Oral Oncolytics Expand Armamentarium in HR+/HER– Early-Stage Breast Cancer in Adjuvant Setting

Breast cancer is the leading type of cancer among women, comprising approximately a third of cancer cases in women in the United States in 2022.¹ Although early detection and screening have improved mortality, breast cancer remains the second leading cause of cancer-related death in women. Hormone receptor–positive (HR+), HER2-negative (HER2–) is the most common breast cancer subtype, accounting for 68% of diagnoses.²

Hormonal agents such as tamoxifen and aroma-tase inhibitors have historically been used in the early-stage setting to reduce the risk of metastatic recurrence. Recently, 3 FDA-approved oral oncolytic medications—abemaciclib (Verzenio; Eli Lilly and Company), olaparib (Lynparza; AstraZeneca), and capecitabine (Xeloda; Genentech)—have shown promising efficacy in improving disease-free survival (DFS).^3-5 However, these drugs have notably different safety profiles and target populations within the adjuvant setting (Table^3-5), making it valuable to assess the clinical trial data and management of key adverse events (AEs) for each drug when making treatment decisions for patients with HR+/HER2–breast cancer.

Abemaciclib

Abemaciclib is the first and only CDK4/6 inhibitor approved for use in the adjuvant setting for early-stage breast cancer.³ In regulated cell division, cyclin D complexes with cyclin-dependent kinases CDK4 and CDK6 to phosphorylate and inhibit tumor-suppressor protein retinoblastoma (Rb).^6,7 Further, CDK4/6 inhibitors block unchecked cell cycle progression in cancer cells by preventing the inactivation of Rb.

In the randomized, open-label, phase 3 monarchE trial (NCT03155997), investigators evaluated the addition of abemaciclib to physician’s choice of standard-of-care (SOC) adjuvant endocrine therapy (ET) for a total of 2 years vs SOC adjuvant ET alone in patients with high-risk HR+/HER2– early breast cancer.⁸

During the trial, the high-risk classification was defined as having lymph node involvement (≤ 4 positive nodes or 1-3 positive nodes) and 1 or more of the following: tumor size at 5 cm orgreater, histologic grade 3, or tumor Ki-67 levels at 20% or greater.

At the median follow-up time of 19.1 months, there was significant improvement in the primary end point of invasive disease-free survival (IDFS) with abemaciclib and ET compared with ET alone after 2 years (hazard ratio, 0.71; 95% Cl, 0.58-0.87; P < .001).⁸ The abemaciclib and ET arm also demonstrated statistically superior benefit in distant relapse-free survival (DRFS) rates at 93.8% vs 90.8% with ET alone (hazard ratio, 0.69; 95% Cl, 0.55-0.86; P < 001).

Additional follow-up data have been recently published, showing continued benefit in both end points beyond 2 years. This is important given that the overall risk of recurrence is highest within the first 2 to 3 years following diagnosis, particu-larly among those with high-risk features.⁹

AEs during the trial were consistent with the safety profile from prior analyses.^10,11 Common AEs in the abemaciclib arm were diarrhea (83.5%), neutropenia (45.8%), and fatigue (40.6%). Most AEs were classified as either grade 1 or 2.

During the first month of treatment, most patients experienced diarrhea; time to onset of diarrhea was 6 to 8 days and lasted 6 to 11 days.³ Early recognition and intervention are important for optimizing the management of diarrhea. Antidiarrheal agents such as loperamide can be started at the first sign of loose stools.

Patients experiencing diarrhea should notify their care team within 24 hours and increase oral fluid and electrolyte intake to prevent dehydration. For grade 2 diarrhea, dose interruption is recommended until toxicity resolves to grade 1 or lower. The manufacturer has additional guidance for dose adjustments with recurrent grade 2 or grade 3 to 4 diarrhea.

