Breast cancer is the most common cancer among women in the United States and the second leading cause of death.^1,2 Data from 2019 reported that almost 3.8 million women are living with breast cancer in the United States, which translates into an average lifetime risk of 13%.¹ In other words, there is a 1 in 8 chance that a woman in the United States will be diagnosed with breast cancer in her lifetime. According to estimates for 2022, approximately 287,850 new cases will be diagnosed, and about 43,250 deaths will be attributed to breast cancer.¹ An analysis of trends from 2010 to 2019 shows an annual increase of 0.4% in the age-adjusted rate of incidence of new breast cancer cases. These data also indicate an average decrease of 1.3% each year in the age-adjusted death rates.¹ Indeed, this is a reflection of the progress in the treatment and management of breast cancer over time, wherein prognosis and therapy decisions are based on the expression of molecular markers for hormone receptors and human epidermal growth factor 2 (HER2).^3,4

The most common subtype of breast cancer is hormone receptor–positive and HER2-negative, which accounts for 65% to 70% of all cases.^5,6 Although this molecular subtype of breast cancer is associated with an overall 4-year survival rate of 92.5%, the rate lowers to between 35.9% and  60% among patients with metastatic disease, thereby indicating a need for more effective therapies.^7,8 Over the years, an increased understanding of the molecular underpinnings of hormone receptor–positive/HER2-negative breast cancer has led to the development and approval of inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6).^9,10 To that end, three CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) have now been added to the treatment arsenal, and the latest guidelines from the National Comprehensive Cancer Network (NCCN) and the American Society of Clinical Oncology (ASCO) recommend a CDK4/6 inhibitor in combination with endocrine therapy for patients with advanced hormone receptor–positive/HER2-negative breast cancer in the front-line setting.^3,4

The addition of CDK4/6 inhibitors for first-line therapy of advanced hormone receptor–positive/HER2-negative breast cancer represents a possible turning point in the treatment of this malignancy. Adam M. Brufsky, MD, PhD

In accordance with this, Adam M. Brufsky, MD, PhD, Professor of Medicine at the University of Pittsburgh School of Medicine, has stated, “The addition of CDK4/6 inhibitors for first-line therapy of advanced hormone receptor–positive/HER2-negative breast cancer represents a possible turning point in the treatment of this malignancy.” And Mark Pegram, MD, Susy Yuan-Huey Hung Endowed Professor of Medical Oncology at the Stanford University School of Medicine, underscored this sentiment by noting, “We now have level 1 evidence from a prospective, randomized controlled phase III clinical trial [MONALEESA-2] that the addition of CDK4/6 inhibition to aromatase inhibition in first-line estrogen receptor–positive/HER2-negative metastatic breast cancer significantly improves overall survival.”⁸

Approaches for Front-Line Treatment

Endocrine therapy was the first targeted approach for hormone receptor–positive/HER2-negative breast cancer and has been the mainstay of treatment for newly diagnosed patients.¹¹ It can consist of aromatase inhibitors (letrozole, anastrozole, or exemestane), selective estrogen receptor modulators (tamoxifen), or a selective estrogen receptor degrader (fulvestrant).^3,4 Use of endocrine therapy has largely replaced chemotherapy in the first line due to its superior therapeutic index (ie, higher response rate and less toxicity).¹¹ For patients without rapidly progressive, symptomatic, or significant visceral disease in the first-line setting, the latest NCCN and ASCO Guidelines suggest either fulvestrant in combination with a nonsteroidal aromatase inhibitor (letrozole or anastrozole) or an aromatase inhibitor plus a CDK4/6 inhibitor or fulvestrant plus a CDK4/6 inhibitor (Figure 1).^3,4

Either of these approaches has a category 1 recommendation and can be suggested for postmenopausal women who present with de novo metastatic breast cancer or those who progress ≥ 12 months from the end of adjuvant endocrine therapy.³ For premenopausal women, aromatase inhibitor therapy needs to accompany oophorectomy or ovarian suppression/ablation therapy.³ According to Dr. Pegram, “The combination of CDK4/6 inhibitors and endocrine therapy has now become the preferred therapy in the first-line setting of hormone receptor–positive/HER2-negative breast cancer.”

