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Our primary objective is to review the safety and tolerability profile of olaparib, a novel anticancer therapy, and to discuss key considerations for symptom management in patients with advanced ovarian cancer. Olaparib is the first of a new class of anticancer therapies, poly (ADP-ribose) polymerase (PARP) inhibitors that target tumors that have deficits in homologous recombination repair (such as BRCA mutations) by a process known as synthetic lethality. Through this process, neither the deficiency in homologous recombination repair nor PARP inhibition alone is cytotoxic, but the combination of these two conditions leads to cell death. In December 2014, olaparib received accelerated approval by the U.S. Food and Drug Administration (FDA) as monotherapy for patients with known or suspected deleterious germline BRCA-mutated (as detected by an FDA-approved test) advanced ovarian cancer who had been treated with at least three lines of chemotherapy. Most adverse events (AEs) reported during olaparib clinical trials conducted in patients with recurrent ovarian cancer and measurable disease were of grade 2 or less severity according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events. Fatigue and gastrointestinal AEs are among the most common in ovarian cancer clinical trials and can be particularly bothersome to patients. We focus on interventions to address these AEs in patients who are candidates for treatment with olaparib and allow them to remain on therapy for as long as clinically indicated.
Olaparib therapy represents a new approach to treating recurrent ovarian cancer. Some associated adverse events can have a substantial effect on quality of life. It is therefore important for patients, caregivers, and health care providers to have realistic expectations and a thorough understanding of the safety and tolerability profile of olaparib to prevent or alleviate key symptoms so that therapy can continue uninterrupted if possible. This report summarizes a practical approach to supportive care for patients receiving olaparib therapy.
Globally, more than 230,000 new cases of ovarian cancer and nearly 152,000 deaths were reported in 2012 . In the U.S., approximately 22,000 women are diagnosed with ovarian cancer each year. More than 70% of cases are detected at an advanced stage and require chemotherapy. Despite improvements in chemotherapy regimens and administration, ovarian cancer remains the most lethal gynecologic malignancy, with approximately 14,000 deaths annually [2, 3]. Since 1996, the standard regimen for first-line treatment after surgery has been a systemic platinum/taxane-based regimen . Unfortunately, despite high initial response rates, most patients experience recurrence and require additional therapies. Throughout treatment, it becomes particularly important to counsel patients and caregivers about the risks and benefits of specific treatments, establish realistic expectations, and help manage adverse events (AEs) and toxicities.
Poly(ADP-ribose) polymerase (PARP) inhibitors constitute a new class of anticancer therapies. PARP enzymes are involved in the repair of single-strand DNA breaks. Inhibition of PARP results in double-strand DNA breaks that can be repaired by homologous recombination [5–7]. BRCA-mutant cells, however, have defects in homologous recombination repair . Although neither the deficiency in homologous recombination repair nor PARP inhibition alone is cytotoxic, the combination of these two conditions, known as synthetic lethality, leads to the accumulation of double-strand DNA breaks and cell death (Fig. 1) [7–10]. As discussed in a recent review, therapeutic development of PARP inhibitors began in 2005, following earlier discoveries of the BRCA1 and BRCA2 genes in 1994 and 1995, respectively .
PARP inhibitors have the potential to change the paradigm of ovarian cancer treatment in comparison with other biologic agents for several reasons. Approximately 15%–21% of high-grade serous ovarian cancers may harbor a BRCA mutation . In addition, approximately 50% of these tumors may bear homologous recombination defects and could therefore be responsive to a PARP inhibitor . PARP inhibitors have a generally acceptable toxicity and tolerability profile  and are orally available, providing ease of administration. It is, however, important to understand the frequency and severity of common AEs and toxicities in order to offer appropriate counseling as well as supportive care and to manage expectations of patients, caregivers, and providers. Recommended dosage modification schemes can and should be used when needed as prophylactic and/or interventional strategies to address AEs, such as fatigue and gastrointestinal (GI) symptoms, and to maintain dose intensity and quality of life (QoL) for patients who are benefitting from PARP therapy.
