CE / CME
Pharmacists: 1.00 contact hour (0.1 CEUs)
Nurses: 1.00 Nursing contact hour
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: March 27, 2023
Expiration: March 26, 2024
Allison Butts, PharmD, BCOP:
I’ll share a couple of practical tips for starting patients on olaparib. How the medication is dosed and administered is important because adherence is key with any of these oral medications. The recommended dose for olaparib is 300 mg twice daily, which comprises two 150-mg tablets taken twice daily.12 Any time patients must take medication twice daily, or if a dose is more than 1 tablet, compliance can suffer. Often this is inadvertent and a consequence of the patient misunderstanding the directions. Thus, understanding how the medication is supplied and dosed is a key point and the patient should be educated on this. Adherence follow-up is also important to ensure that the patient is taking the medication correctly.
Another important practical note is the 150-mg tablets are specified for this indication. Olaparib comes in 100-mg capsules as well, and these 2 dosage forms are not interchangeable. For HCPs who are not as familiar with using these medications, it is key to know which dosage form that they’re using, that there are differences in bioavailability, and to not substitute the capsules for the tablets.
Allison Butts, PharmD, BCOP:
Regarding potential adverse events with olaparib, nausea certainly is a major factor.18 Typically, we’ll prescribe antiemetics as needed for these patients. However, if they have a strong history of nausea from their previous chemotherapy, scheduling an antiemetic is a good idea to ensure tolerability with the medication. In addition, taking olaparib after a small meal may be helpful.
Another adverse effect that was mentioned earlier is fatigue. These patients have typically seen multiple chemotherapy agents, and we know the fatigue is cumulative. By the time they initiate olaparib, they’re pretty worn out and generally tired of being on treatment! That fatigue can also affect adherence, so we need to make sure to talk about it with both patients and caregivers.
Anemia is a common adverse effect of olaparib. A complete blood count should be checked at baseline and monthly thereafter.
Also, as Dr. Geyer previously mentioned, the risk of developing MDS and AML is often on our minds when talking about this class of medications. However, as mentioned, the OlympiA trial did not show an increased risk of these serious adverse effects compared with placebo. It is worth noting that the CPS+EG scoring was incorporated into OlympiA to select for high-risk patients with HR-positive disease to ensure patients selected for olaparib were sufficiently high risk to warrant the risk of MDS/AML.
Finally, the onset of many of these common adverse events is relatively quick—within the first month. So we aim to keep in close contact with our patients; our specialty pharmacy team follows up with patients after approximately 1 week on therapy to ensure that they have everything that they need and that they’re tolerating the medication (and taking it correctly). If we can get patients through the first month and address any adverse effects, then hopefully they’re able to stay on it and tolerate it fairly well thereafter. In OlympiA, 95% of intended olaparib doses were received!
Dose adjustments are recommended in the prescribing information for hematologic as well as gastrointestinal toxicity.
Less common adverse effects include pneumonitis and thromboembolic events, which the care team should monitor for throughout the course of treatment.
Charles E. Geyer, Jr., MD:
I’m curious about the antiemetic. What specific class of drugs do you use for a twice-daily dosing?
Allison Butts, PharmD, BCOP:
Most often I recommend a 5HT3 inhibitor, but I think it’s most important to talk to the patients and find out what antiemetic they did well with previously with their chemotherapy. If there was a class of antiemetic drugs that worked best or that they tolerated best, I think it’s appropriate to plan to start there.
Banu Arun, MD:
Yes, in my clinical practice we have seen very few major adverse effects from olaparib. I think patients are excited about an oral agent and are trying to be compliant. They know they are a special population.
Charles E. Geyer, Jr., MD:
An important issue is the risk of anemia and the need for red blood cell transfusions. In the OlympiA trial, there was a relatively low transfusion rate of 5.8% in the olaparib arm, but the trial protocol was relatively conservative in criteria for holding therapy for anemia.18 If the hemoglobin dropped <9.5 g/dL, olaparib was held and not resumed until the hemoglobin recovered. If recovery took more than 2 weeks, the dose was reduced. If transfusions were needed to maintain hemoglobin at ≥9.5 g/dL on a reduced dose of 200 mg twice daily, olaparib was discontinued. In the metastatic setting the drug would be continued if beneficial, so recurrent transfusions would be tolerable, but the early-stage setting is different.
Perhaps, if a patient had very high–risk disease in the early-stage setting, you might choose to continue the olaparib a while longer even if transfusions are needed, now that clear benefits of the therapy have been demonstrated. It is important to recognize that when patients were treated on OlympiA, we were in a situation in which we knew this new agent had risks but didn’t have proof of benefit at that time. With the documented benefit of olaparib, tolerance for risks is altered even in the setting of curative intent, particularly when the risk of recurrence is very high.
