In this commentary, Allison Butts, PharmD, BCOP, and Kristina F. Byers, PharmD, BCOP, provide a review of recent advances in oral targeted therapies for the treatment of HR-positive/HER2-negative early breast cancer (EBC) and metastatic breast cancer (MBC), adverse event (AE) management, and tools for adherence.

HR-Positive/HER2-Negative EBC

Genomic Profiling
Allison Butts, PharmD, BCOP:
Today, multiple tests are available to assess the biology of tumors and to help us better understand which patients might benefit from chemotherapy and which could be spared. Novel and emerging therapies in the early-stage setting include PARP inhibitors, CDK4/6 inhibitors, PI3K inhibitors, and oral selective estrogen receptor degraders (SERDs).

Germline BRCA Testing
Allison Butts, PharmD, BCOP:
Profiling techniques with major treatment implications for EBC include germline BRCA mutation testing. Historically, germline testing has been recommended if a patient has a high hereditary risk plus personal and/or disease-related risk factors. Today, that has expanded to include patients who are eligible for adjuvant olaparib. The phase III OlympiA study of adjuvant olaparib has enrolled patients with early-stage, high-risk breast cancer and germline BRCA1 and BRCA2 mutations in both triple-negative and hormone receptor–positive cohorts. Patients were randomized to receive olaparib vs placebo for 1 year with the primary endpoint of invasive disease-free survival (iDFS). At 3 years, there was a significant iDFS benefit for olaparib with an absolute difference of 8.8%. An overall survival (OS) benefit of 3.4% at 4 years was recently reported at the European Society for Medical Oncology Congress, representing a significant improvement over placebo.

With the caveat that this subgroup analysis was underpowered, the triple-negative cohort did have a significant iDFS benefit (HR: 0.56) vs no significant benefit in the smaller hormone receptor–positive cohort. To date, the safety profile in OlympiA is consistent with prior studies of the drug.

Based on the 42% lower risk of invasive breast cancer recurrence and death seen in OlympiA, the FDA approved olaparib in early 2022 for adjuvant treatment in patients with germline BRCA-mutated, HER2-negative, high-risk EBC and prior neoadjuvant or adjuvant chemotherapy. Subsequently, BRCA testing to determine eligibility for adjuvant olaparib is expanding into the early-stage setting, as well.

Ki-67 Testing
Allison Butts, PharmD, BCOP:
The nuclear protein Ki-67 is an established prognostic and predictive indicator used to assess biopsies from patients with cancer. This test essentially tries to identify how many cells are replicating; a higher score has been shown to correlate with shorter DFS. Currently, Ki-67 is not recommended as a single biomarker to guide treatment in breast cancer (per the National Comprehensive Cancer Network), with the exception of adjuvant therapy with abemaciclib in patients with HR-positive, HER2-negative, node-positive EBC at high risk of recurrence.

In HR-positive EBC, most recurrences happen early—within the first 1-2 years. Abemaciclib is a CDK4/6 inhibitor studied as adjuvant therapy in the phase III monarchE study. Cohort 1 comprised high-risk patients with ≥4 positive lymph nodes or 1-3 positive nodes plus a tumor size ≥5 cm or grade 3 disease. Cohort 2 had 1-3 positive lymph nodes and a Ki-67 index of ≥20% with smaller, lower-grade tumors.

The FDA approval of abemaciclib in late 2021, based on monarchE data, is complicated and worth discussing. Results in the intention-to-treat population showed a significant benefit for abemaciclib plus standard endocrine therapy (ET) for 2 years vs ET alone; at 3 years, the absolute difference in the primary endpoint of invasive DFS was 5.4%. However, the HR for OS was 1.091, which is detrimental. Based on the interim analysis, the FDA did not approve abemaciclib for the overall population. However, those patients who had a Ki-67 of ≥20% did have an improvement in invasive DFS without diminishing OS. The FDA approval for abemaciclib is specifically for high-risk patients similar to those in cohort 1 of monarchE and with Ki-67 score ≥20%: HR-positive, HER2-negative, node-positive EBC with a Ki-67 score ≥20%. In our clinic, we now request Ki-67 testing for all patients being considered for abemaciclib.

