Posted: Monday, April 9, 2018
Olaparib was the first poly (ADP-ribose) polymerase (PARP) inhibitor to be approved by the U. S. Food and Drug Administration (FDA) for the treatment of cancer. Its first approved use was for women with advanced BRCA1- or BRCA2-mutated ovarian cancer who had received three or more previous lines of chemotherapy.1 Indications have since been expanded to include maintenance therapy for women with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer irrespective of BRCA mutational status.2 Olaparib has also been recently approved for recurrent BRCA1- or BRCA2-mutated, HER2-negative metastatic breast cancer.3 Use of PARP inhibitors is also being investigated in other tumor types including prostate and gastric cancers.4–6
Presence of a BRCA1 or BRCA2 Mutation
According to David O’Malley, MD, a gynecologic oncologist and Professor at The Ohio State University Wexner Medical Center—James Cancer Center in Columbus, women with germline BRCA mutations who are being treated for recurrent ovarian cancer after three lines of chemotherapy “may not have had the option to receive olaparib in the maintenance setting.” In the platinum-sensitive maintenance setting, he continued, there are a number of reasonable options for patients with recurrent ovarian cancer: a PARP inhibitor (olaparib,7 niraparib,8 and now rucaparib9 are all approved), bevacizumab (for women previously treated with chemotherapy/bevacizumab), a clinical trial, or no treatment.10Although a germline BRCA mutation is not a condition of eligibility for treatment in the maintenance setting, “presence of such a mutation may influence the treatment decision in favor of a PARP inhibitor versus the other options,” Dr. O’Malley acknowledged.
Although a number of possible interventions are available for patients with BRCA mutations, Dr. O’Malley asserted that not even half of patients with ovarian cancer are tested at diagnosis for germline BRCA (or other homologous recombination deficiency [HRD] gene) mutations. According to Dr. O’Malley, a strong argument also can be made for tissue testing to identify somatic mutations, a recommendation that is included in the most recent version of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer.10
Likewise, Angeles Alvarez Secord, MD, Professor of Obstetrics and Gynecology at Duke University School of Medicine in Durham, North Carolina, emphasized the need for BRCA testing in patients with epithelial ovarian cancer. “Although those with mucinous cancer of the ovaries11 might not need to be tested,” she said, “as a general recommendation, I’d opt for universal testing.”
Management of patients who have been heavily pretreated can be clinically challenging. For instance, Dr. O’Malley pointed out that gastrointestinal functioning may be affected by the disease process (carcinomatous), as well as by previous therapies. Nevertheless, a PARP inhibitor should be “strongly considered as an option for those women with a BRCA mutation—if they have never received one—despite numerous previous therapies.” The challenge, he explained, is in administering olaparib and ensuring adequate absorption in patients with variable gastrointestinal function and tolerability.
Capsules Versus Tablets Versus Chemotherapy
When it was first approved, the olaparib regimen required patients to swallow 8 capsules twice a day, which represented a considerable challenge. “Now that patients can take 2 tablets twice a day, the regimen is easier,” Courtney Arn, CNP, explained. Ms. Arn, who works with Dr. O’Malley in the Gynecologic Oncology Center and the Gyn Oncology Phase 1 Program at The Ohio State University Wexner Medical Center, noted that despite this improvement, nausea is one of the most common adverse effects of olaparib.
The nausea associated with a PARP inhibitor is different from that associated with chemotherapy, Dr. O’Malley observed, because it is experienced daily. “With chemotherapy,” he said, “gastrointestinal effects will subside within 3 to 5 days of infusion. In contrast, the nausea or vomiting related to a PARP inhibitor may be perceived as more bothersome because it is ongoing, affecting quality of life on a continuing basis, every day.” Patients receiving olaparib tend to have more nausea than vomiting based on clinical trial data. Vomiting is often well controlled by recommended prophylactic antiemetic regimens, whereas nausea may be less amenable to pharmacologic control. The NCCN Guidelines for Antiemesis12 classify olaparib as having moderate to high risk for causing emesis.
Although olaparib-associated nausea occurs on a daily basis, generally related to dosing, patients usually “prefer to take oral therapy every day rather than have chemotherapy infusions, which tend to knock them out for several days,” Ms. Arn said. With olaparib, she continued, “they know how they can expect to feel every day, and they can adjust their activities and go ahead with their lives.”
