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Why CDK 4/6 Inhibitors are Practice Changing in Advanced Breast Cancer

Systemic therapy for advanced, hormone receptor-positive (HR+), human epidermal growth factor receptor 2-unamplified (HER2-) breast cancer has drastically evolved over the past several decades, from oophorectomy to combination endocrine and molecularly targeted therapy. Cyclin-dependent kinase (CDK) 4/6 inhibitors are the latest addition to this arsenal of therapies, and while they have been rapidly adopted by most oncologists, many still question whether they belong in the first-line metastatic setting. Recent reporting of overall survival data, however, has re-invigorated the debate and strongly supports first-line use of CDK 4/6 inhibitors. This article will provide an overview of the evolution of systemic therapy in HR+, HER2breast cancer, summarize the data that led to the approval of CDK 4/6 inhibitors, detail the new overall survival data reported in the PALOMA-3, MONALEESA-7, MONALEESA-3, and MONARCH-2 trials, and then discuss why our patients should receive these drugs in the first-line setting for advanced disease.

Since the approval of palbociclib in 2015, 1 cyclin-dependent kinase (CDK) 4/6 inhibitors have been a heavily researched and discussed class of medication for the management of metastatic, hormone receptor-positive (HR+), human epidermal growth factor receptor 2-unamplified (HER2-) breast cancer. Because their approval and rise to prominence was based on benefit seen in progression-free survival (PFS), the ideal sequencing of therapy has been debated amongst oncologists. More recently, overall survival (OS) data from several studies have matured, hopefully putting to rest concerns about the appropriateness of CDK 4/6 inhibition in the first-line setting. This article will review the evolution of systemic therapy for advanced HR+ breast cancer leading up to the development and rise of CDK 4/6 inhibitors, followed by an overview and discussion of the recently reported survival data in these studies.

