 as an adjuvant treatment for patients with germline 

-mutated, HER2-negative, high-risk early breast cancer and who have already undergone chemotherapy before or after surgery.

 Moreover,the efficacy and tolerability of the agent offers hope to a population of patients who often face a high level of disease burden, according to Charles E. Geyer, MD, FACP.

The regulatory decision was primarily supported by findings from the phase 3 OlympiA trial (NCT02032823), which demonstrated that olaparib yielded a 42% improvement in invasive disease-free survival (iDFS) compared with placebo. These results were deemed both statistically significant and clinically meaningful (HR, 0.58; 95% CI, 0.46-0.74; 

 recently presented at the March 2022 ESMO Virtual Plenary showed that treatment with olaparib reduced the risk of death by 32% compared with placebo (HR, 0.68; 98.5% CI, 0.47-0.97; 

= .009). In addition, the PARP inhibitor was associated with a 3-year survival rate of 92.8% (95% CI, 90.8%-94.4%) compared with 89.1% with placebo (95% CI, 86.7%-91.0%). At a 4-year follow-up, the survival rate was 89.8% (95% CI, 87.2%-91.9%) vs 86.4% (95% CI, 83.6%-88.7%), respectively.

Geyer, who is chief scientific officer of the National Surgical Adjuvant Breast and Bowel Project (NSABP) Foundation, and an investigator in the OlympiA trial, recently met with 

 to discuss the significance of the approval and what the updated data signify for this patient population.

®: Why are these findings and the recent FDA approval significant for this patient population?

: There has always been an extra burden [for this population]; these patients who find out they have a high-risk breast cancer and go through therapy know they have a persisting risk of recurrence, [because] they have this inherited germline mutation that predisposes them to further recurrence. That’s just been a lot to bear.

The thing that is nice about this therapy is [that it is] specific to the very thing that causes the cancer. Although there seems to be benefit from PARP inhibition for patients with ovarian cancer irrespective of their 

 seems to really be necessary [to see a] benefit. This is a new additional therapy, and it works very differently than everything else, and we are seeing a clear, substantial additive benefit with it.

When you're talking about finishing chemotherapy, surgery, radiation, and now we're [recommending], an additional year of therapy, it is good to hear that it is as effective as it is, but it is also really good to hear that it seems to be really fairly well tolerated and that this benefit can be achieved without too much of a burden for the patient.

What is the optimal dosing and administration of olaparib?

The starting dose in the study was 300 milligrams twice a day. The medication comes in tablets, there are 150 milligram tablets that are a greenish color, and 100 milligram tablets, which are yellow. Patients start out by taking 2 green tablets twice a day.

Is there anything related to the safety profile of olaparib that nurses should be aware of?

The most common side effect is nausea; almost 60% of patients reported some degree of nausea. Mostly grade 1, but any grade [of nausea] is not pleasant when you're [taking the agent] twice a day, day after day, so we want to really prevent that. The good thing we saw on the OlympiA trial was that the nausea seemed to be most intense during that first month of therapy, and subsided.

[However], it is important to work with patients to help them understand that. Additionally, doctors on the study found that sometimes patients do not hear how important it is to take [olaparib] with food. It can be a light meal [or] a snack, but we do [stress the importance of] taking it with food. That is a hugely important message.

The other major consideration is anemia. The anemia can cause fatigue as it becomes more pronounced. It will be important for doctors or nurses to learn how we managed that in OlympiA: we were pretty conservative. If the hemoglobin dropped below 9.5, we said to stop the drug until it came back up. If the hemoglobin came back quickly, (within a week or 2), we [returned to the same dose]. If it took longer [than 1 or 2 weeks), we reduced the dose.

Sometimes hemoglobin can drop quick enough [that] patients get symptomatic and might require transfusions; about 6% of the patients required a blood transfusion, but only 2% required more than 1 transfusion. It is important [to monitor] complete blood counts carefully, and [understand] that it is okay to hold the drug.

Sometimes patients feel “I need to take it, I can take it, and I don't feel bad enough to stop it.” However, you don't want the hemoglobin to drop: [the treatment] is a marathon—[they take it] for a whole year, so we want to work to find the correct dose. That will be important to keep in mind.

What will future research efforts involving olaparib entail?

These drugs work by inhibiting PARP, which is part of our DNA repair systems. We know that patients with ovarian cancer who have received PARP inhibition sometimes experience problems like leukemia. That was part of the reason we specifically [enrolled] higher-risk patients. We did not know how patients with breast cancer would do long term.

Thus far, it has been very gratifying to see no difference between placebo and olaparib in this patient population [in developing this specific adverse event], but this remains an important part of the study. We are going to follow these patients for [another] 10 years. We are going to be getting more information about how well the drug works and [any] possible late effects.

However, right now, with this degree of benefit and the tolerability, olaparib warrants consideration [as a treatment option], and the FDA agrees.

Lynparza approved in the US as adjuvant treatment for patients with germline BRCA-mutated HER2-negative high-risk early breast cancer. AstraZeneca. News release. March 11, 2022. Accessed March 23, 2022. https://bit.ly/3tQePcn

Tutt ANJ, Garber JE, Kaufman B, et al. Adjuvant olaparib for patients with 

. 2021;384(25):2394-2405. doi:10.1056/NEJMoa2105215

Tutt A, Garber JE, Kaufman B, et al. OlympiA: a phase III, multicenter, randomized, placebo-controlled trial of adjuvant olaparib after (neo)adjuvant chemotherapy in patients with germline 

 mutations and high-risk HER2-negative early breast cancer. 