Dr. Secord explained that olaparib was initially approved in heavily pretreated patients with significant tumor burden and even bowel involvement. “Now,” she said, particularly in the maintenance setting, with 2 tablets taken twice daily (vs 16 capsules daily) and a less-compromised population, “we’ve seen a much lower incidence of severe gastrointestinal symptoms.” Perhaps the most critical lesson learned, she added, is the need to discuss and manage these side effects proactively and “not to wait for patients to experience them and report them.” Antiemetic regimens are recommended prophylactically before anticancer therapy is initiated because it is difficult to treat emesis once it has started.12
Ms. Arn also noted that when olaparib was first approved, patients had been heavily pretreated and were generally sicker and more symptomatic than patients who are treated off trial today. “Some of them were nauseous even before they started olaparib,” she remembered, “so we needed to intensify antiemetic regimens, sometimes with a second agent. In contrast, patients who are treated in the maintenance setting feel fairly well and do not need more than one antiemetic, if any at all.”
If patients poorly tolerated previous chemotherapy, Ms. Arn said, starting with a full dose of olaparib might be problematic. In those cases, “we will start with 1 tablet twice a day. After 2 weeks, we follow up. If that dose is well tolerated, we will advise an increase to 2 tablets twice a day,” she said.
Preventing or Reducing Nausea
Nausea can be prevented or reduced if patients eat a little something before taking their olaparib dose. In addition, Dr. Secord noted, when olaparib was first approved, “we were cautioned not to prescribe the antiemetic ondansetron in conjunction with it. Therefore, we became quite comfortable using an alternative, olanzapine,12 which seems to be quite effective. The limitation about ondansetron has since been removed from the prescribing information, but we find that olanzapine works well for controlling drug-related nausea throughout the day.”
Nausea is more common than vomiting for patients receiving olaparib, but those who need to may take a prophylactic antiemetic, such as ondansetron, 30 to 45 minutes before they take olaparib. In contrast, for patients who feel nauseous throughout the day, a regimen taken around the clock is more likely to control symptoms, Ms. Arn said. Daily therapy with an oral serotonin (5-HT3) receptor antagonist (eg, ondansetron, granisetron, or dolasetron) is recommended as prophylaxis for oral anticancer agents at moderate to high emetic risk in the NCCN Guidelines for Antiemesis.12
“Many patients have already been treated with chemotherapy and have found medications such as prochlorperazine or metoclopramide as well as routines that work well for controlling their nausea,” Ms. Arn said. Therapy on an as needed basis (PRN) with an oral 5-HT3 receptor antagonist, oral prochlorperazine, or oral metoclopramide is recommended as prophylaxis for oral anticancer agents at low to moderate emetic risk in the NCCN Guidelines for Antiemesis.12 Prochlorperazine, metoclopramide, or other agents are recommended as breakthrough therapy for nausea/vomiting.12
“If those strategies don’t work,” Dr. O’Malley said, “we will try dose reduction to determine whether we can find a dose that the patient can tolerate. We’ve learned that adverse effects such as nausea seem to improve after 1 or 2 cycles. What we haven’t been able to determine, however, is whether this is due to dose reductions, patients’ own efforts and experimentation, or better physiologic tolerance over time.”
Patients should also be educated about the potential for fatigue. “What’s challenging about that,” Dr. Secord said, “is teasing out whether the fatigue is truly drug-related or may be secondary to anemia or disease. We follow blood counts, and if hemoglobin is 8 g/dL or lower, we will do a workup to determine whether there are other causes. Most of the time, though, it is a side effect of the PARP inhibitor, and we can reduce or delay [the PARP inhibitor], which allows hematologic improvement. Occasionally, supportive measures such as transfusions are used, but often holding treatment for a short period allows the blood counts to come back up.”
Dr. Secord often uses the information on the NCCN website (NCCN.org/patients/)13,14 to help during these discussions with patients. Tips include recognizing higher energy periods and prioritizing important activities during those times, as well as acknowledging that patients should pace themselves and rest, as necessary. In addition, light exercise and stretching can release endorphins, which may improve fatigue. “We are also sensitive to anxiety and depression, which can also contribute to fatigue,” Dr. Secord remarked. “Sometimes the problem may be that patients are not sleeping well, which affects daytime energy. I suggest that patients try melatonin to help them sleep at night, rather than immediately prescribing sleep medication. Because of the cancer, fatigue is not likely to disappear completely. How they can live their lives to the fullest is what we try to help with.”
Fatigue is common in patients with cancer and is associated with most anticancer treatments, Ms. Arn observed. “We check blood work monthly, and if hemoglobin (less than 8 g/dL) or platelets (less than 100,000/µL) are dropping, we will hold [the PARP inhibitor] treatment for a week and check laboratory results again. If the fatigue is starting to affect quality of life, we can try a dose reduction. A strategy that we’ve found to be quite effective for fatigue is to reduce the morning dose [of the PARP inhibitor] while maintaining the full bedtime dose,” she said.
A strategy that we’ve found to be quite effective for fatigue is to reduce the morning dose [of the PARP inhibitor] while maintaining the full bedtime dose.