Marissa Marti-Smith, MSN, APRN, AGNP-C, AOCNP:
Typically, we monitor complete blood counts closely as previously described, initially and then monthly when patients come in for follow-up. Initially, I always provide education on signs and symptoms of anemia (weakness, severe fatigue, shortness of breath, dizziness, tachycardia) to verify patients are aware when to call the clinic. Patients with metastatic disease often are more familiar with these symptoms given their previous therapy history. If needed, we dose adjust. But, supportive care can be provided with transfusions as needed.
Charles E. Geyer, Jr., MD:
On the OlympiA trial, olaparib/placebo were initiated following completion of radiation therapy because of concerns for potential overlapping toxicities.18 Concurrent administration of endocrine therapy with the year of olaparib/placebo was recommended but not required. Concurrent therapy was selected by investigators 87% of the time in the olaparib arm without evident problems related to coadministration, and is the preferred approach.
Allison Butts, PharmD, BCOP:
Olaparib can be given concurrently with endocrine therapy, which is how it was studied in the OlympiA trial. It was not given concomitantly with radiation in that study.
The phase I RadioPARP study found that olaparib 200 mg twice daily with locoregional radiation was tolerated without dose-limiting toxicities.34 In addition, a phase I study of olaparib plus capecitabine plus radiotherapy in advanced pancreatic cancer found that olaparib dosed at 150 mg twice daily (with capecitabine 830 mg/m2 twice daily) seemed to be safe.35 However, at this time, olaparib is generally not combined with radiation due to toxicity concerns, and current guidelines recommend administering after completion of radiation.22 Olaparib can also be given safely with bisphosphonate therapy, which may be given in both the adjuvant and metastatic setting with PARP inhibitors.
There is an outstanding question about the combination of olaparib and pembrolizumab as adjuvant therapy for TNBC. There are mixed opinions on this approach at this time and there is not yet a standard recommendation.
Banu Arun, MD:
At present, we have more options in the adjuvant setting, including abemaciclib, capecitabine, and pembrolizumab. These therapies were not included in the OlympiA trial, and we do not have current evidence on sequencing or combining these agents with olaparib. There are currently no data on the combination of olaparib with CDK4/6 inhibitors and there are concerns about overlapping bone marrow suppression. So, I would not recommend that combination.
There are phase I data with immune checkpoint inhibitors in combination with PARP inhibitors in metastatic cancer, including breast and ovarian cancers,36-38 but I think many of us try to sequence these drug classes. In my clinic, I wait until patients finish the immunotherapy—if they received it in the neoadjuvant setting, it’s 6 more months—and then start olaparib.
With capecitabine, my thoughts are that overall the degree of OS benefit with capecitabine in the adjuvant setting was not as impressive as with olaparib39 I would rather use olaparib, with or without capecitabine, thereafter, but even that is very questionable in my opinion. Dr. Geyer, what do you think?
Charles E. Geyer, Jr., MD:
What was so striking about CREATE-X was the initially impressive hazard ratio for DFS of 0.58 in TNBC. However, as more data have been reported, it appears that was the best result reported. A large meta‑analysis of capecitabine in multiple (neo)adjuvant breast cancer studies showed a DFS hazard ratio of 0.88, which is not quite as impressive.40
The GEICAM‑CIBOMA adjuvant study grouped patients with early TNBC into basal vs nonbasal cohorts, with a hypothesis that the basal type would benefit from capecitabine.41 The overall study showed a trend toward improved outcomes with capecitabine but did not meet the prespecified criteria for efficacy. However, when the subsets were evaluated, the smaller nonbasal subgroup appeared to derive benefit from capecitabine whereas the larger basal subgroup did not seem to derive any benefit from capecitabine. The ECOG-ACRIN EA1131 study evaluated platinum vs capecitabine in patients with early-stage basal TNBC and ≥1 cm of residual disease following neoadjuvant chemotherapy, and results showed that patients did poorly on both platinum and capecitabine.42
Overall, the available data support use of olaparib rather than capecitabine after standard neoadjuvant chemotherapy in patients who meet OlympiA eligibility criteria.
Regarding coadminstration of olaparib with adjuvant pembrolizumab in patients with non-pCR status following the KEYNOTE-522 neoadjuvant model, that will be a personal choice. Discontinuation of pembrolizumab is problematic in view of the large event-free survival benefit the non-pCR group received with neoadjuvant and adjuvant pembrolizumab in KEYNOTE-522.43 The benefits of adjuvant olaparib are also substantial and we do not have evidence on the efficacy of olaparib initiated after adjuvant pembrolizumab has been completed.