For comparison, the PALLAS and PENELOPE-B studies both evaluated adjuvant palbociclib in EBC but found no benefit. In PENELOPE, longer follow-up showed the benefit diminishing each year, and in PALLAS, many patients discontinued early due to toxicity. Many trials are currently evaluating CDK4/6 inhibitors in EBC, including the phase III NATALEE trial, which is evaluating 3 years of adjuvant ribociclib in HR-positive, HER2-negative EBC.

HR-Positive/HER2-Negative MBC
Kristina F. Byers, PharmD, BCOP:
Unfortunately, up to 50% of patients with HR-positive MBC either have intrinsic or acquired resistance to endocrine-based therapies. Strategies to overcome endocrine resistance include combining targeted therapy or signal transduction inhibitors with ET.

CDK4/6 Inhibitors
Kristina F. Byers, PharmD, BCOP:
The preferred first-line regimen for HR-positive, HER2-negative metastatic breast cancer includes a CDK4/6 inhibitor in combination with ET (aromatase inhibitor AI or fulvestrant). When selecting among the 3 available CDK4/6 inhibitors, it’s important to consider long-term survival data, the patient’s menopausal status, toxicity profiles, monitoring parameters, potential for drug–drug interactions, and dosing schedules. In addition, premenopausal patients must receive ovarian suppression with a gonadotropin-releasing hormone agonist or undergo oophorectomy.

All 3 of the approved CDK4/6 inhibitors were studied in postmenopausal women in combination with letrozole in the first-line setting. In addition, ribociclib was evaluated in postmenopausal patients in the MONALEESA-3 trial with fulvestrant as the endocrine backbone and then in premenopausal patients in MONALEESA-7 with tamoxifen or an AI. Across all 3 landmark trials, the median progression-free survival (PFS) with the addition of a CDK4/6 inhibitor to first-line ET was approximately 24 months compared with 15-20 months with ET alone. This significant finding changed the treatment of HR-positive MBC.

Of importance, ribociclib is the only CDK4/6 inhibitor to date to demonstrate an OS benefit in the first-line setting. In MONALEESA-3, which included postmenopausal patients receiving ribociclib with fulvestrant in the first-line or second-line setting, at 42 months, median OS was 57.8 months with ribociclib compared with 45.9 months for placebo, corresponding to a 28% relative reduction in risk of death. In addition, an exploratory analysis showed that the OS benefit was maintained beyond 56 months of follow-up. In MONALEESA-7, which included premenopausal and perimenopausal patients, combining ribociclib with a nonsteroidal AI or tamoxifen resulted in an OS benefit: At 42 months, 70.2% of patients remained alive in the ribociclib group vs 46.0% with placebo, with a 29% relative reduction in risk of death.

Most patients with advanced HR-positive breast cancer will eventually develop resistance to a first-line CDK4/6 inhibitor plus ET. So, what do we do after progression on a CDK4/6 inhibitor? At present, data do not support changing the ET backbone and continuing the CDK4/6 inhibitor at time of progression. That said, I would consider continuing the CDK4/6 inhibitor and switching from an AI to fulvestrant in a patient with an ESR1 mutation. After a month or two of close follow-up, if the patient is still progressing, the CDK4/6 inhibitor should be discontinued, and appropriate second-line therapy should be initiated.

Allison Butts, PharmD, BCOP:
Research is ongoing to better understand if there is a benefit to continuing CDK4/6 inhibition after progression. There is some evidence that if a patient progresses on ribociclib or palbociclib, then abemaciclib may retain some activity, but the results are inconsistent.

Kristina F. Byers, PharmD, BCOP:
Cost can be a real issue with CDK4/6 inhibitors. Before the OS data with ribociclib were mature, I had not experienced issues with insurance coverage for any agent. Now we are seeing denials for palbociclib in the first-line setting and in premenopausal patients because some insurance companies prefer ribociclib. But not all patients are ideal candidates for ribociclib because of drug interactions or significant cardiac history. Patients often need help with out-of-pocket costs, specifically those with Medicare or high-deductible insurance plans. Luckily, all 3 agents have manufacturers’ assistance programs for help with costs.

