marrow biopsy also should be considered.
Gastrointestinal AEs and Fatigue
Some individuals receiving PARP inhibitors can experience nausea and fatigue.15,24,26 Fortunately, the nausea tends to be quite responsive to antinausea agents, and the fatigue can often be allayed by dose reductions.
Mild nausea and vomiting are common but tend to diminish over time. Severe nausea and vomiting are rare. Prophylactic management is recommended at initiation of olaparib, and an antiemetic should be taken 30-60 minutes before treatment begins. Aprepitant should be avoided because of CYP3A4 interactions with olaparib.
To reduce the risk of nausea, PARP inhibitors can be taken after meals; keeping a food diary may help identify triggers.
If patients vomit after taking the PARP inhibitor, they should not take an additional dose and should follow-up with their care team.
Pneumonitis
Pneumonitis is rare with olaparib. Signs and symptoms to monitor for include cough, dyspnea, fever, wheezing, or radiographic abnormalities. Olaparib should be permanently discontinued if pneumonitis occurs.
Case 2: 56-Year-Old Woman Experiencing Neutropenia Receiving Adjuvant Olaparib
We now turn to our second case, which illustrates the importance of monitoring for and managing olaparib-related AEs in both the short and long term.
The patient is a 56-year-old postmenopausal woman diagnosed with clinical T3N2M0 disease, grade 3, estrogen receptor expression 90%, progesterone receptor expression 80%, HER2 negative (IHC 0), and invasive ductal carcinoma subtype. Breast imaging shows a 6-cm tumor and bulky axillary lymph node involvement. On physical examination, the axillary lymph nodes are matted; thus, this was clinical N2 disease. PET/CT does not demonstrate findings concerning for distant disease.
She receives neoadjuvant dose‑dense AC-T. Genetic testing demonstrates a germline BRCA2 mutation. She then undergoes mastectomy and axillary surgery with pathology demonstrating a 5-cm tumor with 4/9 lymph nodes involved. She then receives postmastectomy radiation to the chest wall and regional nodes. She begins anastrozole and olaparib 300 mg twice daily.
Four weeks after starting olaparib, her ANC is 400/mm3, indicating grade 4 neutropenia. Olaparib is held and her ANC recovers to 1500/mm3 (grade 1) after 2 weeks.
What should we recommend next? In this case, as her ANC has now recovered to >1000/mm3 (grade ≤2), I would recommend resuming olaparib at the next lower dose level of 250 mg twice daily.
Case 2: Follow-up on Long-term Risks of Olaparib
The patient resumes olaparib at 250 mg twice daily and completes 1 year of olaparib as recommended. She and her oncologist discuss whether to initiate adjuvant abemaciclib for 2 years following olaparib, given that she had very high–risk disease. Ultimately, she decides not to pursue abemaciclib and continues to receive anastrozole alone.
One year later, she has persistent neutropenia with an ANC <1000/mm3 but otherwise feels well. After a few weeks, she undergoes a bone marrow biopsy that unfortunately demonstrates secondary AML.
Balancing OS Benefit vs Risk of MDS/AML
This case raises an important issue: How do you approach the risk-vs-benefit discussion with patients when adjuvant olaparib has demonstrated an OS benefit, but also carries the small but serious risk of secondary MDS/AML?
In my practice, this is often an extended conversation where I let the patient know that secondary MDS/AML occurs in approximately 1% of patients treated with PARP inhibitors.15,25 I will talk with them about their risk of recurrence based on clinicopathologic features and available prediction tools. In many cases, the potential benefit of olaparib in reducing the risk of recurrent breast cancer will far outweigh the risk of MDS/AML and that can help the patient make their decision.
Although rare, secondary MDS/AML is very serious when it occurs. Curative treatment for secondary MDS/AML generally involves a stem cell transplant.27 It is important to counsel patients upfront about the risk of MDS/AML.
Patients frequently ask a question like this: “I’m trying to reduce a cancer that may never come back, but what if I accidentally induce a secondary cancer?” This captures why olaparib is best reserved for those at higher risk of recurrence, where the benefit from the breast cancer risk reduction is large enough to offset the risk of secondary MDS/AML.
Strategies for Promoting Adherence to Oral Therapies
It is vital for healthcare professionals to promote and support adherence to adjuvant olaparib, given the OS benefit demonstrated in OlympiA. Helpful strategies include ensuring that a caregiver is present for education and counseling, providing information in a written form, and supplying medication calendars.28,29
It is essential to address potential “financial toxicity” with all oral therapies, both by screening patients for financial concerns and by linking them to pharmacist or social worker colleagues who can help identify copay assistance and/or other support programs.30 Financial toxicity—being unable to pay for needed medication—is strongly associated with nonadherence to anticancer oral therapy.31 Often, it can be very helpful to ask patients questions such as, “How are you taking your medication?” and “How much does it cost?”
Key Takeaways on Genetic Testing and Treating High-Risk EBC With Germline BRCA Mutation
In summary, we now have phase III data showing that adjuvant olaparib significantly reduces both the risk of recurrence and improves OS in patients with high-risk HR-positive/HER2-negative EBC and high-risk early TNBC harboring germline BRCA1/2 mutations.
Testing for germline BRCA mutations is important and should be performed in patients with TNBC, those with HR-positive/HER2-negative EBC potentially eligible for adjuvant olaparib, and those with significant personal or family history of cancers. The findings can have implications for treatment options as well as cancer screening in both patients and their relatives.
Finally, AEs associated with adjuvant olaparib can be effectively managed with supportive care, dose interruption, and dose reduction.
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