. 2021;39(suppl 15):LBA1. doi:10.1200/JCO.2021.39.15_suppl.LBA1

Lynparza (olaparib) reduced risk of death by 32% in patients with germline BRCA–mutated, HER2–negative high–risk early breast cancer in phase 3 OlympiA trial. Merck. News release. March 16, 2022. Accessed March 22, 2022. https://bit.ly/36ByYeb

Articles

Oncology Nursing News® speaks with the Charles E. Geyer, MD, FACP, an investigator with the phase 3 OlympiA trial to better understand the significance of olaparib’s approval and to determine what oncology nurses need to know about the new agent.

FDA Follow-Up: Utilizing Olaparib in Clinical Practice for BRCA+ High Risk Early Breast Cancer

Adjuvant olaparib (Lynparza) induced a significant improvement in overall survival (OS) among previously treated patients with germline 

-mutated, HER2-negative, high-risk early breast cancer, according to findings of the OlympiA trial (NCT02032823) that were recently presented at the March 2022 ESMO Virtual Plenary.

In the analysis, investigators determined that olaparib reduced the risk of death by 32% compared with placebo (HR, 0.68; 98.5% CI, 0.47-0.97; 

= .009). Furthermore, the 3-year survival rate was 92.8% with the PARP inhibitor (95% CI, 90.8%-94.4%) compared with 89.1% for those on placebo (95% CI, 86.7%-91.0%). At a 4-year follow-up, the survival rate was 89.8% (95% CI, 87.2%-91.9%) vs. 86.4% (95% CI, 83.6%-88.7%), respectively.

Notably, these analyses are based on Kaplan-Meier estimates and are descriptive only.

“We knew that even with our best standard chemotherapy, surgery, [or] radiation therapy, [this high-risk population] would still be left with more than a 20% chance of their cancer coming back within the next 3 to 5 years [following treatment],” said Charles E. Geyer, MD, FACP, chief scientific officer of the National Surgical Adjuvant Breast and Bowel Project (NSABP) Foundation, in an interview with 

®. “We had an unmet need there. [Therefore], we've been looking for possible new therapeutics to try to improve the outcomes.”

Geyer noted that PARP inhibitors have now been under investigation for more than a decade as a specific targeted therapy designed for patients whose disease expresses these mutations. Although there have been many studies assessing the agent among patients with metastatic disease or advanced ovarian cancer, the OlympiA trial was unique because it looked at olaparib in the curative breast cancer population.

“We now are seeing statistically improved, significant improvement in survival [in our study population]. Right now, [there is] already a 3.5% improvement in survival,” he said. “[The] very good, consistent efficacy data, at a relatively early point in the study, is really demonstrating the efficacy of the drug.”

an adjuvant treatment for patients with germline 

-mutated, HER2-negative, high-risk early breast cancer and who have already undergone chemotherapy before or after surgery. The regulatory decision was primarily supported by findings from the OlympiA trial.

The phase 3, double-blind, parallel group, placebo-controlled, international OlympiA trial was designed to evaluate the efficacy and safety of olaparib against placebo as an adjuvant treatment for patient who have already completed definitive local treatment and neoadjuvant or adjuvant chemotherapy for 

-mutated, HER2-negative high-risk early breast cancer. The trial’s primary objective was to evaluate invasive DFS (iDFS), defined as time form randomization to first locoregional or distant recurrence or new cancer or a new cancer or death from any cause. OS represented the key secondary measure.

Previous findings from the OlympiA trial found that the agent yielded statistically significant improvements in iDFS; patients receiving olaparib had reduced their risk of invasive breast cancer recurrences, secondary cancers, or death by 42% (HR, 0.58; 99.5% CI, 0.41-0.82; 

Throughout the trial, olaparib demonstrated a safety and tolerability profile that was consistent with previous assessments. The most common adverse events (AEs) included nausea (57%), fatigue (42%), anemia (24%), vomiting (23%), headache (20%), diarrhea (18%), leukopenia (17%), neutropenia (16%), decreased appetite (13%), dysgeusia (12%), dizziness (11%) and stomatitis (10%). Ten percent of patients needed to discontinue treatment due to an adverse event. The most common serious AEs were anemia (9%), neutropenia (5%), leukopenia (3%), and fatigue (1.8%).

“So far, it's been very gratifying to see no difference between placebo and the olaparib in this patient population, but this remains an important part of the study,” Geyer concluded. “We are going to follow these patients out [for another] 10 years. We are going to be getting more and more information about how well the drug works and any possible late effects.”

However, currently, Geyer noted, the efficacy and tolerability data indicate that this drug is worthy of consideration as a treatment option for this patient population.

Lynparza approved in the US as adjuvant treatment for patients with germline BRCA-mutated HER2-negative high-risk early breast cancer. AstraZeneca. News release. March 11, 2022. Accessed March 11, 2022. https://bit.ly/3tQePcn

The PARP inhibitor demonstrated impressive overall survival benefit in patients with BRCA-mutated, HER2-negative, high-risk early breast cancer.

Olaparib Improves Survival in BRCA+, High-Risk Early Breast Cancer

Most, but not all, immunotherapy-related adverse events (irAE) occur throughout the first 12 weeks of treatment, and can affect any organ, according to La-Urshala Brock, FNP-BC, CNM, RNF, a clinical instructor specializing in breast and gynecologic cancers at the Nell Hodgson Woodruff School of Nursing with Emory University.

 Miami Breast Cancer Conference® about immunotherapy-related adverse event management, in a lecture titled, “Immunotherapy Adverse Effects,” which focused specifically on toxicities associated with pembrolizumab (Keytruda).

In July 2021, the PD-L1 inhibitor pembrolizumab was 

 to treat patients with triple-negative breast cancer (TNBC) in the neoadjuvant meeting in conjunction with chemotherapy, to be continued as an adjuvant monotherapy after surgery.

The approval for pembrolizumab was supported by findings from the randomized, multicenter, double-blind, placebo-controlled KEYNOTE-522 trial (NCT03036488).

