Oncology Overview: Abemaciclib, a CDK4/6 Inhibitor for Prostate Cancer

The American Cancer Society has published good news that more than 3.1 million men in the United States who have been previously diagnosed with prostate cancer are alive.¹ The FDA has approved multiple agents for prostate cancer; however, unmet medical need remains.

Approximately 1 in 8 men will be diagnosed with prostate cancer during their lifetime. Individuals 65 years of age or older and non-Hispanic Black men are more likely to be diagnosed with prostate cancer.¹ In addition, castration-resistant prostate cancer (CRPC) may develop in 10% to 20% of patients within 5 years of diagnosis.²

Mechanism of Action

Abemaciclib (Verzenio; Eli Lilly and Company) is an FDA-approved kinase inhibitor being investigated for new indications in individuals with hormone-sensitive prostate cancer or CRPC.³ The cyclin-dependent kinases 4 and 6 (CDK4/6 proteins) control how quickly cells grow and divide.

These kinases are activated upon binding to D-cyclins.⁴ CDK4/6 inhibitors selectively target CDK4 and CDK6 and lead to the suppression of phosphorylation and subsequent inhibition of G1-S cell cycle progression.⁵

Dosing and Administration

The starting and maintenance dose for individuals in clinical trials with hormone-sensitive and CRPC taking abemaciclib has not yet been reported. Abemaciclib is currently available in 50 mg, 100 mg, 150 mg, and 200 mg tablets for other indications and can be taken orally with or without food.⁴ Prostate cancer studies will determine whether dosing interruption and/or dose reductions may be required, among other requirements.

Clinical Trials

Two late-stage phase 3 abemaciclib clinical trials for individuals with prostate cancer are listed on ClinicalTrials.gov. In the CYCLONE 2 study, researchers are investigating abiraterone acetate for its antiandrogenic effect.⁶ The primary outcome being evaluated is radiographic progression-free survival (rPFS) from baseline to radiographic disease progression or death from any cause within an estimated timeframe of up to 21 months.⁷

An additional trial, titled CYCLONE 3, is investigating rPFS from randomization to radiographic progression or death from any cause within approximately 48 months.⁹

Adverse Events (AEs)

Researchers have not reported specific AE details for abemaciclib in individuals with prostate cancer. For other indications, the most common abemaciclib AEs (incidence ≥20%) are diarrhea, neutropenia, nausea, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, alopecia, and thrombocytopenia.⁴

Drug metabolism and the cytochrome P450 enzyme system are important considerations in oncology. The current FDA-approved prescribing information for other indications warns that ketoconazole, a strong CYP3A inhibitor, can increase abemaciclib’s area under the concentration curve (AUC) up to 16-fold.⁴

Coadministration of 600 mg daily doses of rifampin (a strong CYP3A inducer) with a single 200 mg dose of abemaciclib decreased unbound AUC_0-INF of abemaciclib plus its active metabolites by approximately 70% in healthy subjects.

Special Populations

Researchers have not studied abemaciclib’s effects of on fertility in humans. Abemaciclib may impair fertility in males.⁴

In animals dosed with abemaciclib, cardiovascular and skeletal malformations have been identified. The abemaciclib monarchE breast cancer study required males to use an acceptable method of birth control and not donate sperm during the study and for at least 12 weeks following the last dose of abemaciclib.^10,11

In summary, researchers investigating abemaciclib for prostate cancer are striving to broaden the armamentarium for patients. Pipeline awareness enables pharmacists to be well positioned for health care team discussions.

Awareness of prostate cancer treatment advances, complex treatment regimens, and protocols contributes to enhancing the range of services provided and successful clinical decision-making. The pharmacist’s role as patient advocate and educator is critical as concerned oncology patients request discussion of therapeutic options for personized approach to care.

About the Author

Pamela Sardo, PharmD, BS, is a licensed pharmacist and a freelance medical writer at Sardo Solutions.

References

1. Key statistics for prostate cancer. American Cancer Society. Updated January 12, 2022. Accessed May 10, 2022. www.cancer.org/cancer/prostate-cancer/about/key-statistics.html
2. Cornford P, Bellmunt J, Bolla M, et al. EAU-ESTRO-SIOG guidelines on prostate cancer. Part II: treatment of relapsing, metastatic, and castration-resistant prostate cancer. Eur Urol 2017;71(4):630-42. doi: 10.1016/j.eururo.2016.08.002
3. Eight studies for abemaciclib and prostate cancer. ClinicalTrials.gov. Updated April 19, 2022. Accessed May 10,2022. https://clinicaltrials.gov/ct2/results?cond=Prostate+Cancer&term=abemaciclib&cntry=&state=&city=&dist=
4. Verzenio. Prescribing information. Eli Lilly and Company; 2022. Accessed May 4, 2022. https://uspl.lilly.com/verzenio/verzenio.html#pi
5. Wu C, Peng S, Pilie P, et al. PARP and CDK4/6 inhibitor combination therapy induces apoptosis and suppresses neuroendocrine differentiation in prostate cancer. Mol Cancer Ther. 2021;20(9): 1680–1691. doi:10.1158/1535-7163.MCT-20-0848
6. Zytiga. Prescribing information. Janssen; 2021. Accessed May 10,2022. https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/ZYTIGA-pi.pdf
7. A study of abiraterone acetate plus prednisone with or without abemaciclib(LY2835219) in participants with prostate cancer (CYCLONE 2). ClinicalTrials.gov. Updated April 19, 2022. Accessed May 6, 2022. https://clinicaltrials.gov/ct2/show/NCT03706365?term=cyclone+2&cond=Prostate+Cancer&draw=2&rank=1
8. Abemaciclib CDK4 & 6 Inhibitor Flashcards. Eli Lilly and Company; 2022. Accessed May 10, 2022. https://www.lillyloxooncologypipeline.com/flashcards/cdk_flash_card_off_cycle_feb_2022.pdf
9. A Study of Abemaciclib (LY2835219) With Abiraterone in Men With Prostate Cancer That Has Spread to Other Parts of the Body and is Expected to Respond to Hormonal Treatment (Metastatic Hormone-Sensitive Prostate Cancer) (CYCLONE 3). ClinicalTrials.gov. Updated April 26, 2022. Accessed May 6, 2022.https://clinicaltrials.gov/ct2/show/NCT05288166?term=CYCLONE+3&cond=Prostate+Cancer&draw=2&rank=1
10. VERZENIO® (abemaciclib): Use in Pregnancy and Lactation and Effect on Fertility. Eli Lilly and Company; 2022. Accessed May 6, 2022.https://www.lillymedical.eu/en-gb/answers/verzenios-abemaciclib-use-in-pregnancy-and-lactation-and-effect-on-fertility-91378
11. 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. https://doi.org/10.1200/JCO.20.02514