Among postmenopausal women with hormone receptor–positive breast cancer, combinations of the aromatase inhibitor letrozole with CDK4/6 inhibitors (palbociclib, ribociclib, or abemaciclib) demonstrated improved progression-free survival as compared to an aromatase inhibitor alone in a pooled analysis by the U.S. Food and Drug Administration (FDA).¹² In addition, a meta-analysis of nine randomized trials including more than 5,000 postmenopausal patients reported an overall survival benefit (hazard ratio [HR] = 1.33, 95% confidence interval [CI] = 1.19–1.48) with the addition of CDK4/6 inhibitor to endocrine therapy.¹³ These benefits have also been confirmed by a number of other analyses.^9,10,14,15 “CDK4/6 inhibitors specifically target the uncontrolled proliferation of breast cancer cells and lead to promotion of cellular senescence in target tumor cells. It is remarkable that a fundamental understanding of cell cycle control—which led to the Nobel Prize in Physiology and Medicine in 2001 for Leland Hartwell, Paul Nurse, and Timothy Hunt—has resulted in a novel targeted cancer therapy,” Dr. Pegram noted.

The combination of CDK4/6 inhibitors and endocrine therapy has now become the preferred therapy in the first-line setting of hormone receptor–positive/HER2-negative breast cancer. Mark Pegram, MD

CDK4/6 Inhibitors in the Front-Line Setting

The three approved CDK4/6 inhibitors for hormone receptor–positive/HER2-negative breast cancer—namely, palbociclib, ribociclib and abemaciclib—have been investigated in the PALOMA, MONALEESA, and MONARCH clinical trials, respectively.^9,10 In the PALOMA-1 phase II study, the combination of palbociclib and letrozole was associated with a progression-free survival of 20.2 months vs 10.2 months for letrozole alone among postmenopausal patients with hormone receptor–positive/HER2-negative advanced breast cancer.¹⁶ This was followed by the double-blind, placebo-controlled, phase III PALOMA-2 study, which included postmenopausal women with hormone receptor–positive/HER2-negative advanced breast cancer without a prior treatment for advanced disease.¹⁷ As shown in Table 1, the progression-free survival was 24.8 months for the group receiving palbociclib plus letrozole vs 14.5 months for letrozole alone.¹⁷ Other long-term follow-up data have corroborated the benefit of adding palbociclib to endocrine therapy in terms of patient-reported outcomes and improved quality of life.^18-20

The phase III MONALEESA-2 trial reported a progression-free survival of 25.3 months for ribociclib plus letrozole vs 16 months for letrozole alone among postmenopausal women with hormone receptor–positive/HER2-negative recurrent or metastatic breast cancer who had not received previous systemic therapy for advanced disease.²¹ Importantly, this study showed an overall survival of 63.9 months for ribociclib plus letrozole as compared to 51.4 months for letrozole alone. This difference in overall survival was statistically significant.⁸ Similarly, the efficacy of ribociclib in combination with fulvestrant was established in the MONALEESA-3 trial, which demonstrated a progression-free survival of 20.5 months for the combination vs 12.8 months for fulvestrant alone, as well as a significant overall survival benefit.²² The advantage of adding ribociclib to endocrine therapy was also demonstrated among pre- and perimenopausal women with hormone receptor–positive/HER2-negative advanced breast cancer in the MONALEESA-7 trial (23.8 vs 13 months for endocrine therapy alone).²³

The MONARCH-3 trial investigated the efficacy of abemaciclib plus a nonsteroidal aromatase inhibitor (letrozole or anastrozole) for the initial treatment of postmenopausal women with hormone receptor–positive/HER2-negative advanced breast cancer.²⁴ Although the progression-free survival was not reached for the abemaciclib plus aromatase inhibitor arm (vs 14.7 months for aromatase inhibitor alone), the overall response rate was 59% for the abemaciclib vs 44% for the aromatase inhibitor alone cohort, thereby confirming the utility of abemaciclib in the first-line setting.²⁴ “The availability of these three CDK4/6 inhibitors has expanded the therapy options for hormone receptor–positive/HER2-negative breast cancer,” stated Dr. Brufsky.

