Toxicity Profiles and Real-World Data Guide CDK4/6 Inhibitor Selection for Metastatic Breast Cancer

The strategic management of hormone receptor–positive breast cancer now requires balancing trial-specific adjuvant outcomes, patient-centered toxicity considerations, nuanced differences between available CDK4/6 inhibitors, and the emerging role of oral selective estrogen receptor degraders (SERDs) for patients with ESR1-mutant disease, according to Yelena Novik, MD. 

“We have a lot of clinical questions and unmet needs in this population that we hopefully will [answer], because breast cancer progression or metastasis can occur even many years after original diagnosis,” Novik said in an interview with OncLive® following a State of the Science Summit™ on breast cancer, which she chaired. “[We are] trying to figure out how we can decrease this by extending therapy and potentially changing therapy. We are all looking forward to new additional results in this field.”

In the interview, Novik discussed the use of CDK4/6 inhibitors in estrogen receptor (ER)–positive breast cancer, highlighting conflicting trial results. She also highlighted the role of novel oral SERDs, which are potentially poised to replace aromatase inhibitors in the treatment of select patients with metastatic breast cancer.

Novik is a professor in the Department of Medicine at the New York University Grossman School of Medicine and a breast medical oncologist at the Perlmutter Cancer Center in New York, New York.

OncLive: The phase 3 PALLAS trial (NCT02513394) showed no difference in invasive disease–free survival with adjuvant palbociclib (Ibrance) plus endocrine therapy vs endocrine therapy alone in patients with hormone receptor–positive, HER2-negative early breast cancer. However, the phase 3 monarchE (NCT03155997) and NATALEE (NCT03701334) trials demonstrated significant benefits with adjuvant abemaciclib (Verzenio) and ribociclib (Kisqali) respectively, in patients with this disease subtype. How do you reconcile these conflicting results when choosing an adjuvant therapy for patients with ER-positive breast cancer?

Novik: The PALLAS results were a little disappointing. monarchE, which is probably the more positive study, showed benefit in a higher-risk population than PALLAS had, so that’s one of the criteria that could have demonstrated benefit, potentially, [if PALLAS had been conducted in] a higher-risk group. There have been a lot of analyses ongoing for PALLAS trying to figure out: Were there particular features in patients or clinical scenarios that could have [led to] slightly more positive [results]?

It’s important, in the adjuvant setting, to follow the data. The monarchE and NATALEE [regimens] remain the standards for adjuvant therapy. How do we reconcile [the PALLAS trial outcomes] with excellent results in metastatic disease with palbociclib?

We sometimes have to accept the results as they come without fully understanding. It’s an interesting field where we’ll see a lot of new data coming in. We also [need to] understand how to apply [these data] to different populations.

NATALEE had a lower-risk population, including [patients with] node-negative disease. As time goes on, we’ll have more discussions about the burden of both adverse effects and financial toxicities related to the adjuvant treatment. [That will help inform] how to select the [optimal [patient] populations [for each of these therapies].

Real-world evidence from the observational P-VERIFY study (NCT06495164) showed no significant difference in efficacy between the CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib in patients with hormone receptor–positive, HER2-negative metastatic breast cancer. What are patient factors do you prioritize when selecting a CDK4/6 inhibitor for patients in this population?

Palbociclib was the first cell cycle inhibitor that was FDA approved for clinical practice. It significantly changed and improved the paradigm of how we manage metastatic breast cancer. We also first learned about managing [CDK4/6 inhibitor–related] toxicities [with palbociclib].

[Real-world] data are always helpful because they [show] the depth and breadth of the use of [these agents in] clinical practice. Looking at factors like progression-free survival, not just overall survival, [we see] a lot of equivalencies in terms of choosing cell cycle inhibitors in the metastatic setting. There’s still a big role for all these drugs, and we feel comfortable [using them]. We learned to manage myelosuppression, which isn’t [as] prominent with palbociclib.

[The P-VERIFY] data offer patients treatment options, since [ribociclib, abemaciclib, and palbociclib] are all first-line [agents] and sometimes [used] in the second-line treatment of patients with metastatic disease. I honestly think that [CDK4/6 inhibitors] can be used interchangeably, [however, we need to keep in mind] if a drug like abemaciclib or ribociclib produces significant toxicity. We more commonly see gastrointestinal and sometimes cardiac toxicities or elevated LFTs related to ribociclib, so [palbociclib or abemaciclib are] good alternatives.

The phase 2 MAINTAIN study [NCT02632045] and others showed the efficacy of cell cycle inhibitors in the second-line setting. We’re not talking about tumors that carry PIK3CA or AKT mutations; those belong to [another] category. There’s still a lot of treatment options that all 3 cell cycle inhibitors offer.

Factoring in the FDA approval of elacestrant (Orserdu) for patients with ESR1-mutated advanced or metastatic breast cancer, where might novel oral SERDs fit into the metastatic breast cancer treatment paradigm compared with traditional aromatase inhibitors?

There are new and provocative data about the use of oral SERDs in the adjuvant setting. This creates a whole panoply of new questions and new potential algorithms. I’ve been working with elacestrant since the original studies, and oral SERDs are changing the horizon of how we manage metastatic and eventually adjuvant breast cancer.

Our original thoughts were that oral SERDs were primarily targeting tumors that develop resistance to aromatase inhibitors and carry ESR1 mutations. There are clinical trial data saying they may be also active enough to potentially replace aromatase inhibitors. We still have a big gap to fill there.

Aromatase inhibitors have been FDA approved for approximately 30 years. There’s a lot of experience and a lot of great clinical benefit to using these drugs in the adjuvant setting. We’ll see more trials. We have ongoing trials that switch from aromatase inhibitors to oral SERDs in the adjuvant setting.

References

1. Gnant M, Dueck AC, Frantal S, et al. 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
2. Rugo HS, Layman RM, Lynce F, et al. Comparative overall survival of CDK4/6 inhibitors plus an aromatase inhibitor in HR+/HER2- metastatic breast cancer in the US real-world setting. ESMO Open. 2025;10(1):104103. doi:10.1016/j.esmoop.2024.104103
3. FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. News release. FDA. January 27, 2023. Accessed May 22, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/