 Results demonstrated a 37% reduction in the risk of disease progression that precluded definitive surgery, a local/distant recurrence, a second primary cancer, or death from any cause (HR, 0.63; 95% CI, 0.48-0.82; 

 = .00031).The recommended dose for intravenous pembrolizumab is 200 mg every 3 weeks.

Notably, this approval also marked the first immunotherapy to treat patients with high-risk early-stage TNBC. However, the introduction of the agent also opens the door for more toxicity management education for nurses who care for patient with breast cancer.

“Immunotherapies present with a novel spectrum of AEs that differ in important ways from those associated with chemotherapy and targeted agents,” said Brock. “When you're using immunotherapy, truly any organ can be affected. The median onset is 4 to 5 weeks [after beginning treatment], but adverse events can happen as early as when you start the treatment.”

Atezolizumab (Tecentriq), a PD-L1 inhibitor, was 

 for TNBC to be given every 3 weeks with weekly nab-paclitaxel (Abraxane) in 2019, but this agent was withdrawn from market, since it was not shown to improve survival in patients with locally unresectable metastatic, PD-L1–positive disease.

In her discussion, Brock highlighted a wide range of toxicities that are associated with immune checkpoint inhibitiors (ICI)—particularly for patients with TNBC receiving pembrolizumab. Toxicities of interest include dermatitis, endocrine effects, adrenal insufficiencies, lung effects, colitis, hepatotoxicity, and ocular side effects, in addition to a couple rarer immune-related AEs (irAEs).

ICIs may induce low-grade rashes in many patients. This can include reticular erythema, papules, and plaques. In more rare cases, Stevens-Johnson syndrome or toxic epidermal necrolysis, palmar–planta dysesthesia may also occur.

Effective management of skin-related toxicities involve frequent photo documentation of the toxicity and follow-up photos to track potential changes, as well as consulting a dermatologist to obtain a biopsy. For low-grade toxicities, symptomatic treatment with antihistamines typically prove to be effective. However, for high-grade toxicities, treatment with topical or oral steroids may be appropriate. In addition, if symptoms progress to grade 3, treatment should be withheld, and if symptoms worsen to grade 4, treatment should be discontinued.

“We hold at this point,” said Brock. “You could think about using rituximab [Rituxan] for treatment. You want to continue steroids until the blisters have resolved completely and then [once] the blisters have resolved, you want to slowly taper the steroids.”

Endocrine toxicities occur in approximately 10% of patients receiving pembrolizumab. Nurses should watch for vision changes, weight gain or weight loss, dizziness, constant chilliness or feeling cold, constipation, and hair loss. Other signs of endocrine toxicities include increased headaches or changes in headache patterns, increased heartbeat, increased urination, increased tiredness, increased thirst or appetite, changes in mood, and increased sweating.

Patients suspected to be experiencing these toxicities should have their thyroid-stimulating hormone (TSH) and free thyroxine (FT4) checked every 4 to 6 weeks with complete blood count (CBC) and comprehensive metabolic panel (CMP).

Adrenal insufficiency, or Addison’s disease, means that the adrenal glands produce insufficient amounts of the hormone cortisol, Brock explained. Signs and symptoms include extreme fatigue, darkening skin or hyperpigmentation, low blood pressure or fainting, abdominal pain, muscle or joint pain, salt craving, weight loss, depression or behavioral changes, and nausea, vomiting, or diarrhea.

For primary adrenal insufficiency, the workup should include assessing morning cortisone and adrenocorticotropic hormone (ACTH) levels, as well as CMP to assess sodium, glucose, potassium, and carbon dioxide.

If a patient has elevated TSH levels but normal or low FT4, then hypothyroidism is the cause. So long as the toxicity remains a grade 1 (TSH < 10 ml U/L or asymptomatic), they may continue receiving the checkpoint inhibitor with continued TSH and FT4 monitoring.

For hypophysitis, or inflammation of pituitary gland, the workup should include assessing morning cortisone as well as ACTH, TSH, FT4, testosterone in men, follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrogen in premenopausal women, and an MRI of the brain with or without contrast with pituitary cuts.

If the hypothyroidism progresses to a grade 2 (TSH > 10 mIU/L or symptomatic), the ICI should be withheld, an endocrinologist should be consulted, and a thyroid hormone supplementation should be implemented. The patients will continue to require TSH and FT4 checks every 6 weeks, but if the severity reduces to a grade 1 event, they may continue treatment.

In the event of grade 3/4 hypothyroidism, the ICI should be withheld until symptoms resolve to baseline with thyroid supplementation.

If a patient has low TSH and high, normal, or elevated FT4 levels, then this person is experiencing hyperthyroidism. As long as the toxicity remains at grade 1, they may continue receiving the ICI with continued TSH and FT4 checks every 2 to 3 weeks.

If the hyperthyroidism progresses to a grade 2, the ICI should be withheld until symptoms return to baseline and an endocrinologist should be consulted. A beta blocker might also be considered.

For grade 3/4 hyperthyroidism, the ICI will need to be withheld until symptoms resolve to baseline with thyroid supplementation. In addition, at this grade, hospitalization may be required if thyroid storm occurs. Prednisone should be considered at a dosage of 1 to 2 mg/kg daily and then put on a tapering schedule.

“With hyperthyroidism, what I want to mention here is that if someone is experiencing symptoms, we can use a beta blocker, but we also still want to be consulting endocrinology,” Brock highlighted. “One of the risk factors here when we get to grade 4 is the risk for thyroid storm. That is why it is important to have endocrinology involved.”

In less than 1% of patients, ICI-mediated endocrinopathy type 1 diabetes mellitus may occur with rapid onset anytime following therapy initiation.

