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Our Experiences With BRCA Testing and Adjuvant PARP Inhibition in EBC
Our Experiences With the Expanded Role of BRCA Testing and Adjuvant PARP Inhibition in Early Breast Cancer

Released: April 05, 2023

Banu Arun
Banu Arun, MD
Allison Butts
Allison Butts, PharmD, BCOP
Marissa Marti-Smith
Marissa Marti-Smith, APRN, AGNP-C, AOCNP
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Key Takeaways
  • In the OlympiA trial, adjuvant therapy with olaparib vs placebo demonstrated a benefit in overall survival, invasive disease‒free survival, and distant disease‒free survival in eligible patients with early breast cancer and gBRCA pathogenic variants.
  • With the expanded role of BRCA testing in early breast cancer, completion of testing in eligible patients is critical.
  • Given the survival benefit of adjuvant PARP inhibition in this population, patient and healthcare professional education on the importance of genetic testing and benefits of therapy is key.

The OlympiA trial randomized eligible patients with gBRCA pathogenic variants to receive 1 year of adjuvant olaparib vs placebo following completion of standard treatment with chemotherapy and radiation. Adjuvant olaparib resulted in significantly improved overall survival (OS), invasive disease‒free survival, and distant disease‒free survival vs placebo. This data subsequently led to the approval of olaparib for patients in the adjuvant setting meeting the OlympiA trial eligibility criteria and expanded the role of BRCA testing in early breast cancer (EBC). Here, Banu Arun, MD; Allison Butts, PharmD, BCOP; and Marissa Marti-Smith, MSN, APRN, AGNP-C, AOCNP, discuss the impact of this data and their experiences with implementation in EBC in clinical practice.

What has been your experience with identifying patients eligible for adjuvant therapy with olaparib and implementing this treatment option in clinical practice?

Allison Butts, PharmD, BCOP:
With the OS benefit, it is very important that we identify patients eligible for adjuvant olaparib. We have been screening more patients for genetic testing and discussing the need for genetic testing routinely in interdisciplinary meetings such as tumor boards. All healthcare professionals (HCPs) have a role in ensuring that we are capturing patients eligible for BRCA testing.

Marissa Marti-Smith, MSN, APRN, AGNP-C, AOCNP:
We always have aimed to complete genetic testing as indicated for all eligible patients, although the data really have brought to the forefront the importance of BRCA testing in EBC. Because this finding may affect treatment, we need to ensure that it is being completed so that we optimally tailor treatment to the individual patient. We also have seen an increase in genetic testing since the results of OlympiA and approval of olaparib in the adjuvant setting.

Who is responsible for ensuring that BRCA testing is completed in eligible patients with EBC?

Allison Butts, PharmD, BCOP:
Ideally, BRCA testing should be discussed early in the patient’s care, before considering the entire course of potential treatment options that will be discussed with the patient. It definitely is best to consider it early and for it to be on everyone’s radar. I do not think the medical oncologist alone should be responsible for ensuring that BRCA testing has been completed. Pharmacy also can have a role in recommending testing or ensuring that it is done. Ultimately, it takes a village, given that the criteria are fairly complicated on who should or should not be tested, and all disciplines should be thinking about testing in the course of the patient’s care.

Marissa Marti-Smith, MSN, APRN, AGNP-C, AOCNP:
I agree. It should be part of our checklist when patients come in—pathology, genetics, etc. Although some HCPs are very good at considering the need for genetic testing, it still can be missed. However, I do think that across the multidisciplinary team—surgeons, medical oncologists, nurse practitioners, physician associates/physician assistants, pharmacists—we all review whether genetic testing has been completed. It definitely is easiest to catch patients at the beginning of their care, but sometimes they do not complete the testing. It is important to educate patients that the testing is needed not only for surgical planning, but also because it could affect the treatment plan.

Banu Arun, MD:
We are so used to ensuring that testing has been completed for the estrogen receptor, progesterone receptor, and HER2, but to me this is a fourth biomarker for which we should routinely be testing.

 What barriers have you encountered in implementing BRCA testing and adjuvant olaparib in EBC, and how can we address them?

Allison Butts, PharmD, BCOP:
The need for education on this topic is the first issue that comes to mind. We need to ensure that all disciplines are thinking about BRCA testing. One major barrier at present is the limitation of genetic counselors, which is difficult to overcome.

Marissa Marti-Smith, MSN, APRN, AGNP-C, AOCNP:
Currently, we are ordering the genetic testing at baseline and sending the referral for genetic counseling. I agree that education is key so that patients understand why they need to have the testing completed. Patients may feel overwhelmed by everything that needs to be done at the time of diagnosis, and it is crucial that they understand the reasoning behind testing. I have had patients who did not complete the testing because they did not understand why it was necessary. It helps to write information down for patients and to explain that genetic testing affects both surgical and treatment planning. Ideally, printed information or a written visual aid or checklist with everything that needs to be completed would be provided to patients.

Banu Arun, MD:
Not having enough genetic counselors is really an important issue. In this case, we all need to be innovative and leverage available technologies, such as telemedicine, so that genetic counselors can reach patients more quickly. At my institution, we have implemented physician order testing, which allows the HCP to order genetic testing when indicated and forgo the genetic counseling referral at that time. For positive results, patients then receive counseling via telemedicine by a genetic counselor. Implementation of this process may take some time, but it is one way to overcome potential barriers to ordering testing and ensure that genetic counselors are involved when needed.