In addition to abemaciclib, palbociclib (Ibrance; Pfizer Inc) and ribociclib (Kisqali; Novartis) are 2 other CDK4/6 inhibitors that have been studied in the adjuvant setting. Palbociclib did not show a benefit in its respec-tive clinical trials.^12,13 The clinical trial with ribociclib is ongoing.¹⁴

One hypothesis for the lack of improvement in IDFS with the addition of palbociclib to ET concerns the dosing schedule of palbociclib.^8,15 Palbociclib is dosed on a cyclical basis around a schedule of 3 weeks on and 1 week off repeated every 28 days, whereas abemaciclib is dosed continuously daily. The difference between continuous vs intermittent dosing may have clinically relevant implications on efficacy in terms of achieving sustained inhibition of cell cycle progression and subsequent tumor cell proliferation.

This is especially important in the adjuvant setting where elimination of micromet astatic disease is the goal of treatment.¹⁶ This is one theory that has yet to be explored further. It is still unclear why palbociclib has not demon-strated benefit in this setting, but results from the ongoing NATALEE trial (NCT03701334) are eagerly awaited to provide further clarity.

Olaparib

Olaparib was approved in 2022 for patients with HER2– early-stage, BRCA mutated breast cancer at high risk of recurrence.⁴ BRCA1/2 mutations cause defects in the homologous recombination repair pathway, so tumor cells in patients with BRCA mutations rely on PARP enzymes to repair DNA. In patients with BRCA mutations, the inhibition of PARP enzymes by olaparib syner gistically results in cumulative DNA damage by blocking both DNA repair mechanisms, resulting in synthetic lethality and death of tumor cells.

In the phase 3, double-blind, randomized OlympiA trial (NCT02032823), patients with a germline BRCA mutation were randomly assigned to either olaparib or placebo for 1 year following neoadjuvant or adjuvant chemotherapy.¹⁷

Of enrolled patients, 82.2% had triple-negative breast cancer (TNBC) and 17.7% of patients had HR+/HER2– disease. IDFS (hazard ratio, 0.58; 95% Cl, 0.41-0.82; P< .001) and DRFS (hazard ratio, 0.57; 95% Cl, 0.39-0.83; P < .001) were significantly improved in patients who received olaparib vs placebo. Additionally, fewer deaths were reported with olaparib compared with placebo (59 vs 86; hazard ratio, 0.68; 95% Cl, 0.44-1.05; P = .02).

The most common AEs were nausea (56.9%), fatigue (40.1%), and anemia 23.5%); these were the main reasons for olaparib discontinuation in approximately 10% of patients.¹⁷ Anemia had the greatest frequency of grade 3 or higher events (8.7%). Nausea, generally grade 1 or 2, usually occurred within the first month of treatment, with time to onset of nausea at 5 days.¹⁸

Olaparib is classified as a moderate/high emetic-risk agent.¹⁹ The National Comprehensive Cancer Network (NCCN) recommends that patients who are newly starting olaparib take a serotonin receptor antagonist, such as ondansetron, 30 to 60 minutes prior to each dose.¹⁹ If after the first 2 weeks the patient experiences little to no nausea, it is our practice to have them shift their antiemetic medication to use as needed.

Capecitabine

Capecitabine was approved in 1998 for the treat-ment of metastatic breast cancer.⁵ It is a prodrug of 5-fluorouracil and inhibits thymidylate synthase, blocking production of essential metabolites needed for DNA and RNA synthesis in tumor cells.

In the multicenter, open-label, randomized, phase 3 CREATE-X trial (JBCRG-04), patients with HR+/HER2– breast cancer or TNBC who did not achieve pathological complete response or had node positivity after standard neoadjuvant chemotherapy were randomly assigned to receive adjuvant capecitabine or placebo every 3 weeks for 6 to 8 cycles.²⁰

Adjuvant therapy included ET for at least 5 years in patients with HR+ disease, and radiation therapy if indicated regardless of HR positivity.²⁰ The number of patients with TNBC comprised 32.2%, and the remaining 67.8% had HR+ breast cancer.

The DFS rate was higher in the capecitabine arm (74.1%) than in the control arm (67.6%) at 5 years (hazard ratio, 0.70; 95% Cl, 0.53-0.92; P = .01). Overall survival was also higher in those receiving capecitabine (89.2%) than in those who did not (83.6%) at 5 years (hazard ratio, 0.59; 95% Cl, 0.39-0.90; P = .01).