Management for this toxicity involves monitoring serum glucose at baseline and prior to each cycle of ICI. An endocrinologist should be consulted, and generally, lifelong insulin therapy will be required. Once blood sugar is well controlled, the ICI therapy can be restarted.

Pneumonitis equates to inflammation of the lung parenchyma. This irAE occurs between 0% to 10% of patients, but the odds increase when patients receive combination therapy as opposed to monotherapy, as well as if there has been previous thoracic radiation.

 The onset time for lung toxicity can range from 2 to 24 months, however, the median onset time is 3 months.

Cough, fever, dyspnea, and chest pain should be evaluated when monitoring for lung toxicity. Patients who experience these symptoms will need a chest x-ray and CT scan. The threshold for obtaining a CT scan of the chest and a pulmonary consultation should be low, noting that CT findings typically lag patient symptoms.

Management includes routine pulse oximetry checks in addition to potential CT scans, as well as administration of high-dose steroids, starting at 1 to 2 mg/kg daily, and tapering across 45 to 60 days. If symptoms return, the steroids may require retapering.

If within 72 to 96 hours of steroid initiation there is no symptom relief, patients should receive infliximab-axxq (Avsola) at 5 mg/kg. In most cases, the addition of immunosuppressants will help to resolve the issue.Infectious workup should include a nasal swab for potential viral pathogens, including COVID-19.

Notably, lung toxicity has been associated with immune checkpoint inhibitors but is an uncommon AE; less than 5% of patients experience this irAE, and less than 1% report high-grade lung toxicity while receiving this type of immunotherapy. In comparison, lung toxicity tends to present more in patients receiving ipilimumab (Yervoy) plus nivolumab (Opdivo), explained Brock.

Colitis occurs in approximately 8% to 27% of patients receiving ICIs. Onset of GI toxicities typically appear about 5 to 10 weeks after treatment begins but can occur months after treatment with the ICI has stopped.

Initial workup for colitis should include CBC, CMP labs to assess TSH, c-reactive protein (CRP), HIV, hepatitis A and B; whereas interferon gamma release assay should be used to look for tuberculosis (TB). In addition, stool cultures to identify C. diff, CMB, ova, and parasites are recommended; lactoferrin should identify inflammation of digestive tracts and calprotectin can determine immune bowel disease (≤80 ug/g) vs inflammation (levels on 80 ≥ 1, 60 ug/g); and a CT scan.

At grade 1 severity, the ICI can either continue or be temporarily withheld. Providers should discuss dietary changes with their patients and review hydration strategies, and antdiarrheal administration may also be effective.

If the inflammation progresses to grade 2 level, the ICI should be withheld until symptoms return to grade 1 or less. A GI specialist should be consulted for an EGD/colonoscopy and prednisone should be administered at a dosage of 1 mg/kg daily. In addition, stools should be checked for inflammatory markers, such as lactoferrin and calprotectin. Once the symptom returns to grade 1, the steroids should be tapered across 4 to 6 weeks.

Grade 3 inflammation requires a hold on the ICI. Hospitalization may be required if there is electrolyte imbalance and dehydration. Providers should rule out CMV via colonoscopy and consult a GI specialist. Corticosteroids given at a dosage of 1 to 2 mg/kg day or infliximab at a dosage of 5 to 10 mg/kg daily should be administered.

“With colitis, there could be another rebound,” said Brock. “Someone could resolve back to a ready to a grade 1; if that occurs then, of course, we restart the steroids or increase the steroids and start again—slowly tapering once the symptoms improve.”

If the severity level reaches a grade 4, it is now life-threatening, and treatment should be discontinued permanently.

Hepatotoxicity or immune-mediated hepatitis occurs in approximately 2% to 10% of patients receiving pembrolizumab and onset usually occurs between 6 to 12 weeks after treatment initiation. Symptoms include drowsiness, jaundice, right-sided abdominal pain, severe nausea or vomiting, increased bleeding, or bruising, decreased appetite, and abnormal liver blood tests (aspartate aminotransferase [AST], alanine transaminase [ALT], and bilirubin).

For grade 1 inflammation (AST or ASLT > upper limit of normal [ULN] to 3.0 and/or total bilirubin 1.0 ULN > 1.5 ULN), ICI treatment may continue but liver function should be monitored 1 to 2 times weekly. For grade 2 inflammation (ASR or ALT > 3.0 ULN to 

 5.0 and/or total bilirubin 1.0 ULN to 3.0 ULN with symptoms), the ICI should be held until severity resolves to a grade 1.

In addition, the liver should be monitored every 3 days if the patient is symptomatic. If the symptom reaches statistical significance, after 3 to 5 days they can receive corticosteroids at a dosage of 0.5 to 1.0 mg/kg daily. This will require tapering over 1 month. Lastly, any hepatoxic medication should be halted.

For grade 3 inflammation (ASR or ALT 5 x 20 x ULN and/or total bilirubin >3-10 x ULN with symptoms such as biopsy-fibrosis or cirrhosis), the ICI should be discontinued permanently, and the patient should be monitored every 1 to 2 days. Corticosteroids should be administered at a dosage of 1 to 2 mg/kg/day, and the patient should be referred to a hepatologist.

If the symptom progresses to grade 4 (ASR or ALT >20 x ULN and/or total bilirubin > 10 x ULN, with symptoms such as ascites or encephalopathy), they will need to be hospitalized with daily lab monitoring and consultation from a hepatitis. They should receive methylprednisone at a dosage of 2 mg/kg daily.

Ocular symptoms typically occur in less than 1% of patient receiving PD-1/PD-L1 inhibitors alone or in combination. Symptoms include eyelid swelling, blurred vision, double vision, or color vision changes, photophobia, painful eye movement, scotomas, proptosis or bulging eyes, and visual field changes.

