February 13, 2024

My Experience Managing Key Adverse Events With Oral Targeted Therapy for High-Risk Early Breast Cancer

Posted By: Kevin Kalinsky, MD, MS

Recent years have seen the approval of oral targeted therapy options for the treatment of high-risk early breast cancer (EBC), including 2 key agents: the CDK4/6 inhibitor abemaciclib and the PARP inhibitor olaparib. Abemaciclib is approved in combination with endocrine therapy (ET) for the adjuvant treatment of HR-positive/HER2-negative, node-positive EBC at high risk of recurrence. Olaparib is approved for the adjuvant treatment of germline BRCA-mutated HER2-negative EBC after receipt of (neo)adjuvant chemotherapy. As with any oral therapy used as cancer treatment, education on potential adverse events (AEs) as well as proper management of AEs that do occur are critical to ensure patient adherence and optimal outcomes. Dr Kevin Kalinsky summarizes his experience with key toxicities and recommended management strategies with abemaciclib and olaparib to improve outcomes for patients with EBC.

Abemaciclib

AEs
Diarrhea is the most common AE that we see with adjuvant abemaciclib. Any grade diarrhea was reported in 84% of patients in the monarchE trial evaluating adjuvant abemaciclib vs placebo in high-risk patients with EBC. Fatigue may also present an issue for a subset of patients. Elevated hepatic transaminases are a potential AE with abemaciclib as with other CDK4/6 inhibitors including ribociclib. In addition, alopecia was reported in a small subset of patients (11%) in monarchE. Though less common, there is also a risk of interstitial lung disease (ILD)/pneumonitis, which is a class effect with the CDK4/6 inhibitors, as well as venous thromboembolism, which is a risk unique to abemaciclib.

AE Management
As mentioned, diarrhea is the primary issue we encounter with abemaciclib. Patient education is critical to aid in early identification and management of diarrhea and ensure patients are comfortable discussing any changes in their bowel movements. Patients should be instructed to start antidiarrheal agents such as loperamide and increase their oral fluid intake at the onset of diarrhea. It is important to understand how many stools per day the patient normally has in order to determine the grade of diarrhea they are experiencing. For grade 1 diarrhea (an increase of less than 4 stools/day), abemaciclib can be continued. For grade 2 diarrhea (increase of 4-6 stools/day), abemaciclib should be held if the diarrhea does not improve to grade 1 or less within 24 hours; otherwise, it should be held until improvement and then may be resumed at the same dose. For grade 2 diarrhea that persists or recurs despite maximal supportive measures, grade 3 or 4 diarrhea, or diarrhea that requires hospitalization, abemaciclib should be held until improvement to grade 1 or less and then restarted with a dose reduction.

Hepatotoxicity may also warrant dose interruption and/or reduction, depending on the degree of hepatic impairment. Because of the risk of ILD/pneumonitis, patients should be monitored for any new or worsening pulmonary symptoms such as cough or dyspnea. Abemaciclib should be held, and the dose reduced for persistent or recurrent grade 2, and permanently discontinued for grade 3 or 4 ILD/pneumonitis.

The recommended starting dose of abemaciclib in combination with ET is 150 mg PO twice daily. The dose should be reduced to 100 mg twice daily and then 50 mg twice daily; therapy should be discontinued in those unable to tolerate 50 mg twice daily. It is worth noting that within the monarchE trial, patients who received a lower dose of abemaciclib still experienced clinical benefit. We have recent data showing that 4-year invasive disease-free survival rates were generally consistent regardless of relative dose intensity. Something that I mention to my patients is that even if they require a dose reduction, they may still see a benefit from the addition of abemaciclib to ET.

Olaparib

AEs
In my clinical practice, I have most commonly observed anemia, followed by fatigue and gastrointestinal issues such as nausea with adjuvant olaparib. We may also see cytopenias. A major question that accompanied the use of olaparib as adjuvant therapy earlier in the disease course was whether an increased rate of myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) or new primary malignancies would be observed, as PARP inhibitors carry a warning for this serious AE. Fortunately, this is not something that we are seeing in practice to date.

AE Management
It is important that we monitor complete blood count with differential routinely—at least monthly—in patients receiving adjuvant olaparib. In the OlympiA trial evaluating adjuvant olaparib, treatment was held and potentially dose reduced for grade 2 or higher anemia, grade 3 or higher neutropenia or febrile neutropenia, and grade 2 or higher thrombocytopenia. If held for anemia, olaparib was resumed upon hemoglobin recovery to >9.5 g/dL. Dose reduction of olaparib was recommended if hemoglobin recovery took more than 2 weeks without a transfusion or if a transfusion was given. If transfusions were needed to maintain hemoglobin >9.5 g/dL on the reduced dose of 200 mg PO BID, olaparib was discontinued. Transfusions are typically indicated for symptomatic anemia and hemoglobin <7 g/dL. Given the warning for MDS/AML with PARP inhibitors, prolonged hematologic toxicities that do not recover to grade 1 or lower within 4 weeks of olaparib therapy interruption should prompt further investigation. As olaparib carries a moderate risk of emetogenicity, patients initiating therapy should have a prophylactic antiemetic available; typically, ondansetron is provided unless contraindicated. The recommended starting dose of olaparib is 300 mg PO BID, with reductions to 250 mg BID followed by 200 mg BID as indicated.

Strategies to Promote Patient Adherence to Oral Targeted Therapies
Patient adherence is a key component to the success of any oral therapy. In addition to providing comprehensive education to ensure patients understand how to take the medication and when to call the clinic, there are several strategies that can be recommended to increase patient adherence. Depending on their preferences, patients may utilize methods such as pill boxes, treatment calendars, or cell phone alarms. It is also critical that they remain in close contact with the clinic, with a follow-up phone call or office visit shortly following initiation of the oral targeted therapy and regularly thereafter throughout.

Summary
In conclusion, we now have more oral targeted therapy options in the adjuvant setting for our patients with high-risk EBC. Ensuring comprehensive patient education is completed prior to therapy initiation and employing effective management strategies to mitigate AEs can help us to achieve optimal outcomes for our patients.

Filed under: Oncology/Hematology , NPs & PAs

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