The results for DFS indicate that the greatest benefit was seen in patients with TNBC.²⁰ These results led to the inclusion of capecitabine within the NCCN guide-lines as postneoadjuvant therapy, with emphasis on use in patients with TNBC.

Of note, the study consisted of an Asian patient population in which pharmacogenomic and pharmaco-kinetic differences in the metabolism of capecitabine may contribute to the ability to tolerate the higher starting dose of 1250 mg/m² twice daily vs 1000 mg/m² (the standard dose commonly used in the United States).²¹ There is also evidence that a lower dietary folate intake predisposes Asian patients to lower incidences of toxicity from capecitabine.²²

When assessing the trial results, the investiga-tors observed that the most frequent AE was hand-foot syndrome (HFS; all grades, 73.4%; grade > 3, 11.1%).²⁰ Other common AEs were mostly grade 1 and included thrombocytopenia and anemia.

The median time to onset for HFS is 79 days but can range from 11 to 360 days.⁵ When counseling patients, oncology professionals should emphasize preventive measures, as HFS is a dose-dependent AE.²³

It is recommended that patients prophylactically use creams or other moisturizers multiple times per day on the hands and feet to prevent the development of HFS. Other supportive measures include wearing appropriately fitting clothes and shoes to reduce skin friction and avoiding prolonged direct heat exposure.²⁴ For grade 2 to 3 HFS, dose interruption is recom-mended until symptoms resolve or decrease to grade 1 or lower. Following grade 3 HFS, subsequent dose reductions are recommended.

Summary

The use of oral oncolytics in the adjuvant treatment of HR+/HER2– early-stage breast cancer continues to grow. Current use is restricted to specific subgroups of patients with HR+, node-positive disease with high-risk features or HER2– disease with BRCA mutations, or in those who did not experience a pathologic complete response after receiving neoadjuvant chemotherapy.^3-5

Abemaciclib, olaparib, and capecitabine all had low incidences of grade 3 or greater toxicities, and discontinuation due to AEs was low.^8,17,20

Pharmacists play a key role in monitoring therapy and optimizing supportive care to ensure most AEs can be managed in the outpatient setting. As more oral oncolytic options continue to emerge within this treatment setting, patients can be offered a highly tailored approach to therapy selection to achieve optimal outcomes.