La-Urshala Brock, FNP-BC, CNM, RNFA, discusses effective toxicity management for patients with breast cancer receiving pembrolizumab. 

Checkpoint Inhibitors Present Unique Adverse Events, Require Careful Management Strategies in Breast Cancer

The technology for bioimpedance spectroscopy (BIS) has evolved rapidly in the past couple decades, according to Sheila L. Ridner, PhD, RN, FAAN. Moreover, the current technology is both easy to use and patient friendly.

“It is as easy to use as putting someone on a scale and getting their weight,” Ridner, a research professor at Vanderbilt University School of Nursing, explained in an interview with 

®,noting that the underlying technology is based on electrical current that measures the fluid between the cells. “It’s very simple. It’s very quick. It takes less than a minute to do.”

“The first patient that I ever measured loved the technology and said, ‘This makes so much more sense than being measured with a tape,’” Ridner recalled. “Because, [patients can] tell that tape measurements techniques vary from therapist to therapist or doctor to doctor or nurse to nurse. [Therefore], [BIS] standardizes the way you do the measurement, you cannot get it wrong: a nurse could weigh a patient, get their blood pressure, check their arm with BIS and take them right on to see their nurse practitioner, or their oncologist or their surgeon as part of a routine posttreatment visit. It is that easy.”

Videos

Sheila L. Ridner, PhD, RN, FAAN, provides an overview of bioimpedance spectroscopy and how the simple design allows for standardized subclinical lymphedema surveillance in breast cancer survivors.

Bioimpedance Spectroscopy: How It Functions and How It Improves Subclinical Lymphedema Detection

Agents such as gabapentin and olanzapine are effective treatments for breast cancer–related hot flashes and aches, according to Charles L. Loprinzi, MD. Furthermore, for the future, cryotherapy and laser therapy may also be effective for related toxicities, such as neutropenia and vaginal dryness.

Loprinzi, a consultant in the Division of Medical Oncology in the Department of Oncology at Mayo Clinic in Rochester, Minnesota, has conducted more than 100 symptom-control clinical trials, a research area that is critical to defining the best interventions to lessen treatment-related adverse effects (TRAEs).

“Symptom-control research is...aimed at trying to prevent, treat, and better understand symptoms caused by cancer and cancer treatment,” Loprinzi said in an interview with 

. “Patients with breast cancer can [experience] AEs from the treatments that we give them or from the disease itself.”

For example, patients with breast cancer frequently receive chemotherapy, which can lead to chronic nausea, vomiting, and neuropathy. Moreover, patients who receive endocrine therapy may experience hot flashes and aches and pains, and those who undergo surgery or radiation affecting the lymph nodes may develop lymphedema. However, the decision to stop treatment because of AEs can be controversial, and research regarding best practices is in its infancy, according to Loprinzi.

However, developing strategies for the nonestrogenic management of chemotherapy-induced hot flashes in patients with breast cancer is a topic that Loprinzi can speak to, having been involved in approximately 30 clinical trials on the subject throughout his career and now serving as the principal investigator of an ongoing phase 3 trial (NCT02961790). The study is evaluating lower doses of oxybutynin in patients who are not candidates for or not interested in hormone replacement therapy, with the goal of determining whether the lower dose results in fewer AEs than higher doses.

 Miami Breast Cancer Conference®, Loprinzi shared some of the most common treatment-related toxicities in breast cancer and provided insight into various current and investigational approaches available to patients.

 What are some common TRAEs in the breast cancer setting, and how are they typically managed?

 Hot flashes are sometimes caused by the treatments we give to patients with breast cancer. Sometimes that is because we deny them use of estrogen because we’re afraid of what estrogen might do in relation to [the] breast cancer. Because of that, looking at ways of inhibiting and treating hot flashes in patients without using estrogen has been a big topic [of discussion] over the past 15 to 20 years. We found a number of nonhormonal agents [as treatment options], such as antidepressants and other [gabapentinoids], oxybutynin, and progesterone-type hormones.

Another common problem for patients with breast cancer, which can be a long-standing problem, are AEs from aromatase inhibitor [AI] medications. [These] medications can cause some aches and pains that are going to be prominent, and they can lead to a lot of patients wanting to, or actually stopping, the medications. [However, data from] randomized placebo-controlled trials [have shown] that acupuncture can be helpful. There’s also some evidence that exercise [and] duloxetine may be helpful [in preventing or lessening aches and pains].

The other way to think about dealing with these AEs is [switching] to a different medication [besides] the AIs, [such as] tamoxifen, which does not have this problem. [Clinicians need to] decide what the benefit is that [they’re] trying to get from this medication and whether is it worth going forward with the treatment if the patient is experiencing a lot of AEs.

What are the optimal strategies for common TRAEs with chemotherapy?

Chemotherapy-induced neuropathy [is common]. A lot of the chemotherapy drugs can cause numbness, tingling, and pain, which can be problematic as patients are taking these medications and can limit how much the patients can take. [Unfortunately,] when you stop the medications, the effects can persist for months or years after and can cause patients to have more falls [and] hurt themselves and inhibit their quality of life for a long period. We want to give the chemotherapy the best chance to beat the cancer, but sometimes that judgment needs to be made if the help it provides [the patient] is outweighed by the toxicity caused by the treatment. Sometimes stopping therapy earlier might be the right answer, although it’s something that we don’t necessarily want to do.

To date, we don’t have anything that has been shown to be helpful in preventing this problem, other than not giving or lowering the dose of the chemotherapy. Having said that, one promising area is using cryotherapy as patients are getting chemotherapy. We know that when we put ice caps on patients’ scalps, it decreases blood flow [and] decreases metabolism, and patients could [experience] less hair loss when we go that route. [The same sort of thought process may also be true] for the hands or the feet. We don’t have proof of benefit yet, but there is a large effort toward doing a clinical trial, which hopefully will be able to answer this question. Some help [is provided with the addition of] duloxetine, which can be helpful for decreasing the [effects of certain AEs]; it doesn’t work very well, but it is [an option].