Talking About Rare Risks
“I do not prescribe olaparib or any other PARP inhibitor to a patient without discussing the risk for development of MDS or AML,” Dr. O’Malley said. The risk of MDS is less than 1.5%.7 Whether this is roughly comparable to the risk associated with platinum agents is unknown, but if a patient’s hematologic toxicity persists, one must consider MDS.”
Pneumonitis has also been reported with olaparib, albeit rarely, in less than 1% of patients.7 However, if a patient reports a dry cough or increased shortness of breath and/or hypoxia is identified, pneumonitis should be considered. In a gynecologic oncology setting, and especially with standard chemotherapy regimens, Dr. O’Malley remarked, “pneumonitis is not at the top of our minds. Those professionals who frequently treat patients with immune checkpoint inhibitors and other immune-modulating drugs are now much more sensitive to the signs of pneumonitis, but it is less common in gynecologic oncology.”
Dr. Secord’s experience has been similar. “None of my patients have developed pneumonitis on olaparib, but it is important to be aware of this side effect and monitor accordingly. In addition, patients who receive chemotherapy can develop pneumonitis, and certainly those on immune checkpoint inhibitors are at risk.”
Education, Communication, and Adherence
Adherence continues to be a challenge with any oral therapy, particularly in the maintenance setting, where patients continue treatment until they have disease progression or unacceptable toxicity. “We encourage patients to keep track of their doses by marking them off once they have taken their tablets,” Ms. Arn explained, noting that some patients use a calendar, and others maintain a simple journal or make a chart for themselves. This is important because “we are talking about 2 tablets twice a day. If dose reductions are introduced and the morning dose is different from the evening dose, things can get confusing,” she said. Sometimes we will proactively write out everything for a patient, if we sense she might have trouble understanding or keeping track. And of course, we follow up often, especially with patients whom we think will be reluctant to report any issues.” Dr. O’Malley’s team also uses an FDA handout for patients about “how to take olaparib,” which describes administration details, including the warning about avoiding grapefruit juice, grapefruit, Seville oranges, and Seville orange juice because they inhibit CYP3A and can lead to increased levels of olaparib.
A Question of Cost
Patients who are prescribed a PARP inhibitor may face large co-pays, which can complicate the issue of proper adherence, Dr. O’Malley said. “Because cost is a huge issue for patients,” Ms. Arn added, “we start talking about maintenance early in the treatment course. If the plan is to start with 6 cycles of chemotherapy followed by maintenance, we have a discussion to determine whether the patient is interested. By cycle 4 or 5, if the patient wants to move forward with PARP inhibitor maintenance, our pharmacist will initiate the paperwork associated with a prescription for olaparib, with the instruction ‘Do Not Dispense.’ This way, we can discover how much of the cost, if any, insurance will cover, what the co-pay would be, and whether the patient is eligible for any assistance programs.”
At The Ohio State University Wexner Medical Center, the staff who administer the Medication Assistance Program work with the patient on her eligibility for assistance and/or grants. “The pharmacy department coordinates with us, so we can have our conversation with the patient first and give her notice that someone will be in touch about the financial aspects of treatment. By the time the patient is ready to start olaparib,” Ms. Arn said, “we know how much it will cost and whether/how much may be offered in assistance.”
Encourage Patients to Consider Clinical Trials
According to Dr. O’Malley, there are approximately 14 clinical trials of PARP inhibitors in the upfront and recurrent platinum-sensitive disease settings that are enrolling, ongoing, or planned. To optimize these regimens and “to get closer to the goal of curing more of these patients, we want to encourage patients to be treated on clinical trials. We don’t know whether use of combination regimens will ultimately be the best way to use a PARP inhibitor, but the only way to find out is to conduct well-designed, prospective, randomized clinical trials,” he said.
PARP Inhibitor Combination Regimens?
“We have been involved in trials of combinations with PARP inhibitors, and it’s usually the ‘partner’ drug that is associated with a side effect. In other words,” Dr. Secord said,” we might have to dose reduce the partner drug, leaving the dose of olaparib the same. Those investigational combinations come at a toxicity cost but may be more effective for patients without BRCA or other HRD mutations.”
Although olaparib has been approved in the maintenance setting for “all comers” (ie, even patients who are completely biomarker-negative [wild-type]), Dr. Secord noted that the magnitude of benefit is not usually as high for patients with wild-type disease as for those with germline BRCA or HRD mutations. “We believe that PARP inhibitor combinations may be more effective for those patients [with wild-type disease], pending results of clinical trials.” Even in those patients with mutations, Dr. Secord explained, resistance eventually develops, perhaps as a result of reversion mutations.15,16 “We don’t completely understand these reversions, but the addition of another drug at that point may be necessary to maintain anticancer efficacy.”