Evolution of systemic therapy for metastatic, hormone receptor positive breast cancer
In the textbook "Popular Medicine or The American Family Physician" published by Drs. George Capron and David Slack in 1854, the entry on "Cancer" comprises 2.5 pages in a 705-page tome, and breast cancer is the paradigm: 2 "The scirrhous… is a hard and irregular lump, which forms under the skin, in the breasts of women" and when "attended with a burning, shooting pain and the skin over it has become dusky, purple, or livid, it has become a confirmed cancer.
[…] The axillary glands and the arms will swell and become stiff and hard, and the whole body will partake of the disease. […] In some, the progress of the disease is rapid, and in others, exceedingly slow. […] Almost the only hope of a cure in this disease is found in having it removed by the knife. […]" 2 Fortunately, astute observers of the time noted that the size of some breast tumors changed during the menstrual cycle and that progression of disease might slow if a woman with breast cancer underwent menopause, leading to the hypothesis that ovarian hormones were linked to breast cancer progression. Dr. George Thomas Beatson of Glasgow Cancer Hospital published the results of bilateral oophorectomy in three women in The Lancet in 1896. 3 Having miraculously survived surgery in the late 19th century, one of his patients, a pre-menopausal, 40-year-old woman with inoperable breast cancer, had complete remission of disease and lived for another 4 years.
Professor Elwood Jensen's work, defining the role of estrogen and estrogen receptors in the 1950s-1970s, set the stage for development of targeted treatment for estrogen receptor-positive breast cancer, 4,5 the first of which was tamoxifen ( Figure 1). In the 1980s, the use of tamoxifen prior to chemotherapy, with chemotherapy, or after chemotherapy in women with advanced breast cancer was explored in DOI: https://doi.org/10.17925/OHR.2020. 16.1.23 Review Breast Cancer clinical trials with results showing that although the overall response rate to first-line cytotoxic chemotherapy is higher than that of tamoxifen, OS is virtually the same if chemotherapy is given prior to tamoxifen, tamoxifen prior to chemotherapy, or if tamoxifen and chemotherapy are given in combination. [6][7][8][9] Being far less toxic compared with cytotoxic chemotherapies (prior to the advent of powerful anti-emetics and granulocyte growth factors), tamoxifen became a preferred first-line therapy.
Aromatase inhibitors were originally studied and developed for clinical use by Harry and Angela Brodie, who were studying the enzyme, aromatase. 10 Aromatase inhibitors block estrogen biosynthesis by preventing the peripheral conversion of androgens to estrogens by the enzyme aromatase.
The current generation of aromatase inhibitors are anastrozole, letrozole, and exemestane, with anastrozole being US Food and Drug Administration (FDA)-approved in 1995, letrozole in 1996, and exemestane in 1999.
These aromatase inhibitors improved upon the tolerability and ease of administration of earlier generations of aromatase inhibitors. 11,12 The use of aromatase inhibitors in pre-menopausal women requires chemical ovarian suppression, oophorectomy, or ablation by radiation. Goserelin, a gonadotropin-releasing hormone analog, causes estrogen depletion via suppression of the hypothalamic-pituitary-gonadal hormone axis, and was approved for use in pre-menopausal women with breast cancer in 1995. [13][14][15] All three aromatase inhibitors have been evaluated in phase III clinical trials in post-menopausal patients with HR+, HER2-breast cancer in the first-line metastatic setting versus tamoxifen, with results demonstrating superiority in terms of median PFS; however, there are no clinical trials demonstrating the superiority of one aromatase inhibitor over another. [16][17][18][19][20][21] Fulvestrant is a selective estrogen receptor degrader/downregulator administered by depot intramuscular (IM) injection with a first-month loading dose followed by a monthly maintenance dose. FDA-approved in 2002 for use in the HR+, HER2-metastatic setting, fulvestrant was originally studied in clinical trials at a maintenance dosage of 250 mg IM monthly, which in 2010 was found to be suboptimal to a maintenance dosage of 500 mg IM monthly. 22 In the interim period between 2002-2010, fulvestrant 250 mg IM monthly was found to have efficacy similar to oral tamoxifen 20 mg daily in the first-line setting, 23 oral anastrozole 1 mg daily in the second-line setting, 24,25 and oral exemestane 25 mg daily in the second-line setting. 26 The FALCON study, published in 2016, compared fulvestrant 500 mg IM every 2 weeks x2 doses, followed by 500 mg every 28 days, to oral anastrozole 1 mg daily in the first-line metastatic HR+, HER2-setting, demonstrating a statistically significant median PFS of 16.6 months in the fulvestrant group versus 13.8 months in the anastrozole group. 27 In 2012, the concept of combining endocrine therapy with an additional molecular target was ushered in by the BOLERO-2 trial. BOLERO-2 was a phase III clinical trial studying the combination of everolimus, a mammalian target of rapamycin (mTOR) inhibitor, with exemestane in the Targeted therapies for HR+, HER2-breast cancer have evolved over the last and current centuries from bilateral oophorectomy for pre-menopausal women with breast cancer to more targeted therapies as more has been discovered about the biology of HR+, HER2-breast cancer. Aminoglutethimide and formestane were early aromatase inhibitors studied in clinical trials that were never FDA-approved for use. Raloxifene is a SERM that is not FDA-approved for use in patients with breast cancer. Leuprolide and goserelin were first FDA-approved for prostate cancer in 1985 and 1989, respectively. Leuprolide is used off-label for ovarian suppression in pre-menopausal women with breast cancer; goserelin was FDA-approved for this purpose in 1995. Everolimus is approved for use in combination with exemestane. The CDK 4/6 inhibitors are approved for use in combination with the non-steroidal aromatase inhibitors anastrozole and letrozole or with fulvestrant. Abemaciclib is also approved for use as a monotherapy. Olaparib and talazoparib are approved for use in breast cancers associated with pathogenic germline BRCA1 or BRCA2 mutations. Alpelisib is approved for use in breast cancers with activating PIK3CA mutations in combination with fulvestrant.