Another [top concern of mine] is nausea and vomiting when we give chemotherapy. Over the decades, we’ve had different treatments that are unhelpful for decreasing [these]. However, over the past few years, olanzapine, which is an antipsychotic-type medication, has come around, and we’ve been able to demonstrate that it’s helpful for decreasing nausea and vomiting, and it has [since] become established in [the breast cancer] setting. There is also relatively new information that the drug olanzapine can be helpful in patients with advanced cancers who are not getting chemotherapy or radiation therapy. Oftentimes, these are patients in their last weeks to months of their life, and they can have a lot of trouble with nausea and vomiting from the cancer or the other medications they’re [receiving]. There are data that olanzapine in that setting can decrease nausea and vomiting and stimulate appetite.

Beyond the scope of systemic therapy, what research is being done to address some of the AEs of surgery?

There’s a long list of [questions because] you can always try to make things better. [For example,] lymphedema—swelling of the arm—[is often a result of] surgery or radiation therapy affecting the lymph nodes under the arm, [and investigators are conducting the ongoing ARMtrial (NCT03333226), which is evaluating axillary reverse mapping to prevent lymphedema]. We know that when we [perform] surgery on the breast and take out the lymph nodes under the arm, that can cause swelling because those lymph nodes helped to drain the arm. The past decades have come to show that if you take out that sentinel lymph node and it’s negative, you don’t have to [remove] all the other lymph nodes in the arm. [This has resulted in] a lot less trouble with arm swelling. The way you find the lymph nodes that drain the breast is to put radioactive material or dye in the breast area, which goes to a lymph node, and the surgeon can look and see if the lymph node is blue or see that it has some reactivity and then knows to take it out. [A] randomized trial that’s ongoing right now [SCURCTN3276] is close to completing accrual, where [half of the] patients have the lymph [node] procedure and half of the patients do not.

What research has the potential to improve the future of toxicity management in breast cancer care?

There is a large effort with cryotherapy, and we’re well along in discussions with the [National Cancer Institute (NCI) to start a trial] that will randomize patients who are getting neurotoxic-type chemotherapy [such as] paclitaxel to cryotherapy [vs standard of care]. The group that developed the Paxman scalp caps for decreasing alopecia [is working to reduce chemotherapy-induced peripheral neuropathy] using a machine [placed on] the hands and feet. The coldness [from the machine is provided] in a regulated manner like the scalp [technology] and can also cause some compression too.

Data on why the process works [show] it decreases blood flow to that area when there’s a lot of chemotherapy in route, and there are data [showing] if you give some compression there, using tight surgical gloves, which was the easy way to do that, you get a compression that might be helpful.

Vaginal dryness [is another malady] that can create a big problem for patients as they go through menopause. It’s more problematic in patients with breast cancer because some of the treatments we give [such as] AIs decrease estrogen. Estrogen keeps the vagina relatively healthy, and when you decrease estrogen, it can cause vaginal dryness and pain with intercourse. There’s an approach called laser therapy where an instrument is put into the vagina and gives little pulses of laser, which may cause some irritation to the vaginal wall [but can] make the vaginal wall reproduce itself more to become thicker and better along that line. This protocol has NCI approval, and [investigators of the trial] will randomize patients with this condition to get the vaginal laser treatment vs vaginal treatment without a laser. The [objective of the] randomized trial is to help determine whether that’s a helpful approach for patients. It’s been controversial over the years as to whether [laser treatment is] beneficial or can cause more AEs than it is worth.

Clinical trials: oxybutynin chloride in managing hot flashes. Mayo Clinic. Accessed February 17, 2022. 

https://www.mayo.edu/research/clinical-trials/cls-20463111

Bordeleau L, Pritchard KI, Loprinzi CL, et al. Multicenter, randomized, cross-over clinical trial of venlafaxine versus gabapentin for the management of hot flashes in breast cancer survivors. 

. 2010;28(35):5147-5152. doi:10.1200/JCO.2010.29.9230

Mao JJ, Xie SX, Bowman MA, et al. A randomized, placebo-controlled trial of acupuncture and gabapentin for hot flashes among breast cancer survivors. 

. 2015;75(suppl 9):PD4-7. doi:10.1158/1538-7445.SABCS14-PD4-7

Henry NL, Unger JM, Schott AF, et al. Randomized, multicenter, placebo-controlled clinical trial of duloxetine versus placebo for aromatase inhibitor-associated arthralgias in early-stage breast cancer: SWOG S1202. 

. 2018;36(4):326-332. doi:10.1200/JCO.2017.74.6651

Fisher B, Costantino J, Redmond C, et al. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. 

. 1989;320(8):479-484. doi:10.1056/NEJM198902233200802

This article was originally published on OncLive as “Loprinzi Shares Top Concerns, Best Practices for Treatment-Related Toxicity Management in Breast Cancer”

Charles L. Loprinzi, MD, discusses the efficacy of agents like gabapentin and olanzapine to combat breast cancer treatment-related pains and speaks to the future of nonestrogenic toxicity management within this space. 

Expert Discusses Best Practices for Managing Breast Cancer–Related Toxicities

The FDA recently approved olaparib as an adjuvant treatment for patients with germline 

The approval is based on data from the phase 3 OlympiA trial (NCT02032823), which showed that olaparib led to a 42% improvement in invasive disease-free survival (iDFS) vs placebo, which was reportedly statistically significant and clinically meaningful (HR, 0.58; 95% CI, 0.46-0.74; 

Moreover, updated data showed that adjuvant olaparib also led to a 32% reduction in the risk of disease progression or death compared with placebo (HR, 0.68; 95% CI, 0.50-0.91; 

 = .0091). Overall survival findings will be presented at the upcoming ESMO virtual plenary on March 16, 2022.