Allison Butts, PharmD, BCOP:
It also is helpful to triage when genetic testing needs to be completed—whether immediately or after a few months of adjuvant therapy. Another paradigm shift that needs to occur with education is that patients generally may think genetic testing is being done for the next generation. So, it is important to point out that testing could affect the treatment plan today.

Marissa Marti-Smith, MSN, APRN, AGNP-C, AOCNP:
I agree, and I have seen patients refuse genetic testing for that exact reason—if they do not have children, they do not think it needs to be done. Patients always can decline genetic testing, but it helps if they have a clear understanding as to the purpose of the testing.

Banu Arun, MD:
It all comes down to education—at both the HCP and patient levels.

 What is your approach to patients who are eligible for both olaparib and other approved systemic therapies in the adjuvant setting?

Allison Butts, PharmD, BCOP:
What may complicate treatment planning in its entirety is that we do not always have BRCA testing completed early. Generally speaking, many of the patients we are discussing are higher risk, so they are receiving chemotherapy up front whether they are triple negative or hormone receptor positive and then receiving olaparib after surgery as adjuvant therapy. What can be complicated is choosing among available therapies—abemaciclib, capecitabine, and pembrolizumab—if a patient is eligible for 1 or more of these, as well as olaparib. Perhaps olaparib and pembrolizumab are not mutually exclusive and may be administered together in the adjuvant setting. There currently is a lack of data on administering these agents either in combination or sequentially. At this point, the data should be critically evaluated in the context of the individual patient to determine the optimal course of therapy. 

Banu Arun, MD:
It is very individualized. Again, ideally, we have BRCA testing completed up front. As for deciding among therapies, if I have, for example, a patient with triple-negative breast cancer (TNBC) with a BRCA1/2 pathogenic variant who received neoadjuvant chemotherapy plus pembrolizumab, as in the KEYNOTE-522 regimen, and has residual disease, I think it makes sense to continue the pembrolizumab. With the OS benefit with olaparib, I definitely would want to ensure that is incorporated into the treatment plan. The question is whether you administer the pembrolizumab and olaparib concurrently or complete the 6 months of adjuvant pembrolizumab and then initiate the year of olaparib sequentially. There also is consideration of adjuvant therapy with capecitabine for patients with TNBC and residual disease. Personally, I would have a more difficult time adding adjuvant capecitabine on top of pembrolizumab and olaparib, which we have no data for in the adjuvant setting. If everything were administered sequentially, that would result in almost 2 years of adjuvant therapy. Furthermore, although the CREATE-X trial did show a benefit with adjuvant capecitabine in patients with TNBC and residual disease, a recent meta-analysis has shown that the benefit is perhaps not as exciting as what was reported initially in CREATE-X. So, considering all of the available data, I would administer both pembrolizumab and olaparib, either together or sequentially.

For patients who are hormone receptor positive who qualify for both abemaciclib and olaparib, treatment selection becomes more difficult. We have early data showing that CDK4/6 inhibition plus PARP inhibition is rather cytotoxic, so I would not recommend administering olaparib and abemaciclib together. Again, if we gave these 2 therapies sequentially, it would be 3 years of adjuvant treatment. Given the OS benefit for olaparib in patients with gBRCA pathogenic variants and the absence of data on gBRCA-positive patients in the monarchE study with abemaciclib, I would favor olaparib plus endocrine therapy for eligible patients. But again, we have no data to guide us here.

Marissa Marti-Smith, MSN, APRN, AGNP-C, AOCNP:
With all of these adjuvant therapy options and potentially combining or sequencing them, time is added to patients’ treatments. The more information we have up front, the more we can prepare patients for their treatment course, which—again—highlights the benefit of early genetic testing. Even if we have all the data, patients may not be prepared to undergo another year of adjuvant therapy. The earlier we can prepare them for that, the better.

 What have you seen in terms of patient tolerability of adjuvant olaparib?

Banu Arun, MD:
At this time, my experience with single-agent PARP inhibitors largely comes from the use of olaparib or talazoparib in the metastatic setting. I have not seen much thrombocytopenia or anemia with olaparib in our patients with metastatic disease, many of whom are pretreated. I have 1 patient for whom I initiated olaparib after completion of pembrolizumab, so I cannot comment on the tolerability of the combination.

Marissa Marti-Smith, MSN, APRN, AGNP-C, AOCNP:
Most of my experience with olaparib also has been in the metastatic setting, where patients have been more heavily pretreated. Overall, patients do relatively well receiving single-agent olaparib. Nausea tends to improve after the first 1-2 months. Fatigue can be bothersome and may be affected by prior therapies. We do monitor blood counts closely during the first few months.

Allison Butts, PharmD, BCOP:
Likewise, we have had a limited number of patients begin receiving olaparib in the adjuvant setting, with no new safety signals observed. I mainly have seen mild nausea that can be managed with as-needed antiemetics. I have not had any patients need to schedule antiemetic premedication with olaparib. I have not observed any issues with anemia. Again, many of these issues happen early in the course of treatment with olaparib, so if no issues are seen initially, in my experience that should predict well for future tolerance. I would say that fatigue is the biggest issue, because although these patients may not be as heavily pretreated as those in the metastatic setting, they still are coming out of (neo)adjuvant therapy, surgery, and potentially radiation. Overall, it is well tolerated in my experience. 

Banu Arun, MD:
We know premenopausal patients receiving ovarian suppression and an aromatase inhibitor may struggle with adverse events such as arthralgias/myalgias, hot flashes, and fatigue, and adding olaparib may compound that. So, we may see a slightly different toxicity profile in patients in the adjuvant vs metastatic setting because of concomitant medications and recent surgery with or without radiation.

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