Front-Line Therapy Considerations

The choice of the endocrine therapy backbone is a key question that remains unanswered, and the latest guidelines suggest either an aromatase inhibitor or fulvestrant.³ Some experts believe that for patients who do not relapse on adjuvant aromatase inhibitor, fulvestrant can be reserved for the second-line setting, and an aromatase inhibitor backbone can be used in the first-line setting.⁹ On the other hand, use of fulvestrant in combination with CDK4/6 inhibitors can be considered in the first-line for patients with de novo metastatic breast cancer.⁹ Data from the PARSIFAL trial, however, showed that fulvestrant and letrozole appeared to perform comparably when paired with palbociclib in the first-line treatment of metastatic breast cancer.²⁵

Another important question is how to choose between available CDK4/6 inhibitors. Since palbociclib, ribociclib, and abemaciclib have not been compared in head-to-head trials, clinicians will have to rely on safety and efficacy data to choose one over the other for individual patients. Dr. Pegram pointed out that, “The three approved agents have similar progression-free survival rates and overall response rates. Given that the gold standard for cancer therapy is overall survival, at face value, ribociclib would be the agent of choice currently until overall survival data become available for palbociclib and abemaciclib.” However, he emphasized that “Not all of these clinical trials are adequately powered to decisively measure overall survival benefits, and therefore in my mind all three CDK4/6 inhibitors may well have similar efficacy. Moreover, there were differences in baseline characteristics between the trials, crossover rates differed between the trials, and the trials were conducted in varied geographic regions—some of which have different standards of care for the treatment of advanced estrogen receptor–positive breast cancer. Therefore, cross-trial comparisons of the overall survival endpoint may be hazardous.”

Not all of these clinical trials are adequately powered to decisively measure overall survival benefits, and therefore in my mind all three CDK4/6 inhibitors may well have similar efficacy. Mark Pegram, MD

Dr. Brufsky agreed and clarified that “Overall survival was a secondary endpoint in the PALOMA-2, MONALEESA-2, and MONARCH-3 trials.” He further cautioned against cross-trial comparisons, encouraged considering the safety and toxicity profiles of CDK4/6 inhibitors, and suggested monitoring for interstitial lung disease when using any of the FDA-approved CDK4/6 inhibitors. As shown in Table 2, each of the CDK4/6 inhibitors have distinct adverse effects and drug-drug interactions that can greatly influence treatment decisions among diverse patients.²⁶ For instance, ribociclib can result in prolongation of the corrected QT interval (QTc) on electrocardiography. Therefore, its use in combination with other drugs that can cause QTc prolongation is contraindicated to avoid arrythmia.²⁷ Similarly, abemaciclib may not be advisable for use among patients with diarrheal disorders such as inflammatory bowel disease, since one of its known common side effects is diarrhea.²⁸ Palbociclib is associated with neutropenia and transaminase elevation, but both toxicities can usually be mitigated by dose modification.^16,29

“Clinicians need to inform patients about the available efficacy data and toxicity profiles of these agents,” Dr. Pegram advised. According to Dr. Brufsky, “Real-world data can possibly be useful in guiding treatment decisions for front-line hormone receptor–positive/HER2-negative advanced breast cancer.” Moreover, drug-drug interactions are also a critical factor to consider when deciding on front-line therapy for patients with comorbidities. To this end, concomitant use of strong CYP3A inhibitors/inducers may interact with some CDK4/6 inhibitors. Additionally, drugs with the potential to prolong the QT interval (amiodarone, haloperidol, methadone, moxifloxacin, ondansetron, sotalol) should be avoided with ribociclib, and abemaciclib should not be co-administered with ketoconazole.^26-28 Both Dr. Pegram and Dr. Brufsky echoed that the exorbitant cost of CDK4/6 inhibitors remains a major barrier towards their use. “Improving access to these efficacious therapies is therefore an urgent priority,” they concluded.

Published on May 19, 2022.