PI3K Inhibitors
Kristina F. Byers, PharmD, BCOP:
The PI3K/AKT/mTOR pathway is frequently altered in HR-positive breast cancer and has been implicated in resistance to ET; up to 40% of advanced HR-positive breast cancers harbor a PI3KCA-activating mutation. Hyperactivation of the pathway and excessive PI3K signaling promote estrogen-independent growth of breast cancer cells. Inhibiting this signaling pathway can restore some degree of endocrine sensitivity. SOLAR-1 is a phase III study that looked at the combination of the PI3K inhibitor alpelisib with fulvestrant in patients with advanced HR-positive breast cancer with or without a PIK3CA mutation after a prior AI. Median PFS in the PIK3CA-mutant cohort (primary endpoint) was 11.0 months vs 5.7 months with placebo. Of note, no significant OS benefit has been seen despite a median follow-up of 42 months. The ongoing phase II BYLieve trial is evaluating second-line alpelisib in combination with either fulvestrant or letrozole in PIK3CA-mutant patients who had previously received a CDK4/6 inhibitor. This is more reflective of modern-day practice, where CDK4/6 inhibitors are typically used in the first-line setting. Patients in cohort A who received alpelisib plus fulvestrant after a CDK4/6 inhibitor plus AI had a median PFS of 7.3 months. Hyperglycemia was the most common grade >3 AE reported with alpelisib, occurring in 28.3% of patients (58.3% all grade). Patients in cohort B who received alpelisib in combination with letrozole after progression on a CDK4/6 inhibitor with fulvestrant had a median PFS of 5.7 months, and 46% remained alive without progression at 6 months (primary endpoint met).

Kristina F. Byers, PharmD, BCOP:
PARP inhibitors also have been evaluated in patients with HER2-negative MBC and germline BRCA1 or BRCA2 mutations. Olaparib and talazoparib were evaluated in the phase III OlympiAD and EMBRACA trials, respectively, both of which demonstrated an approximately 3-month absolute PFS benefit compared with chemotherapy in pretreated patients. As PARP inhibitors provide a shorter PFS than endocrine-based combination therapies, they are typically reserved for patients with a germline BRCA mutation who progress on a CDK4/6 inhibitor.

Oral SERDs
Kristina F. Byers, PharmD, BCOP:
Oral SERDs are currently being evaluated for the treatment of MBC. The phase III EMERALD trial compared elacestrant with fulvestrant or an AI in an estimated 466 men and postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had progressed after 1-2 lines of ET including a CDK4/6 inhibitor. Results to date show a small but significant PFS benefit for elacestrant in all patients (approximately 1 month) and in patients with an ESR1 mutation (approximately 2 months). Although the data are immature, there is a trend toward an OS benefit in patients with an ESR1 mutation, which is promising because these patients have poor response to estrogen-receptor modulators.

The ongoing phase I/II AMEERA-1 trial is evaluating another oral SERD amcenestrant, plus palbociclib, in postmenopausal women with MBC and progression on ET, either in the adjuvant or advanced setting. This is both a dose-escalation and dose-expansion study, and the recommended phase II dose of amcenestrant is 200 mg (with palbociclib). After a median follow-up of 14.8 months, the overall response rate was 32.4%, the clinical benefit rate was 73.5%, and the median PFS was 14.7 months. The ongoing phase Ia/Ib EMBER trial is evaluating the oral SERD imlunestrant in a planned 500 patients with ER-positive/HER2-negative advanced or metastatic breast cancer and up to 3 prior regimens. Early results indicate an overall response rate of 22% and a clinical benefit rate of 78% in patients (n = 9) receiving the recommended phase II dose of 400 mg daily. Treatment-emergent AEs were mostly low-grade, with the most common being nausea, diarrhea, and fatigue. Phase III trials of elacestrant, amcenestrant, and imlunestrant are ongoing.