We searched PubMed for prospective studies examining the use of olaparib in patients with recurrent ovarian cancer to characterize its safety and tolerability and for pivotal studies for all U.S. Food and Drug Administration (FDA)-approved therapies for patients with ovarian cancer. We tabulated the incidence of common AEs and examined the oncology literature to evaluate recommended approaches to managing the most common treatment-related AEs. We also developed a practical approach to supportive care for patients receiving olaparib therapy from our clinical experience, supported by general recommendations from the National Comprehensive Cancer Network (NCCN) guidelines and our literature review.
Olaparib (AZD2281) is administered orally and has activity against PARP-1, PARP-2, and PARP-3 . This agent (Lynparza; AstraZeneca Pharmaceuticals, LP, Wilmington, DE, http://www.lynparza.com) was the first in this class to receive approval by the FDA (on December 19, 2014) and is indicated as “monotherapy in patients with deleterious or suspected deleterious germline BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy” [13, 14]. The indication received accelerated approval based on objective response rate (ORR) and duration of response in clinical studies. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory studies. It is important to review the approved prescribing information carefully for guidance on using olaparib appropriately.
Outside the U.S., olaparib has been approved in the maintenance setting. For example, in the European Union, olaparib “is indicated as monotherapy for the treatment of adult patients with platinum-sensitive relapsed BRCA-mutated (germline and/or somatic) high grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete response or partial response) to platinum-based chemotherapy” .
Olaparib has undergone comprehensive clinical evaluation as single and combination therapy in heavily pretreated patients with ovarian cancer and has demonstrated efficacy in platinum-sensitive as well as platinum-resistant disease (Table 1) [16–20]. Note that most studies were not comparative, and caution should be exercised when comparing results with other agents. On the basis of initial studies, the current FDA-approved recommended dose is 400 mg twice daily (totaling sixteen 50-mg capsules) , which imposes a large pill burden for patients. A tablet formulation has therefore been developed to facilitate delivery of olaparib doses in fewer units. Currently, three phase III trials are evaluating the efficacy of olaparib 300 mg twice daily in tablet formulation in patients with BRCA-mutated advanced ovarian cancer (ClinicalTrials.gov identifiers: NCT01844986, NCT018743105, and NCT02282020).
In phase II studies, ORRs for the twice-daily, 400-mg dose ranged from 31% to 48%, and median progression-free survival (PFS) ranged from 7 to 9 months. Notably, relatively similar response rates were reported for both platinum-sensitive (38%) and platinum-resistant (30%) disease. However, in patients with non–BRCA-mutated tumors, ORRs were higher in platinum-sensitive tumors (50%) than in platinum-resistant tumors (4%) .
In a comparative study with pegylated liposomal doxorubicin (PLD), results revealed no statistically significant differences between the activity of olaparib and PLD in recurrent BRCA-associated ovarian cancer for PFS or ORR . When olaparib was studied in combination with cediranib, an oral tyrosine kinase inhibitor directed against vascular endothelial growth factor receptor 1, 2, and 3, a post hoc analysis showed that the BRCA wild type or unknown patient cohort achieved a significantly greater PFS benefit from the combination (PFS, 16.5 vs. 5.7 months; hazard ratio [HR], 0.32 [95% confidence interval (CI), 0.14–0.74]; p = .008) than the BRCA mutation group (PFS, 19.4 vs. 16.5 months; HR, 0.55 [95% CI, 0.24–1.27]; p = .16) . This difference was attributed to the possibility of greater synergy between the two agents in the setting of homologous recombination-proficient tumors and cediranib-induced hypoxia.
Safety and tolerability data for olaparib have been reported in the full prescribing information and in several published clinical studies. It is not generally possible to determine the extent to which symptoms are disease- or treatment-related. In the safety database for the FDA-approved indication (olaparib monotherapy in patients with deleterious or suspected deleterious germline BRCA-mutated [as detected by an FDA-approved test] advanced ovarian cancer who received at least 3 previous lines of chemotherapy), the most frequent AEs (≥20%) of all grades across 6 studies (n = 223) were fatigue (including asthenia), nausea, abdominal pain/discomfort, vomiting, anemia, diarrhea, nasopharyngitis/upper respiratory infection, dyspepsia, decreased appetite, myalgia, and arthralgia/musculoskeletal pain . In this population, the most frequent laboratory abnormalities (≥25%) of all grades were increase in creatinine and mean corpuscular volume elevation and decreases in hemoglobin, lymphocytes, absolute neutrophil count, and platelets. A large majority of AEs and laboratory abnormalities had severity of grades 1 and 2 . Dose interruptions as a result of AEs occurred in 40% of patients. Dose reductions and discontinuations occurred in 4% and 7% of patients, respectively.