The safety findings with olaparib were consistent with what has been reported in prior studies of the PARP inhibitor.

“Today’s approval of olaparib is great news for patients with a specific inherited form of breast cancer," Professor Andrew Tutt, global chair of the OlympiA trial and professor of oncology at The Institute of Cancer Research, London and King’s College London, said in a press release.

"Most breast cancers are identified in the early stages and many patients will do very well, but for those with higher risk disease at diagnosis, the risk of cancer returning can be unacceptably high and new treatment options are needed. OlympiA has shown that identifying a 

 mutation in women with high-risk disease opens the additional option of eligibility for olaparib treatment, which reduces the risk of recurrence and improves survival for these breast cancer patients.”

The multicenter, randomized, placebo-controlled OlympiA trial enrolled 1836 patients with HER2-negative breast cancer harboring a germline 

 mutation. Patients were randomized 1:1 to receive 300 mg of oral olaparib twice daily for 1 year (n = 921) or placebo (n = 915). Additionally, patients had to have been treated for stage II or III breast cancer, and have completed surgery and chemotherapy, with or without radiotherapy.

Inclusion criteria also required that patients have a high risk of disease recurrence. Those who had received prior treatment with a PARP inhibitor were not eligible for enrollment.

The primary end point for the study was iDFS; secondary end points included distant disease-free survival (DDFS), overall survival (OS), health-related quality of life, and safety.

Additional findings indicated that patients who received olaparib experienced a 43% reduction in DDFS, including metastatic disease, new cancer, and death due to any cause (stratified HR, 0.57; 99.5% CI, 0.39-0.83; 

 < .0001). The difference in the 3-year DDFS rate between olaparib and placebo was 7.1% (87.5% vs 80.4%, respectively; 95% CI, 3.0%-11.1%).

At the time of the interim analysis, OS data were immature. Although fewer deaths were reported in patients who received olaparib vs placebo, OS was not significantly different between the 2 study arms (stratified HR, 0.68; 99% CI, 0.44-1.05; 

 = .024). The difference in the 3-year OS rate between the olaparib and placebo arms was 3.7% (92.0% vs 88.3%, respectively; 95% CI, 0.3%-7.1%).

Regarding the safety profile, the adverse effects (AEs) reported in the olaparib arm were consistent with what has been previously reported with the agent. Additionally, olaparib did not increase serious AEs, including hospital admissions or occurrences of other cancers, such as leukemia.

However, grade 3 or higher AEs were reported more often in patients who received olaparib, and included anemia (9%), neutropenia (5%), leukopenia (3%), and fatigue (2%).

The most common AEs of any-grade reported in patients who received olaparib included nausea (57%), fatigue (40%), anemia (23%), vomiting (23%), and headache (20%). The most common AEs of any-grade reported in the placebo arm were fatigue (27%), nausea (23%), headache (17%), diarrhea (14%), and arthralgia (12%).

This article was originally published on OncLive as “FDA Approves Adjuvant Olaparib for BRCA+, High-Risk Early Breast Cancer”

Olaparib is now FDA approved for patients with germline BRCA-mutated, HER2-negative, high-risk early breast cancer and who have already undergone chemotherapy before or after surgery.

FDA Greenlights Olaparib for BRCA-Mutated, HER2-Negative Breast Cancer

Postmenopausal patients with hormone receptor–positive, HER2-negative advanced breast cancer achieved a statistically significant improvement in overall survival (OS) following treatment with ribociclib (Kisqali) plus letrozole vs letrozole alone. The results, which show that this benefit continues to increase over time, shine favorably on the use of the CDK4/6 inhibitor as a frontline treatment for this patient population.

Data from the phase 3 MONALEESA-2 trial (NCT01958021), which were published in the 

, showed that at a median follow-up of 6.6 years, the median OS achieved with ribociclib plus letrozole (n = 334) was 63.9 months (95% CI, 52.4-71.0) vs 51.4 months (95% CI, 47.2-59.7) with placebo plus letrozole (n = 334; HR, 0.76; 95% CI, 0.63-0.93; two-sided 

The Kaplan-Meier estimated 60-month OS rate with the doublet was 52.3% (95% CI, 46.5%-57.7%) vs 43.9% (95% CI, 38.3%-49.4%) with letrozole alone; at 72 months, these estimated rates were 44.2% (95% CI, 38.5%-49.8%) and 32.0% (95% CI, 26.8%-37.3%), respectively.

The OS benefit achieved with ribociclib plus letrozole over letrozole alone in exploratory patient subsets defined by patient and disease characteristics, geographic region, prior therapies received, and metastatic sites proved to be consistent with what had been observed in the overall patient population.

“What’s most compelling about these MONALEESA-2 data is to see that the OS benefit of [ribociclib] plus letrozole was improving over time for patients, regardless of disease characteristics,” Susanne Schaffert, PhD, president of Novartis Oncology, stated in a press release. “These meaningful outcomes are elevating the standard of care for people living with advanced breast cancer, who now have hope for a longer quality life. Data continue to show that [ribociclib] sets itself apart from other CDK4/6 inhibitors, and we look forward to continue studying all its potential benefits for patients living with hormone receptor–positive/HER2-negative breast cancer.”

MONALEESA-2 enrolled postmenopausal women with locally confirmed, hormone receptor–positive, HER2-negative recurrent or metastatic breast cancer who did not previously receive systemic therapy for advanced disease. To be eligible for enrollment, patients needed to have an ECOG performance status of 0 or 1, measurable disease per RECIST v1.1 criteria or at least 1 predominantly lytic bone lesion, as well as acceptable bone marrow and organ function.