References

1. Cancer facts & figures 2022. American Cancer Society. Accessed April 11, 2022. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2022/2022-cancer-facts-and-figures.pdf
2. Cancer stat facts: female breast cancer subtypes. National Cancer Institute Surveillance, Epidemiology, and End Results Program. Accessed April 11, 2022. https://seer.cancer.gov/statfacts/html/breast-subtypes.html
3. Verzenio. Prescribing information. Lilly USA, LLC; 2021. Accessed May 26, 2022. https://uspl.lilly.com/verzenio/verzenio.html#pi
4. Lynparza. Prescribing information. AstraZeneca Pharmaceuticals LP; 2022. Accessed May 26, 2022. https://den8dhaj6zs0e.cloudfront.net/50fd68b9-106b-4550-b5d0-12b045f8b184/00997c3f-5912-486f-a7db-930b4639cd51/00997c3f-5912-486f-a7db-930b4639cd51_viewable_rendition__v.pdf
5. Xeloda. Prescribing information. Genentech USA, Inc; 2021. Accessed May 26, 2022. https://www.gene.com/download/pdf/xeloda_prescribing.pdf
6. Burstein HJ. Systemic therapy for estrogen receptor-positive, HER2-negative breast cancer. N Engl J Med. 2020;383(26):2557-2570. doi:10.1056/NEJMra1307118
7. George MA, Qureshi S, Omene C, Toppmeyer DL, Ganesan S. Clinical and pharmacologic differences of CDK4/6 inhibitors in breast cancer. Front Oncol. 2021;11:693104. doi:10.3389/fonc.2021.693104
8. Harbeck N, Rastogi P, Martin M, et al; monarchE Committee Members. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study. Ann Oncol. 2021;32(12):1571-1581. doi:10.1016/j.annonc.2021.09.015
9. Cheng L, Swartz MD, Zhao H, et al. Hazard of recurrence among women after primary breast cancer treatment––a 10-year follow-up using data from SEER-Medicare. Cancer Epidemiol Biomarkers Prev. 2012;21(5):800-809. doi:10.1158/1055-9965.EPI-11-1089
10. Johnston SRD, Harbeck N, Hegg R, et al; monarchE Committee Members and Investigators. Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2–, node-positive, high-risk, early breast cancer (monarchE). J Clin Oncol. 2020;38(34):3987-3998. doi:10.1200/JCO.20.02514
11. Rugo HS, O’Shaughnessy J, Boyle F, et al; monarchE Committee Members. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: safety and patient-reported outcomes from the monarchE study. Ann Oncol. 2022;33(6):616-627. doi:10.1016/j.annonc.2022.03.006
12. Gnant M, Dueck AC, Frantal S, et al; PALLAS groups and investigators. Adjuvant palbociclib for early breast cancer: the PALLAS trial results (ABCSG-42/AFT-05/BIG-14-03). J Clin Oncol. 2022;40(3):282-293. doi:10.1200/JCO.21.02554
13. Loibl S, Marmé F, Martin M, et al. Palbociclib for residual high-risk invasive HR-positive and HER2-negative early breast cancer–the Penelope-B trial. J Clin Oncol. 2021;39(14):1518-1530. doi:10.1200/JCO.20.03639
14. A trial to evaluate efficacy and safety of ribociclib with endocrine therapy as adjuvant treatment in patients with HR+/HER2– early breast cancer (NATALEE). ClinicalTrials.gov. Updated February 18, 2022. Accessed June 20, 2022. https://clinicaltrials.gov/ct2/show/NCT03701334
15. Abdel-Razeq H, Sharaf B. Expanding the clinical use of CDK4/6 inhibitors in the treatment of hormone receptor-positive, HER2-negative breast cancer from metastatic setting to adjuvant setting. Drug Des Devel Ther. 2022;16:727-735. doi:10.2147/DDDT.S356757
16. Torres-Guzmán R, Calsina B, Hermoso A, et al. Preclinical characterization of abemaciclib in hormone receptor positive breast cancer. Oncotarget. 2017;8(41):69493-69507. doi:10.18632/oncotarget.17778
17. Tutt ANJ, Garber JE, Kaufman B, et al; OlympiA Clinical Trial Steering Committee and Investigators. Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer. N Engl J Med. 2021;384(25):2394-2405. doi:10.1056/NEJMoa2105215
18. Dosing and adverse reaction management strategies for Lynparza. AstraZeneca. Accessed July 3, 2022. https://www.lynparzahcp.com/breast-cancer/dosing.html
19. NCCN. Clinical Practice Guidelines in Oncology. Antiemesis, version 2.2022. Accessed July 3, 2022. https://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf
20. Masuda N, Lee SJ, Ohtani S, et al. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med. 2017;376(22):2147-2159. doi:10.1056/NEJMoa1612645
21. Zujewski JA, Rubinstein L. CREATE-X a role for capecitabine in early-stage breast cancer: an analysis of available data. NPJ Breast Cancer. 2017;3:27. doi:10.1038/s41523-017-0029-3
22. Yap YS, Kwok LL, Syn N, et al. Predictors of hand-foot syndrome and pyridoxine for prevention of capecitabine-induced hand-foot syndrome: a randomized clinical trial. JAMA Oncol. 2017;3(11):1538-1545. doi:10.1001/jamaoncol.2017.1269
23. Huang XZ, Chen Y, Chen WJ, et al. Clinical evidence of prevention strategies for capecitabine-induced hand-foot syndrome. Int J Cancer. 2018;142(12):2567-2577. doi:10.1002/ijc.31269
24. Kwakman JJM, Elshot YS, Punt CJA, Koopman M. Management of cytotoxic chemotherapy-induced hand-foot syndrome. Oncol Rev. 2020;14(1):442. doi:10.4081/oncol.2020.442