The phase II basket study, which supported accelerated approval for olaparib monotherapy for fourth-line treatment and beyond, enrolled patients with confirmed BRCA mutations in whom standard therapies had failed. It highlights the variation in frequency of toxicities experienced by patients with ovarian cancer, as well as with breast and pancreatic cancer (Table 2) . Fatigue of any grade was most common in patients with pancreatic, ovarian, and breast cancer (73.9%, 60.1%, and 48.4%, respectively). Nausea was most common in ovarian cancer, followed by breast and pancreatic cancer (61.7%, 53.2%, and 47.8%, respectively). Diarrhea was most common among patients with ovarian and pancreatic cancer and less prevalent for those with breast cancer (29%, 30.4%, and 17.7%, respectively). In addition, dyspepsia and dysgeusia were highest among patients with ovarian cancer compared with those who had breast and pancreatic cancer (dyspepsia: 19.7%, 14.5%, and 8.7%, respectively; dysgeusia: 20.2%, 6.5%, and 4.3%, respectively). These differences in toxicities for patients with ovarian cancer compared with other solid tumors require special attention and early intervention to maintain dose intensity and prevent unnecessary drug discontinuation.
In the comparative phase II study with PLD for recurrent treatment of ovarian cancer, the rates of any grade nausea, fatigue, abdominal pain, vomiting, diarrhea, and anemia with olaparib were 72%, 56%, 25%, 47%, 38%, and 19%, respectively . Corresponding rates for PLD-treated patients were 50%, 38%, 31%, 28%, 25%, and 3%, respectively. The rates of grade 3 or 4 events were relatively low (<10%) for both olaparib and PLD treatment except for anemia, which occurred in 13% of olaparib-treated patients and 0% of PLD-treated patients.
Olaparib has been compared with placebo as maintenance therapy in patients with platinum-responsive disease in a randomized, phase II, double-blind study . The rate of key AEs are shown in Table 3, alongside the corresponding rates from monotherapy in the recurrent setting, to provide a framework for assessing the likelihood of AEs. Note, however, that direct comparisons cannot be made between studies because of numerous differences in design and study populations. Nausea, fatigue, vomiting, anemia, and dysgeusia of any grade occurred at rates at least 10% higher in the olaparib group than in the placebo group (Table 3): 68% versus 35%, 49% versus 38%, 32% versus 14%, 17% versus 5%, and 16% versus 6%, respectively). Rates of any grade 3 or 4 AEs were 35% in the olaparib group versus 20% in the placebo group. Generally, the rate and types of AEs are consistent with those of other olaparib studies.
A subsequent analysis of the maintenance study data showed that nausea, vomiting, fatigue, and anemia occurred early during treatment; were mainly grade 1 or 2; were generally transient; and resolved with supportive care without the need to change the olaparib regimen . AEs greater than grade 2 were reported as uncommon and were manageable with dose interruptions or reductions plus supportive care. The tolerability profile of patients with a known BRCA mutation did not differ from that of the overall population .
In another combination study, olaparib plus carboplatin and paclitaxel was compared with chemotherapy alone, which was then followed by a maintenance phase of olaparib alone compared with no treatment . In the first phase of the study, alopecia, nausea, neutropenia, diarrhea, headache, and dyspepsia occurred at a rate at least 10% higher in the combination group than in the group receiving chemotherapy alone. In the olaparib combination group, 65% of patients had AEs of grade 3 or higher compared with 57% in the chemotherapy-alone group. AEs occurring with a frequency at least 10% greater with olaparib maintenance therapy versus no treatment included nausea, fatigue, headache, constipation, decreased appetite, vomiting, and nasopharyngitis.
Relieving distress associated with disease- and treatment-related symptoms can involve a multidisciplinary team as well as an integrative approach. Many useful screening tools can help assess distress (Table 4). The Distress Thermometer Screening Tool is validated, is relatively simple to incorporate into clinical practice, and assesses a broad range of symptoms [25, 26]. Patients and caregivers may ask about complementary interventions, such as massage, yoga, acupuncture, meditation, and other stress-reduction therapies. Although data are limited, several of these approaches are effective in alleviating symptoms associated with cancer or its treatment, including fatigue, nausea, and vomiting [27, 28].