If patients received prior CDK4/6 inhibitors, systemic endocrine therapy, or chemotherapy for advanced disease, they were excluded. Notably, patients who received prior neoadjuvant or adjuvant endocrine therapy were permitted.

A total of 668 participants were randomized 1:1 to receive ribociclib at a daily dose of 600 mg or a matching placebo. Participants in both arms received letrozole at a daily dose of 2.5 mg on a continuous schedule.

The primary end point of the trial was investigator-assessed progression-free survival. A key secondary end point was OS. Other secondary end points included overall response rate and safety. Biomarker analysis served as an exploratory end point.

Earlier data from the trial showed that at a median follow-up of 26.4 months, the median PFS with ribociclib plus letrozole was 25.3 months (95% CI, 23.0-30.3) vs 16.0 months (95% CI, 13.4-18.2) with placebo plus letrozole (HR, 0.568; 95% CI, 0.457-0.704; log-rank 

At the final analysis of OS, the median duration of exposure to trial treatment in the investigative and control arms was 20.2 months (interquartile range [IQR], 7.4-45.1) and 14.1 months (IQR, 7.1-28.9), respectively. The data cutoff date for OS was June 10, 2021.

Additional findings showed that among those who discontinued treatment, subsequent antineoplastic therapies were received by 87.8% of the 304 patients in the ribociclib/letrozole arm vs 90.2% of the 317 patients in the placebo/letrozole arm.

The most common subsequent therapy received was endocrine therapy alone, and this was received by 32.9% and 29.0% of those in the investigative and control arms, respectively. Fewer patients in the ribociclib arm vs the placebo arm received subsequent CDK4/6 inhibitors like palbociclib (Ibrance; 16.1% vs 31.5%), abemaciclib (Verzenio; 2.6% vs 3.8%), and ribociclib (Kisqali; 4.6% vs 1.9%) in any line of therapy, at 21.7% and 34.4%, respectively.

When adjusting for subsequent treatment with a CDK4/6 inhibitor, the estimated median OS in the placebo arm was 50.5 months (95% CI, 45.0-55.4) vs the 51.4 months (95% CI, 47.2-59.7) reported in the main analysis (HR, 0.73; 95% CI, 0.59-0.92).

In the intent-to-treat population, 28.9% of 621 patients who discontinued trial treatment subsequently received chemotherapy alone or as part of a combination; this included 28.0% and 29.7% of those in the investigative and control arms, respectively.

The median time to first subsequent chemotherapy received was 50.6 months and 38.9 months in the ribociclib/letrozole and letrozole/placebo arms, respectively (HR, 0.74; 95% CI, 0.61-0.91). Moreover, the median chemotherapy-free survival in the ribociclib arm was 39.9 months vs 30.1 months in the placebo arm (HR, 0.74; 95% CI, 0.62-0.89).

Regarding safety, the most frequently experienced toxicities that were grade 3 or 4 in severity and of special interest in the investigative and control arms, respectively, included neutropenia (63.8% vs 1.2%), hepatobiliary toxic effects (14.4% vs 4.8%), and prolonged QT interval (4.5% vs 2.1%). Additionally, 2 patients in the ribociclib arm experienced grade 3 interstitial lung disease (ILD) or pneumonitis vs no patients in the placebo arm. Notably, no grade 4 effects or deaths associated with ILD were reported in the investigative arm.

“This analysis of the MONALEESA-2 trial showed a significant and clinically meaningful difference in OS of 12.5 months with first-line ribociclib plus letrozole as compared with placebo plus letrozole in postmenopausal patients with advanced hormone receptor–positive, HER2-negative breast cancer, with a 24% reduction in the risk of death, the study authors concluded. “Taken together, the MONALEESA trials of ribociclib have shown a consistent OS benefit regardless of accompanying endocrine therapy, line of therapy, or menopausal status.”

Hortobagyi GN, Stemmer SM, Burris HA, et al. Overall survival with ribociclib plus letrozole in advanced breast cancer. 

. 2022;386(10):942-950. doi:10.1056/NEJMoa2114663

NEJM publication of Novartis Kisqali data shows longest median overall survival ever reported in HR+/HER2- advanced breast cancer. News release. Novartis; March 9, 2022. Accessed March 10, 2022. 

Hortbagyi GN, Stemmer SM, Burris HA, et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. 

. 2018;29(7):1541-1547. doi:10.1093/annonc/mdy155

This article was originally published on OncLive as “NEJM Data Underscore OS Benefit With Ribociclib/Letrozole in HR+ Advanced Breast Cancer”

New data support the use of ribociclib plus letrozole in the treatment of patients with postmenopausal patients with hormone receptor–positive, HER2-negative advanced breast cancer.

Ribociclib Regimen Elicits Longest Reported Median OS in HR+ Breast Cancer

Today, embryo and oocyte cryopreservation are 2 mainstays of fertility preservation in the realm of breast cancer treatment, according to Lindsay Kroener, MD, an assistant clinical professor in the Department of OB/GYN at UCLA David Geffen School of Medicine.

Kroener recently discussed the topic during the 

, “Answering Your Patient’s Questions About Fertility,” outlined the scope of the fertility preservation in cancer, different treatment options and candidate considerations, and conversations surrounding pregnancy following cancer treatment. In an interview with 

Kroener highlighted how egg and embryo cryopreservation have evolved over the years to represent the most reliable options for patients.

“These treatments are not going to be for everyone. But in terms [of oncofertility], egg and embryo cryopreservation are the best options we have,” she said.

Lindsay Kroener, MD, offers an overview of current fertility preservation options for patients about to undergo cancer therapy. 

Breast Cancer