Despite speculation about the potential effectiveness of combination regimens and/or the patient subsets in which they might be particularly useful, Dr. O’Malley offered these words of caution: “I would strongly discourage the use of combinations outside of clinical trials, particularly with platinum agents. The toxicities of such combinations can become significant.”
Maintaining Good Quality of Life
According to Ms. Arn, patients generally tolerate a PARP inhibitor well. “The greatest challenge,” she said, “is finding the right dose, one that is effective yet tolerable. That process is patient-dependent and highly individual.”
The most common side effects—nausea, constipation, and fatigue—are usually manageable, she noted. It is important to control these adverse effects, “so that nausea doesn’t become vomiting, for example. It’s also critical that providers keep up with the monthly laboratory assessments, adjusting dosing according to results and encouraging patients to call whenever they have an issue or question. “Some patients experience changes in the way food tastes and may lose their appetite,” Ms. Arn said. “We don’t want side effects to become so challenging that we need to stop therapy. Our goal as clinicians is to give effective treatment that still allows the patient to do what she wants to do, whether it is travel, spend time with grandchildren, work, attend the theater, etc.”
Our goal as clinicians is to give effective treatment that still allows the patient to do what she wants to do.
“I would advise providers to read and become familiar with the specific prescribing information for olaparib because each PARP inhibitor is a little different,” Dr. Secord said. “The adverse events are different, the drug interactions may be different, and the monitoring requirements are different,” she noted.
“We’ve been impressed with how well most patients do with PARP inhibitor therapy. Many are thriving,” Dr. Secord reported. Those with germline BRCA or other HRD mutations “have done particularly well, and we’ve been excited about having this option for our patients. For those who do not have these mutations, we may need to think about adding another agent, which is what ongoing clinical trials are investigating. Nevertheless, in the originally published Study 1917 and subsequently in SOLO2,2 some patients have been on olaparib for 6-plus years, and 40% of those women have BRCA wild-type disease. We need to understand more about those patients,” she concluded.
David O’Malley, MD, has disclosed that he has participated in consulting and/or advisory boards for AstraZeneca, Clovis, Tesaro, Janssen, AbbVie, GOG Foundation, and Myriad.
Angeles Alvarez Secord, MD, has disclosed that she has received clinical trial grant funding from AbbVie, Amgen, Astellas Pharma Inc., Astex Pharmaceuticals Inc., AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Endocyte, Incyte, Merck, PharmaMar, and Tesaro. She has also participated on advisory boards for Alexion, AstraZeneca, Clovis, Janssen/Johnson & Johnson, Myriad, Roche/Genentech, and Tesaro.
Courtney Arn, CNP, disclosed no relevant relationships.
- Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA 1/2 mutation. J Clin Oncol 2015;33: 244–250.
- Pujade-Lauraine E, Ledermann JA, Selle F, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 2017;18:1274–1284.
- Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med 2017;377:523–533.
- Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med 2015;373:1697–1708.
- O’Sullivan CC, Moon DH, Kohn EC, et al. Beyond breast and ovarian cancers: PARP inhibitors for BRCA mutation-associated and BRCA-like solid tumors. Front Oncol 2014;4:42.
- Bang YJ, Xu RH, Chin K, et al. Olaparib in combination with paclitaxel in patients with advanced gastric cancer who have progressed following first-line therapy (GOLD): a double-blind, randomised, placebo-controlled phase 3 trial. Lancet Oncol 2017;18:1637-1651.
- Lynparza® (olaparib). Full prescribing information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208558s000lbl.pdf. Accessed March 6, 2018.
- Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med 2016;375:2154–2164.
- Coleman RL, Oza AM, Lorusso D, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet 2017;390:1949–1961.
- Armstrong DK, Plaxe SC, Alvarez RD, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer. Version 1.2018. Accessed March 6, 2018. For the most recent version of these guidelines, visit NCCN.org.
- Brown J, Frumovitz M. Mucinous tumors of the ovary: current thoughts on diagnosis and management. Curr Oncol Rep 2014;16:389.
- Ettinger DS, Berger MJ, Aston J, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Antiemesis. Version 1.2018. Accessed March 15, 2018. For the most recent version of these guidelines, visit NCCN.org.
- NCCN: Patient and Caregiver Resources. Fatigue. Available at https://www.nccn.org/patients/resources/life_with_cancer/managing_symptoms/fatigue.aspx. Accessed March 13, 2018.
- Christie EL, Fereday S, Doig K, et al. Reversion of BRCA1/2 germline mutations detected in circulating tumor DNA from patients with high-grade serous ovarian cancer. J Clin Oncol 2017;35:1274–1280.
- Mayor P, Gay LM, Lele S, et al. BRCA1 reversion mutation acquired after treatment identified by liquid biopsy. Gynecol Oncol Rep 2017;21:57–60.
- Ledermann J, Harter P, Gourley C, et al: Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med 2012;366:1382–1392.