Fatigue and GI toxicities can be particularly problematic in patients with ovarian cancer because they may have baseline disease-related fatigue, overlapping myelosuppression from conventional chemotherapy, and GI symptoms from disease burden. Given the established toxicity profile of olaparib, prophylactic measures should be discussed and enacted to minimize the GI toxicities from treatment outset. It is important to set realistic expectations and reassure patients that dose modification may allow patients to continue receiving treatment despite potential fatigue and myelosuppression. In some cases, therapy can also be interrupted and restarted .
Fatigue and GI toxicities can be particularly problematic in patients with ovarian cancer because they may have baseline disease-related fatigue, overlapping myelosuppression from conventional chemotherapy, and GI symptoms from disease burden. Given the established toxicity profile of olaparib, prophylactic measures should be discussed and enacted to minimize the GI toxicities from treatment outset.
It is always important to evaluate patients for possible underlying causes or contributors to fatigue as an initial management step. Understanding key drivers of fatigue in any individual can be helpful in determining the best management plan for that patient .
Fatigue is common in patients receiving olaparib. Therefore, all patients taking olaparib should be screened for fatigue as if it were another vital sign; its management should be a routine part of care. For adults, fatigue can be graded on a 0–10 scale, with 10 being the worst fatigue imaginable . It is important to reassure patients that fatigue does not necessarily indicate disease progression. Patients should be advised to self-monitor and report their perceived grade of fatigue. They should receive guidelines on conserving energy by prioritizing tasks, using energy-saving devices, timing activities when energy is highest, and avoiding multitasking.
Patients who score their fatigue as moderate or higher may require additional active intervention, which may be both nonpharmacologic and pharmacologic. Nonpharmacologic options include massage therapy, cognitive-behavioral therapy, mind-body approaches, and other psychosocial methods [27, 29]. Early involvement of supportive and palliative care specialists will facilitate many of these interventions and reduce fatigue among patients, allowing them to continue on therapy with fewer interruptions. In addition, exercise and maintenance of physical fitness can help alleviate fatigue and distress. The amount of physical activity will of course depend on the individual’s physical condition and possible treatment-related limitations . Published recommendations, such as those of the American College of Sports Medicine, can be consulted .
Pharmacologic interventions, such as the psychostimulant methylphenidate, help improve fatigue. It is important to address other underlying causes of fatigue, such as pain or depression, and sleep disturbances with appropriate medications as needed . If all non-treatment-related causes have been addressed and fatigue is still an issue, the olaparib dose can be interrupted for a number of days to allow for symptom improvement back to baseline and then either restarted at the same dose or modified from 400 mg twice daily to 200 mg twice daily . For mild to moderate fatigue, we find a temporary dosing interruption helpful to allow fatigue to return to baseline, followed by resumption at the same dose level. Occasional breaks in dosing may be required during long-term olaparib therapy. In the case of more severe fatigue or fatigue that recurs despite dose interruptions, a dose reduction can be helpful.
Aside from fatigue, the experience of nausea and/or vomiting is one of the main toxicity challenges of olaparib treatment . Addressing nausea and vomiting proactively and aggressively is key to helping patients maintain adherence to the prescribed dose without significant deterioration in their QoL. The risk for chemotherapy-induced nausea and vomiting (CINV) is related to the treatment used (Table 5) , along with patient risk factors. The risk for olaparib-related nausea and vomiting has been well established across multiple studies but, fortunately, the risks for grade ≥3 nausea and emesis were relatively low (≤4%) in both the safety database and in published studies (Table 3) [13, 19, 21]. The incidence of all grades as well as grade 3 or higher nausea and emesis in the maintenance setting was consistent with that reported in the treatment setting (Table 3), suggesting that these AEs are truly drug-related and not disease-related [19, 21].
Importantly, even low-grade nausea and vomiting can be distressing to patients and must be addressed. According to the emetogenic potential described in Table 4, the emesis rate of 32% in the olaparib randomized clinical trial qualifies it as a “low emetogenic” agent [13, 31]. Risk factors that increase the chances of CINV include female sex, age <50 years, history of low prior long-term alcohol intake, and history of CINV with prior regimens , but specific risk factors that may increase the chance of nausea and vomiting with olaparib are not yet known.