Rise of CDK 4/6 inhibitors
Though endocrine therapy had been the mainstay of treatment for HR+ breast cancer for decades, eventual endocrine resistance was almost universal. Alterations of key checkpoints in the cell cycle, including the CDK 4/6 pathway, were identified to be commonly associated with resistance to endocrine therapy. 32 Within the cell cycle, the transition between G1 and S phase is heavily regulated, and only occurs if the cell can proceed past the restriction point, or the "R point". 33 In its active, de-phosphorylated state, retinoblastoma protein (Rb) prevents this transition. CDK 4 and CDK 6, when associated with cyclin-D, regulate Rb by hyperphosphorylating and de-activating it, thereby allowing progression through the cell cycle.

Overall survival with CDK 4/6 inhibitors
These studies led to the widespread approval of palbociclib, ribociclib, and abemaciclib by regulatory agencies and the subsequent widespread adoption of these agents in the first-line metastatic setting. Over the last 2 years, OS data from some of these trials have matured (summarized in Table 1). The first trial to report on OS data was PALOMA-3. 45 The prespecified threshold of significance, taking into account a planned interim analysis, was a two-sided p-value of 0.047. The median OS in the palbociclib-fulvestrant group was longer than that of the placebo-fulvestrant group (34.9 versus 28.0 months). This 6.9-month absolute difference translated into a HR for death of 0.81 with a 95% CI 0.64-1.03 and a p-value of 0.09, and was therefore not considered statistically significant.

Review Breast Cancer
The median time to receipt of chemotherapy, however, was significantly improved in the fulvestrant-palbociclib group ( Since the approval of CDK 4/6 inhibitors, oncologists have questioned the appropriate sequencing of endocrine therapy in the metastatic setting. Is it best to start with aromatase inhibitor monotherapy and then add CDK 4/6 inhibition upon progression, or to start with the combination at the outset?
Prior to the CDK era, everolimus was the only approved agent that could be added to endocrine therapy, and it was common to utilize this only upon progression after NSAI and fulvestrant. The major reason for this choice of sequencing was due to the substantial side effect profile of everolimus.
Additionally, BOLERO-2 did not show significant OS benefit with the addition of everolimus. 51 Given the lack of OS benefit and more challenging side effect profile, adding mTOR inhibition seemed appropriate to delay until a later line of therapy. side-effect profile of these drugs facilitates first-line treatment, even in patients who are asymptomatic from their disease. 52 With palbociclib and ribociclib, the most common adverse event is neutropenia, which is largely asymptomatic, and very rarely associated with neutropenic fever. 52 Dose modification for neutropenia does not seem to impact survival outcomes, 53 and palbociclib-associated neutropenia may in fact be associated improved PFS (though more data are needed to confirm this). 54 While it is clear that these agents should be used in the first-line metastatic setting, several important clinical questions remain unanswered. Firstly, since the OS benefit seen in PALOMA-3 was not statistically significant, can the OS benefit seen with ribociclib and abemaciclib be extrapolated to palbociclib? While the Kaplan-Meier PFS curves were nearly interchangeable, suggesting equivalent efficacy, the three drugs differ in their chemical structure and have different side-effect profiles (i.e., QT prolongation with ribociclib, more diarrhea with abemaciclib). Therefore, it is possible that the observed differences in OS are related to these varying biochemical properties. However, it is important to keep in mind that while the OS benefit seen in PALOMA-3 was not statistically significant, it bordered on significance, and differences in outcomes could also be explained by differing patient populations in the two trials. Additionally, a real-world retrospective comparative effectiveness analysis of the Flatiron Health database by DeMichele and colleagues did show a statistically significant difference in OS in patients receiving first-line palbociclib and

Conclusions
Systemic therapy for HR+, HER2-breast cancer has steadily evolved over the past several decades. While the relatively recent introduction of CDK 4/6 inhibitors has resulted in rapid adoption of these agents, many oncologists rightfully questioned whether or not it was appropriate to Review Breast Cancer though these findings have been confirmed in a prior systematic review and meta-analysis. 50 These medications have helped patients live longer, with an acceptable side-effect profile, and have changed the game in the treatment of metastatic breast cancer. Ongoing trials will hopefully identify biomarkers that may predict response to these drugs, as well as understand whether or not these agents will improve disease-free survival in early stage breast cancer, potentially helping more patients live free of this disease. q