AEs With Oral Targeted Therapy
Kristina F. Byers, PharmD, BCOP:
Neutropenia is the most common AE seen with palbociclib and ribociclib, and neutropenia is less common with abemaciclib. It is recommended that complete blood count (CBC) with differential be monitored every 2 weeks during the first 2 cycles, as neutropenia most often presents during this period. Diarrhea is the most common AE seen with abemaciclib, which occurs in up to 90% of patients. It is important to counsel patients to initiate antidiarrheal therapy with loperamide and increase oral fluid intake at the first sign of diarrhea. With alpelisib, the major dose-limiting AE is hyperglycemia due to the on-target effect of PI3K inhibition (PI3Kα plays a key role in glucose homeostasis). Overall, 65% of patients developed hyperglycemia in SOLAR-1, and 37% developed grade 3 or higher. Risk factors for hyperglycemia include a fasting plasma glucose ≥100 mg/dL or A1C ≥5.7%, BMI ≥25 kg/m², and prior history of gestational diabetes. Fasting plasma glucose and hemoglobin A1C should be assessed at baseline to identify patients at risk for hyperglycemia and be closely monitored during the first 2 cycles and periodically throughout treatment. In addition, patients should be educated on dietary and lifestyle modifications to minimize hyperglycemia. Toxicities associated with PARP inhibitors are primarily gastrointestinal (nausea, constipation, and diarrhea) and hematologic (anemia, neutropenia, and thrombocytopenia).

An online decision support tool with recommendations for the management of AEs with oral targeted therapies for HR-positive/HER2-negative breast cancer is available here. 

Adherence: Challenges and Strategies to Promote
Allison Butts, PharmD, BCOP:
Adherence is key to success with any therapy, including oral anticancer therapy. Factors that affect adherence may be related to well-being and how the patient feels that communication is going with the care team, in addition to other barriers such as access and lack of support. The patient needs to understand what AEs to expect, how the medication is taken, how long it must be taken, behavioral modifications to help with adherence, and what realistic outcomes look like. Also, timing matters. If a patient just received a diagnosis, they are often overwhelmed, and it may not be the best time to have that conversation. That said, these conversations should be conducted early and often.

Adherence to oral CDK4/6 inhibitors may be affected by pill burden and dosing schedule. Abemaciclib and palbociclib require only 1 tablet/capsule, whereas the starting dose with ribociclib is 3 tablets. Abemaciclib is dosed twice daily on a continuous schedule, whereas palbociclib and ribociclib are dosed once daily for 3 weeks and then 1 week off to allow for bone marrow recovery. Most can be taken with or without food, except for palbociclib capsules that should be taken with food (tablets can be taken with or without food).

With regard to AEs, neutropenia and fatigue are the main dose-limiting toxicities associated with CDK4/6 inhibition. Abemaciclib in particular can have dose-limiting gastrointestinal concerns that also can affect compliance. This includes increased diarrhea with bloating or discomfort in the abdomen and nausea.

For monitoring, the CBC is the main parameter with this class of drugs, as neutropenia is dose limiting. However, with abemaciclib, routine monitoring of liver function tests is also necessary, with more frequent testing near the start of therapy. Finally, ribociclib has additional monitoring parameters—EKG and electrolytes—due to the risk of cardiac abnormalities. Patients receiving alpelisib are often coprescribed antihyperglycemics, antidiarrheal medications, and antihistamines to try to minimize some of the most common serious AEs with this drug. However, this all adds to the overall pill burden. In addition, patients may require an antiemetic with the PARP inhibitors due to the higher risk of nausea and vomiting. In our clinic, we do not start a prophylactic antiemetic unless the patient has a history of significant nausea and vomiting. Also, PARP inhibitors carry the risk of progression to myelodysplastic syndromes or acute myeloid leukemia, which can be monitored via routine CBC.

Overall, a multidisciplinary approach is key to successfully initiating and maintaining a patient with breast cancer on oral targeted therapy. A good nurse navigator can help facilitate a holistic approach to ensure that the patient is involved in decision-making and has good communication with the care team. All of these practices have been shown to increase compliance and therefore clinical success with these agents.