CINV associated with intravenous, weekly, or greater than weekly chemotherapy has been classified as anticipatory, acute, delayed, breakthrough, and refractory , but these categories may not be entirely relevant with oral anticancer therapies, such as olaparib, which are taken on an ongoing basis with no scheduled time off. Thus, in our experience with oral agents, delayed-onset nausea/emesis does not occur, and no cumulative effects have been noted. Refractory nausea/vomiting can occur if control is inadequate.
For low oral-emetogenic risk regimens, the NCCN recommends that metoclopramide, prochlorperazine, or haloperidol be started before treatment and continued daily, according to the suggested schedule or as needed . Alternatively, a serotonin antagonist, such as dolasetron, granisetron, or ondansetron, can be used daily. If needed, physicians can add lorazepam and/or a histamine-2 blocker or proton-pump inhibitor . Caution should be used with serotonin antagonists in patients at risk for prolonged corrected QT intervals, and use of haloperidol should be accompanied by careful monitoring for dystonic reactions. The American Society of Clinical Oncology Clinical Practice Guideline update recommends only dexamethasone before chemotherapy for low-emetogenic agents . Although dexamethasone is effective, ongoing daily use may have unwanted AEs that may emerge during long-term olaparib treatment. Given the low oral-emetogenic risk of olaparib, we would not anticipate the need for aprepitant. In the event of severe or refractory nausea or emesis, aprepitant should be avoided because it is a CYP3A inhibitor and can increase olaparib plasma concentrations. If aprepitant use is not avoidable, the olaparib dose should be reduced one level .
We counsel patients proactively about the risk for nausea and emesis, provide upfront prescriptions for prochlorperazine and lorazepam, and escalate antiemetic regimens as needed. As with fatigue, dose interruption with resumption of starting dose or dose modifications of olaparib to 200 mg twice daily can be attempted if the antiemetic regimen has been optimized and other causes for nausea and emesis have been ruled out. It is useful to attempt dose interruption before dose reduction. Holding dosing of olaparib until symptoms have returned to baseline for a day or two may permit successful reintroduction of olaparib at the same dose. If this does not control symptoms, dose reduction as just described would be appropriate.
Diarrhea can lead to dehydration, electrolyte abnormalities, and psychosocial distress . Guidelines for managing diarrhea are based on the complexity of the symptom burden or toxicity grade. Patients with uncomplicated symptoms (Common Terminology Criteria for Adverse Events [CTCAE] grade 1 or 2) can be managed conservatively, whereas those with complicated symptoms (CTCAE grade (≥3) require thorough evaluation and close monitoring. Regardless of grade, patients with moderate to severe cramping, accompanying grade 2 or higher nausea and/or emesis, decreasing performance status, fever, sepsis, neutropenia, frank bleeding, or dehydration are considered complicated and require more aggressive management .
The rates of any-grade diarrhea in the recurrent ovarian cancer setting and the maintenance setting were similar (29% and 23%, respectively) (Table 3) [19, 21]. Interestingly, the prevalence of any-grade diarrhea among patients receiving placebo was 23%, indicating that some component of disease- and drug-related symptoms was occurring here. We do not have data on the percentage of patients who had complicated diarrhea based on concomitant symptoms as just described, so judicious evaluation and management of symptoms are important. It is essential to rule out other reasons for diarrhea, including infectious (e.g., Clostridium difficile) and dietary causes, obstipation, and other concurrent diseases, before attributing these symptoms to olaparib. If diarrhea appears to be olaparib-related, behavioral modification may be the first option.
Dietary modification with or without pharmacologic therapy can be used for uncomplicated symptoms. This includes eating smaller, more frequent meals; avoiding certain foods and beverages; and adopting the BRAT (bananas, rice, apples, toast) diet for mild cases . Many additional tips for managing diarrhea can be found in The Clinical Guide to Oncology Nutrition . These include avoiding food products with sorbitol, increasing fluid intake, and ensuring that fiber intake is predominantly of soluble rather than insoluble fiber .