Personally, I would complete the planned year of pembrolizumab and begin a year of oral olaparib in these patients concurrent with the adjuvant pembrolizumab. Of note, oncologists combine many chemotherapeutic agents with pembrolizumab with acceptable safety profiles, and phase II studies have not identified safety concerns when PD-1/PD-L1 inhibitors have been combined with PARP inhibitors. Thus, I do not see a need to avoid coadministration of olaparib and pembrolizumab in this setting. However, it is important to recognize that this combination was not included in the OlympiA study.
Marissa Marti-Smith, MSN, APRN, AGNP-C, AOCNP:
Anecdotally, we have used olaparib in the metastatic setting with 1 patient concurrently with pembrolizumab off label and it was very well tolerated.
Charles E. Geyer, Jr., MD:
The HR-positive group has become more complicated recently, with the updated monarchE data presented at SABCS 2022 by Johnston and colleagues.44,45 It appears the abemaciclib benefit in this study seems to be getting stronger with time. After PENELOPE-B demonstrated iDFS curves that came together following completion of 1 year of palbociclib,46 oncologists have been wondering whether a similar pattern would occur following completion of 2 years of abemaciclib. However, the iDFS curves in monarchE appear to be moving apart with a progressively more impressive hazard ratio over time.
OlympiA and monarchE both focused on patients with high-risk, ER-positive disease, but with the obvious difference that pathogenic variants in germline BRCA1 or BRCA2 were required for entry in OlympiA, whereas in monarchE, germline BRCA status was not a consideration for eligibility. The median age in monarchE was 51 years vs 42 years in OlympiA, so the study populations were clearly different. Due to overlapping toxicities, abemaciclib and olaparib cannot be coadministered, so HCPs must make a choice between the 2 agents in patients meeting eligibility criteria for both OlympiA and monarchE.
OlympiA demonstrated improvement in OS across the study population predominantly comprising patients with TNBC but with negative tests for interaction by HR status. This supports therapy with olaparib. By contrast, the monarchE trial has yet to demonstrate improvement in OS, although the hazard ratios for both iDFS and distant relapse-free survival are improving over time. Retrospective studies have also suggested that patients with germline pathogenic variants in BRCA2 with metastatic breast cancer may not respond as well to CDK4/6 inhibitors.47 Based on current information, olaparib would be preferred in patients with germline pathogenic variants and high-risk ER-positive/HER-negative early breast cancer. Abemaciclib could be considered as a viable alternative in patients with strong staining for ER and PgR in lower-grade tumors but with high clinical risk.
Charles E. Geyer, Jr., MD:
Another question that can be asked is: What about the patients who are high risk but would not have been eligible for adjuvant olaparib in OlympiA, for example, patients with high‑grade, HR-positive breast cancer with 3 positive nodes? Can we broaden eligibility now that we know the efficacy and have safety data with a median follow-up of 3.5 years? Personally, in patients with TNBC, I might do that a bit, although criteria were already fairly broad with that subgroup. But in the HR-positive group with the updated data from monarchE, I think olaparib will be difficult to justify. If patients with pathogenic variants in BRCA1 or BRCA2 and ER-positive breast cancer do not meet eligibility criteria for OlympiA, but do meet criteria for monarchE, I would employ abemaciclib.
Charles E. Geyer, Jr., MD:
What if a PALB2 mutation is identified in the high-risk, early-stage setting? Studies of PARP inhibitors in the metastatic setting have suggested that patients with PALB2 mutation–positive disease tend to respond comparably with those with BRCA1/2 pathogenic variants.48,49 We’re never going to get a study in early breast cancer launched specifically in patients with PALB2-mutated disease, and the consensus among my colleagues in the OlympiA leadership was that, yes, if the risk is high enough, it would be reasonable to consider PARP inhibition if they met criteria. Beyond that, probably not.
Allison Butts, PharmD, BCOP:
As a practical matter, we’re very limited, at times, by what insurance will cover. Any time we’re looking at going outside of the study population, insurance coverage becomes a very real concern and that could tie your hands and force you into one direction or the other. So, I think that’s important to point out too, unfortunately.
Charles E. Geyer, Jr., MD:
I agree it is important to recognize that when you go beyond the guidelines, you may run into insurance coverage issues. There’s always the risk that you may discuss a particular therapy with a patient and then later have to tell the patient that although you believe it might be beneficial, they can’t access the drug because of coverage and cost issues. That’s really not a good message. The effects of insurance coverage on treatment decisions are very challenging to manage because coverage can be so variable from carrier to carrier.
Back