Pharmacologic treatment focuses on reducing gut motility and secretions and increasing absorption. Options include loperamide or other opioids that reduce transit time, antiabsorbents (such as methylcellulose or pectin), and antisecretory agents (such as aspirin, bismuth subsalicylate, corticosteroids, or octreotide) . Dose interruption followed by dose modification of olaparib is an acceptable way to manage significant treatment-related diarrhea. We find that dose interruption that allows for resolution of diarrhea and institution of prophylactic medications permits resumption of olaparib at the starting dose and is our recommended first step for low-grade diarrhea. Higher-grade diarrhea is uncommon but may require earlier dose modification in addition to antimotility agents.
Dose interruption followed by dose modification of olaparib is an acceptable way to manage significant treatment-related diarrhea.
Dyspepsia, an uncomfortable, often painful feeling in the stomach, results from impaired digestion . The incidence of these symptoms among patients receiving olaparib in the recurrent setting was slightly higher (approximately 20%) than in the maintenance setting (approximately 16%) compared with only 4% for patients receiving placebo, indicating that this is a true drug-related AE (Table 3) [19, 21]. Discussing this possible AE with patients and early initiation of proton-pump inhibitors can help minimize the dyspepsia-related discomfort.
Dysgeusia, an abnormal experience with the taste of food, is graded as 1 or 2. Grade 1 is altered taste, but no change in diet. Grade 2 is altered taste with change in diet, along with a noxious or unpleasant taste or loss of taste . Dysgeusia was reported in approximately 20% of olaparib-treated patients with recurrent ovarian cancer [13, 19] and 14% of patients receiving olaparib for maintenance . Regardless of its grade, dysgeusia has a significant effect on a patient’s QoL .
Behavioral management strategies and patient education are critical for treatment for dysgeusia. Various strategies have been reviewed that can help patients improve how food tastes [37, 40]. Some examples include adjusting the temperature of the food to cool or room temperature, adding a sweet flavor to meat that can taste bitter, using more or fewer flavorings, adding fats or sauces, using saliva substitutes and sialogogues, rinsing the mouth with a baking soda solution, and practicing good dental hygiene [37, 40, 41]. Dysgeusia management must be tailored to the individual’s perceived taste alteration. There is no known pharmacologic intervention for dysgeusia.
Although several different PARP inhibitors are in development, olaparib was the first to be studied in patients with ovarian cancer and has undergone extensive clinical evaluation in both germline BRCA-mutated and sporadic ovarian cancer. Clinical data suggest appreciable prolongation of PFS, and olaparib is generally well-tolerated in heavily pretreated patients with ovarian cancer. Its toxicity profile consists predominantly of fatigue, GI-related AEs, and myelosuppression. Nevertheless, it is important that patients and caregivers be counseled on potential AEs and made aware that many of these can be effectively managed so that therapy can continue (Tables 6, ,7).7). PARP inhibitors offer a novel approach to the treatment of ovarian cancer because of their unique mechanisms of action, oral formulations, and ease of administration. Because most toxicities are relatively acceptable and addressable, management strategies can be tailored to each person’s circumstances. Undoubtedly, additional studies are needed to delineate long-term outcomes after PARP inhibitor use; however, the duality of promising outcomes and relatively limited toxicity is exciting and lends support to the recent approval of olaparib as the second biologic agent available for the treatment of ovarian cancer in the U.S.
This article was supported by AstraZeneca LP. Writing assistance from Paula G. Davis, Ph.D., and editorial support were provided by SCI Scientific Communications & Information, Parsippany, NJ, and The Lockwood Group, Stamford, CT (funded by AstraZeneca LP).
Conception/Design: Kathleen N. Moore, Bradley J. Monk
Provision of study material or patients: Kathleen N. Moore, Bradley J. Monk
Collection and/or assembly of data: Kathleen N. Moore, Bradley J. Monk
Data analysis and interpretation: Kathleen N. Moore, Bradley J. Monk
Manuscript writing: Kathleen N. Moore, Bradley J. Monk
Final approval of manuscript: Kathleen N. Moore, Bradley J. Monk
Kathleen N. Moore: Advaxis, Amgen, AstraZeneca, Immunogen, Roche, Genentech (C/A); Bradley J. Monk: AstraZeneca, Tesaro, Inc. (C/A), Tesaro, Inc. (RF), Astra Zeneca (H).
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board